Yann Klimentidis' Weblog

Antagonistic pleiotropy - the case for BRCA mutations

2011-10-21T09:53:00.004-06:00

In a natural fertility population, these authors find that carriers of BRCA mutations have more children, shorter birth intervals, a later end to child-bearing, and "excess post-reproductive mortality risks".

Effects of BRCA1 and BRCA2 mutations on female fertility
Ken R. Smith, Heidi A. Hanson, Geraldine P. Mineau, and Saundra S. Buys
Proc. R. Soc. B Published online before print October 12, 2011

Abstract
Women with BRCA1/2 mutations have a significantly higher lifetime risk of developing breast or ovarian cancer. We suggest that female mutation carriers may have improved fitness owing to enhanced fertility relative to non-carriers. Here we show that women who are carriers of BRCA1/2 mutations living in natural fertility conditions have excess fertility as well as excess post-reproductive mortality in relation to controls. Individuals who tested positive for BRCA1/2 mutations who linked into multi-generational pedigrees within the Utah Population Database were used to identify putative obligate carriers. We find that women born before 1930 who are mutation carriers have significantly more children than controls and have excess post-reproductive mortality risks. They also have shorter birth intervals and end child-bearing later than controls. For contemporary women tested directly for BRCA1/2 mutations, an era when modern contraceptives are available, differences in fertility and mortality persist but are attenuated. Our findings suggest the need to re-examine the wider role played by BRCA1/2 mutations. Elevated fertility of female mutation carriers indicates that they are more fecund despite their elevated post-reproductive mortality risks.

Taino and African ancestry in Puerto Ricans

2011-10-20T09:35:00.003-06:00

Here's a news story about a talk given at the latest ASHG/ICHG meeting. Bustamante et al. have been looking at admixture among Puerto Ricans (apparently the latest addition to the 1000 Genomes project), and specifically looking at the lengths of DNA segments belonging to different groups in order to infer the temporal and geographic patterns of historical admixture.
Rebuilding the genome of a hidden ethnicity

Persistence hunting - is it really possible?

2011-06-16T05:53:00.000-06:00

Here's an interesting post from John Hawks' blog about a magazine article about running, evolution (and hunting?) enthusiasts who try to see how hard it would be to track a pronghorn in New Mexico.
Apparently they failed. I'm still not convinced that this really debunks the theory that this type of hunting is possible or was important in our evolutionary history, but pretty cool to see people trying it...sounds like fun!

Scientists like to "fondle their problems"

2011-02-22T07:22:00.000-07:00

I thought this was a funny quote from an interesting article in Nature discussing the fact, that despite the identification of many disease-relevant proteins, "75% of protein research still focuses on the 10% of proteins that were known before the genome was mapped".

This is actually probably mostly driven by the conservative nature of funding sources.
From the authors:

Granting systems must be more daring, institutions must foster and reward risk, and the entire biomedical community must play down the legacy of the literature and let new evidence guide research. Genome-wide tools such as the DNA microarrays used in association studies have allowed geneticists to ignore preconceived ideas about disease mechanisms and pursue a remarkably successful broad-brush approach; this approach should be embraced more generally.

Too many roads not taken
Aled M. Edwards, Ruth Isserlin, Gary D. Bader, Stephen V. Frye, Timothy M. Willson & Frank H. Yu
Nature Volume: 470, Pages:163–165

Wolpoff interviewed by Razib

2011-02-20T12:47:00.003-07:00

Here's a very interesting video of a discussion between Razib Khan and Milford Wolpoff.
They cover a pretty wide range of topics, but mostly centered on the multiregional model of human evolution, with some discussion about the "sociology of science" weaved in throughout.

Jared Diamond on type-2 diabetes in India

2011-01-27T08:40:00.002-07:00

The latest issue of Nature has a piece by Jared Diamond about the diabetes epidemic in India, and how some aspects of its pathology are unique among Indians as compared to other groups.

Medicine: Diabetes in India
Jared Diamond
Nature Volume: 469, Pages:478–479 : 27 January 2011

Some of the more interesting points:

In 2010, the average age-adjusted prevalence of diabetes in India was 8%, higher than that in most European countries

In India, as in the West, diabetes is ultimately due to chronically high levels of blood glucose, and some of the clinical consequences are similar. But whereas Westerners think of type 2 diabetes as an adult-onset disease appearing especially after the age of 50, Indians (and Chinese, Japanese and Aboriginal Australians) with diabetes exhibit symptoms at an age one or two decades younger than that. The age of onset in India has been shifting towards ever-younger people even within the past decade9 — among Indians in their late teens, 'adult-onset' diabetes already manifests itself more often than does 'juvenile-onset' diabetes. In Britain, the prevalence of type 2 diabetes is 14 times higher in Asian than European children. And although obesity is a risk factor for diabetes both in India and in the West, the disease appears at a lower threshold of obesity in India, as is also the case in China, Japan and other Asian countries.

Symptoms also differ between Indians and Westerners: Indians with diabetes are less likely to develop blindness and kidney disease, but much more likely to suffer coronary artery disease at a relatively young age

He stresses the difference in prevalence between rich and poor Indians, and discusses how these differences are the opposite of what we observe in the US and Europe, for example, where socio-economic status is positively correlated with health.
Given Jared Diamond's past speculation on the evolutionary and/or genetic causes of these types of epidemics, I thought he might have expounded on that, as others have, but alas, he didn't.

Selection can increase genetic diversity - the example of Somali camel herders

2011-01-20T14:14:00.001-07:00

The interesting finding here is that diversity in the LCT/MCM6 region is increased rather than reduced among those who are lactose tolerant compared to those who are lactose intolerant. Unlike in Europe where a single mutation swept through much of the population, among this East African population, there are several mutations that arose on different haplotype backgrounds that have a similar phenotypic effect. The result is that genetic diversity in this genomic region is increased. The authors have a pretty good discussion about the possible reasons for the patterns they observe.
These types of examples, albeit simplistic compared to other traits, are great for our basic understanding of the genetic basis of complex traits, and for our understanding of the genetic avenues leading to adaptation.

Multiple rare variants as a cause of a common phenotype: several different lactase persistence associated alleles in a single ethnic group.
Ingram CJ, Raga TO, Tarekegn A, Browning SL, Elamin MF, Bekele E, Thomas MG, Weale ME, Bradman N, Swallow DM.
J Mol Evol. 2009 Dec;69(6):579-88.

Abstract:Persistence of intestinal lactase into adulthood allows humans to use milk from other mammals as a source of food and water. This genetic trait has arisen by convergent evolution and the derived alleles of at least three different single nucleotide polymorphisms (-13910C>T, -13915T>G, -14010G>C) are associated with lactase persistence in different populations. Each allele occurs on an extended haplotype, consistent with positive directional selection. The SNPs are located in an 'enhancer' sequence in an intron of a neighboring gene (MCM6) and modulate lactase transcription in vitro. However, a number of lactase persistent individuals carry none of these alleles, but other low-frequency single nucleotide polymorphisms have been observed in the same region. Here we examine a cohort of 107 milk-drinking Somali camel-herders from Ethiopia. Eight polymorphic sites are identified in the enhancer. -13915*G and -13907*G (a previously reported candidate) are each significantly associated with lactase persistence. A new allele, -14009*G, has borderline association with lactase persistence, but loses significance after correction for multiple testing. Sequence diversity of the enhancer is significantly higher in the lactase persistent members of this and a second cohort compared with non-persistent members of the two groups (P = 7.7 x 10(-9) and 1.0 x 10(-3)). By comparing other loci, we show that this difference is not due to population sub-structure, demonstrating that increased diversity can accompany selection. This contrasts with the well-documented observation that positive selection decreases diversity by driving up the frequency of a single advantageous allele, and has implications for association studies.

How/why did selection for lactase persistence occur and spread?

2010-10-27T09:06:00.003-06:00

Interesting, albeit speculative, hypothesis for the origins of the selective advantage associated with lactase persistence. Basically, looks like there is evidence for increased reliance on milk products and dairy animals at the same time as a sudden cold and dry spell - about 8,000 years ago.
Link to new story in Science

...on a related note, see a post by Razib pointing to a story about "How Middle Eastern Milk Drinkers Conquered Europe".

Selection in fruitflies - what kind of genomic signatures does it leave?

2010-10-16T07:36:00.000-06:00

We are pretty confident that we know what signatures of selection look like for some loci in humans (skin color, lactase etc...) but how about less clear-cut/subtle cases which may represent the majority of cases? This experiment gives us some much needed insight into what signatures of selection we might expect for most instances of natural selection.

Genome-wide analysis of a long-term evolution experiment with Drosophila
Molly K. Burke, Joseph P. Dunham, Parvin Shahrestani, Kevin R. Thornton, Michael R. Rose & Anthony D. Long
Nature 2010

Abstract: Experimental evolution systems allow the genomic study of adaptation, and so far this has been done primarily in asexual systems with small genomes, such as bacteria and yeast. Here we present whole-genome resequencing data from Drosophila melanogaster populations that have experienced over 600 generations of laboratory selection for accelerated development. Flies in these selected populations develop from egg to adult ~20% faster than flies of ancestral control populations, and have evolved a number of other correlated phenotypes. On the basis of 688,520 intermediate-frequency, high-quality single nucleotide polymorphisms, we identify several dozen genomic regions that show strong allele frequency differentiation between a pooled sample of five replicate populations selected for accelerated development and pooled controls. On the basis of resequencing data from a single replicate population with accelerated development, as well as single nucleotide polymorphism data from individual flies from each replicate population, we infer little allele frequency differentiation between replicate populations within a selection treatment. Signatures of selection are qualitatively different than what has been observed in asexual species; in our sexual populations, adaptation is not associated with ‘classic’ sweeps whereby newly arising, unconditionally advantageous mutations become fixed. More parsimonious explanations include ‘incomplete’ sweep models, in which mutations have not had enough time to fix, and ‘soft’ sweep models, in which selection acts on pre-existing, common genetic variants. We conclude that, at least for life history characters such as development time, unconditionally advantageous alleles rarely arise, are associated with small net fitness gains or cannot fix because selection coefficients change over time.

More loci to explain eye color variation, but still not great prediction

2010-09-09T08:33:00.006-06:00

Here they do a GWAS for a continuous/refined eye phenotype based on hue and saturation. The authors find three new loci in addition to the other known loci, and are able to explain 50% of the variance in an independent (I think) sample of Dutch individuals. HERC2 alone explains 45% or so of the variance.

Regarding prediction of eye color categories:

The accuracy in predicting 3-category eye color was 0.92 for blue, 0.74 for intermediate, and 0.93 for brown,...

There is some discussion about the limited quality of the photos due in part to the un-standardized lighting conditions.
I wonder how much better prediction would have been in a more diverse sample.

Digital quantification of human eye color highlights genetic association of three new loci.
Liu F, Wollstein A, Hysi PG, Ankra-Badu GA, Spector TD, Park D, Zhu G, Larsson M, Duffy DL, Montgomery GW, Mackey DA, Walsh S, Lao O, Hofman A, Rivadeneira F, Vingerling JR, Uitterlinden AG, Martin NG, Hammond CJ, Kayser M.

PLoS Genetics 2010 May 6;6:e1000934.

Abstract: Previous studies have successfully identified genetic variants in several genes associated with human iris (eye) color; however, they all used simplified categorical trait information. Here, we quantified continuous eye color variation into hue and saturation values using high-resolution digital full-eye photographs and conducted a genome-wide association study on 5,951 Dutch Europeans from the Rotterdam Study. Three new regions, 1q42.3, 17q25.3, and 21q22.13, were highlighted meeting the criterion for genome-wide statistically significant association. The latter two loci were replicated in 2,261 individuals from the UK and in 1,282 from Australia. The LYST gene at 1q42.3 and the DSCR9 gene at 21q22.13 serve as promising functional candidates. A model for predicting quantitative eye colors explained over 50% of trait variance in the Rotterdam Study. Over all our data exemplify that fine phenotyping is a useful strategy for finding genes involved in human complex traits.

Diet, disease, and pigment variation in humans

2010-04-26T08:04:00.005-06:00

Some interesting hypotheses about the relationships between skin pigmentation, vitamin D, and immune response in Europe.

Diet, disease and pigment variation in humans.
Med Hypotheses. 2010 Apr 19. [Epub ahead of print]

Abstract: There are several hypotheses which explain the de-pigmentation of humans. The most prominent environmental explanation is that reduced endogenous vitamin D production due to diminished radiation at higher latitudes had a deleterious impact on fitness. This drove de-pigmentation as an adaptive response. A model of natural selection explains the high correlations found between low vitamin D levels and ill health, as vitamin D's role in immune response has clear evolutionary implications. But recent genomic techniques have highlighted the likelihood that extreme de-pigmentation in Eurasia is a feature of the last 10,000years, not the Upper Pleistocene, when modern humans first settled northern Eurasia. Additionally the data imply two independent selection events in eastern and western Eurasia. Therefore new parameters must be added to the model of natural selection so as to explain the relatively recent and parallel adaptive responses. I propose a model of gene-culture co-evolution whereby the spread of agriculture both reduced dietary vitamin D sources and led to more powerful selection on immune response because of the rise of infectious diseases with greater population densities. This model explains the persistence of relatively dark-skinned peoples at relatively high latitudes and the existence of relatively light-skinned populations at low latitudes. It also reinforces the importance of vitamin D as a micronutrient because of the evidence of extremely powerful fitness implications in the recent human past of pigmentation. Copyright © 2010. Published by Elsevier Ltd.

Does Usain Bolt lack the ACTN3 R577X polymorphism?

2010-03-11T08:39:00.000-07:00

...that's the question that pops into my mind after reading the title and abstract. I wonder if they genotyped the elite of the elite (Bolt, Powell) or just the "elite"? It looks like they did:

Forty-six of these international athletes had won medals at major international competition or held sprint world records.

Nevertheless, another negative finding on the association between the ACTN3 fast twitch muscle fiber, "sprint" genotype and sprint phenotypes. In fact, two of the elite-elite Jamaican sprinters were homozygous for the slow-twitch variant! They acknowledge that the power to detect a difference here is pretty low because of the very low frequency of the ACTN3 R5777X polymorphism in West Africans... so much for personalized prediction of sports ability, at least for now. I say just look at your big toe... does it extend out farther than your second toe? if so, you could probably be pretty fast.
Given these results, Usain probably does lack the ACTN3 polymorphism, but on the other hand, he could be the one of the two out of the 46 elite-elite sprinters who is homozygous for it.

P.S. - gotta love the senior author's name!

ACTN3 and ACE Genotypes in Elite Jamaican and US Sprinters
SCOTT, ROBERT A; IRVING, RACHAEL; IRWIN, LAURA; MORRISON, ERROL; CHARLTON, VILMA; AUSTIN, KRISTA; TLADI, DAWN; DEASON, MICHAEL; HEADLEY, SAMUEL A.; KOLKHORST, FRED W.; YANG, NAN; NORTH, KATHRYN; PITSILADIS, YANNIS P.

ABSTRACT The angiotensin-converting enzyme (ACE) and the [alpha]-actinin-3 (ACTN3) genes are two of the most studied "performance genes" and both have been associated with sprint/power phenotypes and elite performance. Purpose: To investigate the association between the ACE and the ACTN3 genotypes and sprint athlete status in elite Jamaican and US African American sprinters. Methods: The ACTN3 R577X and the ACE I/D and A22982G (rs4363) genotype distributions of elite Jamaican (J-A; N = 116) and US sprinters (US-A; N = 114) were compared with controls from the Jamaican (J-C; N = 311) and US African American (US-C; N = 191) populations. Frequency differences between groups were assessed by exact test. Results: For ACTN3, the XX genotype was found to be at very low frequency in both athlete and control cohorts (J-C = 2%, J-A = 3%, US-C = 4%, US-A = 2%). Athletes did not differ from controls in ACTN3 genotype distribution (J, P = 0.87; US, P = 0.58). Similarly, neither US nor Jamaican athletes differed from controls in genotype at ACE I/D (J, P = 0.44; US, P = 0.37). Jamaican athletes did not differ from controls for A22982G genotype (P = 0.28), although US sprinters did (P = 0.029), displaying an excess of heterozygotes relative to controls but no excess of GG homozygotes (US-C = 22%, US-A = 18%). Conclusions: Given that ACTN3 XX genotype is negatively associated with elite sprint athlete status, the underlying low frequency in these populations eliminates the possibility of replicating this association in Jamaican and US African American sprinters. The finding of no excess in ACE DD or GG genotypes in elite sprint athletes relative to controls suggests that ACE genotype is not a determinant of elite sprint athlete status.

More than one molecular way to adaptively change a phenotype

2010-03-11T05:11:00.002-07:00

The authors report on their finding of different mutations in the same gene MC1R affecting different molecular pathways on the way to lighter pigmentation in lizards. There are several likely examples of molecularly divergent phenotypic convergence in humans, some of which may originate in the same gene: MC1R - skin color in Europeans and E. Asians, LCT - lactase persistence in Europe, Middle East, and E. Africa, and probably, adaptation to high altitude in E. Africa, Andes, and Himalayas.

The cool thing about this paper is that they use cell culture to find that even though the mutations are in the same gene, they result in lighter pigmentation through different molecular pathways.

Molecular and functional basis of phenotypic convergence in white lizards at White Sands
Erica Bree Rosenblum, Holger Römpler, Torsten Schöneberg, and Hopi E. Hoekstra
PNAS February 2, 2010 vol. 107 no. 5 2113-2117

Abstract: There are many striking examples of phenotypic convergence in nature, in some cases associated with changes in the same genes. But even mutations in the same gene may have different biochemical properties and thus different evolutionary consequences. Here we dissect the molecular mechanism of convergent evolution in three lizard species with blanched coloration on the gypsum dunes of White Sands, New Mexico. These White Sands forms have rapidly evolved cryptic coloration in the last few thousand years, presumably to avoid predation. We use cell-based assays to demonstrate that independent mutations in the same gene underlie the convergent blanched phenotypes in two of the three species. Although the same gene contributes to light phenotypes in these White Sands populations, the specific molecular mechanisms leading to reduced melanin production are different. In one case, mutations affect receptor signaling and in the other, the ability of the receptor to integrate into the melanocyte membrane. These functional differences have important ramifications at the organismal level. Derived alleles in the two species show opposite dominance patterns, which in turn affect their visibility to selection and the spatial distribution of alleles across habitats. Our results demonstrate that even when the same gene is responsible for phenotypic convergence, differences in molecular mechanism can have dramatic consequences on trait expression and ultimately the adaptive trajectory.

Chinese prefer darker-skinned pigs and MC1R tells part of the story

2010-03-02T20:45:00.000-07:00

I'm not yet able to get full text access to this paper, but after looking into the related literature, I was suprised to see that there is quite a lot out there. Given that variation in MC1R was selected upon to lighten skin in Europeans, I was somewhat surprised to see the opposite happen in pigs.
Spaniards also like black pigs.
By the way, I'm not too fond of the term "artificial" in this type of context.

Artificial selection of the melanocortin receptor 1 gene in Chinese domestic pigs during domestication.
Li J, Yang H, Li JR, Li HP, Ning T, Pan XR, Shi P, Zhang YP
Heredity. 2010 Feb 24. [Epub ahead of print]

Abstract: Black coat colour is common in Chinese indigenous domestic pigs, but not among their wild ancestors, and it is thus presumed to be a 'domestication trait.' To determine whether artificial interference contributes to morphological diversification, we examined nucleotide variation from 157 Chinese domestic pigs and 40 wild boars in the melanocortin receptor 1 (MC1R) gene, which has a key role in the coat pigmentation of Sus scrofa. Compared with a pseudogene GPIP, our results showed that the joint effects of demography and selection have resulted in markedly low genetic diversity of MC1R in Chinese domestic pigs. Coalescent simulation and selection tests further suggest that the fixation of two non-synonymous substitutions associated with black colour is the result of artificial selection. In contrast, a much higher genetic diversity and only a single non-synonymous substitution were found among the wild boars, suggesting a strong functional constraint. Moreover, our conclusion is consistent with the preference for black colour in the ancient Chinese sacrificial culture. This case provides an interesting example of a molecular evaluation of artificial livestock selection and its associated cultural impact in ancient China.

Predicting hair, eye, and skin color from a small set of SNPs

2010-02-28T05:57:00.001-07:00

They examined the association between 75 SNPs in 24 genes and skin, eye and hair color among 789 people of various ethnic backgrounds. Since this is for forensic purposes, they were looking for a small set of SNP markers (i.e. 3) that could reliably predict these pigmentation phenotypes, independent of ethnic origin. Their sample consisted mostly of individuals of European descent, but a decent number of several other ethnic groups.

Hair color:
SLC45A2, SLC24A5 and MC1R - R squared: 76.3% (one SNP per gene listed)
Skin color:
SLC24A5, SLC45A2, ASIP - R squared: 45.7% ... interaction term of ASIP and SLC45A2 increased r-squared to 49.6% (one SNP per gene listed)
Eye color:
HERC2, SLC24A5, SLC25A2 - R squared: 76.4%... (HERC2 appears to be doing the vast majority of the explaining)

The obvious remaining question from all this is how high does the proportion of variance explained go if you use information from all markers together. Anyway, it appears that, as they mention, five SNPs in five genes account for much of the variation.
Given that most subjects were Eur, it would have been nice to see the extent to which they were driving the results, by for example, doing the same analysis only on them. In other words how different would the results be if most subjects were African or Native American etc...?
I did not know that HERC2 is adjacent (5' side) to OCA2, and contains a promoter region for OCA2.

Predicting Phenotype from Genotype: Normal Pigmentation
Valenzuela RK, Henderson MS, Walsh MH, Garrison NA, Kelch JT, Cohen-Barak O, Erickson DT, John Meaney F, Bruce Walsh J, Cheng KC, Ito S, Wakamatsu K, Frudakis T, Thomas M, Brilliant MH.
J Forensic Sci. 2010 Feb 11. [Epub ahead of print]

Abstract:Genetic information in forensic studies is largely limited to CODIS data and the ability to match samples and assign them to an individual. However, there are circumstances, in which a given DNA sample does not match anyone in the CODIS database, and no other information about the donor is available. In this study, we determined 75 SNPs in 24 genes (previously implicated in human or animal pigmentation studies) for the analysis of single- and multi-locus associations with hair, skin, and eye color in 789 individuals of various ethnic backgrounds. Using multiple linear regression modeling, five SNPs in five genes were found to account for large proportions of pigmentation variation in hair, skin, and eyes in our across-population analyses. Thus, these models may be of predictive value to determine an individual's pigmentation type from a forensic sample, independent of ethnic origin.

Predicting lactase persistence from genetic data ... not yet!

2010-02-15T11:49:00.005-07:00

...especially in Africa, SE Europe, and parts of Asia.
It seems like their genetic information consists of the four SNPs that are so far known to be associated with lactase persistence.

A worldwide correlation of lactase persistence phenotype and genotypes
Itan Y, Jones BL, Ingram CJ, Swallow DM, Thomas MG
BMC Evol Biol. 2010 Feb 9;10(1):36. [Epub ahead of print]

ABSTRACT: BACKGROUND: The ability of adult humans to digest the milk sugar lactose - lactase persistence - is a dominant Mendelian trait that has been a subject of extensive genetic, medical and evolutionary research. Lactase persistence is common in people of European ancestry as well as some African, Middle Eastern and Southern Asian groups, but is rare or absent elsewhere in the world. The recent identification of independent nucleotide changes that are strongly associated with lactase persistence in different populations worldwide has led to the possibility of genetic tests for the trait. However, it is highly unlikely that all lactase persistence-associated variants are known. Using an extensive database of lactase persistence phenotype frequencies, together with information on how those data were collected and data on the frequencies of lactase persistence variants, we present a global summary of the extent to which current genetic knowledge can explain lactase persistence phenotype frequency. RESULTS: We used surface interpolation of Old World lactase persistence genotype and phenotype frequency estimates obtained from all available literature and perform a comparison between predicted and observed trait frequencies in continuous space. By accommodating additional data on sample numbers and known false negative and false positive rates for the various lactase persistence phenotype tests (blood glucose and breath hydrogen), we also apply a Monte Carlo method to estimate the probability that known lactase persistence-associated allele frequencies can explain observed trait frequencies in different regions. CONCLUSION: Lactase persistence genotype data is currently insufficient to explain lactase persistence phenotype frequency in much of western and southern Africa, southeastern Europe, the Middle East and parts of central and southern Asia. We suggest that further studies of genetic variation in these regions should reveal additional nucleotide variants that are associated with lactase persistence.

Signatures of selection in dog breeds

2010-01-24T14:00:00.001-07:00

10 breeds, 21,000 SNPs, breed-specific Fst.

Their most notable hits:
HMGA2 and IGF1R (size)
SILV, MITF (coat color and texture)
CDH9, DRD5, HTR2A (behavior)
SOX9 (skeletal morphology)
FTO, SLC2A9, SLC5A2 (physiology)

Unfortunately they only use Fst to detect evidence of selection. It would have been interesting to try out some haplotype or other tests of selection, but they were probably constrained by the total number of SNPs they had.

Most interestingly:

Similar to analyses of selection in natural populations (23), we find that genes involved in immunity and defense are also significantly overrepresented in the 155 candidate selection
regions. This is somewhat surprising, as natural and artificial selection would not necessarily be expected a priori to act on similar classes of genes, and suggests that immune related genes are pervasive targets of selection because of their critical role in pathogen defense or propensity for pleiotropic effects (24).

...also:

We note that as an initial foray into comparative selection mapping, of the 1,506 genes located in putatively selected regions in dogs, 169 overlap with genes located in well-supported selected regions in humans (10). Although this result should be interpreted with caution, as the specific targets of selection are generally not known with certainty in either dogs or humans, it does raise the intriguing possibility that recent selection has influenced common loci in both the human and dog lineages.

Tracking footprints of artificial selection in the dog genome
Joshua M. Akey, Alison L. Ruhe, Dayna T. Akey, Aaron K. Wong, Caitlin F. Connelly, Jennifer Madeoy, Thomas J. Nicholas, and Mark W. Neff
PNAS January 19, 2010 vol. 107 no. 3 1160-1165

Abstract: The size, shape, and behavior of the modern domesticated dog has been sculpted by artificial selection for at least 14,000 years. The genetic substrates of selective breeding, however, remain largely unknown. Here, we describe a genome-wide scan for selection in 275 dogs from 10 phenotypically diverse breeds that were genotyped for over 21,000 autosomal SNPs. We identified 155 genomic regions that possess strong signatures of recent selection and contain candidate genes for phenotypes that vary most conspicuously among breeds, including size, coat color and texture, behavior, skeletal morphology, and physiology. In addition, we demonstrate a significant association between HAS2 and skin wrinkling in the Shar-Pei, and provide evidence that regulatory evolution has played a prominent role in the phenotypic diversification of modern dog breeds. Our results provide a first-generation map of selection in the dog, illustrate how such maps can rapidly inform the genetic basis of canine phenotypic variation, and provide a framework for delineating the mechanistic basis of how artificial selection promotes rapid and pronounced phenotypic evolution.

More on the genetics of European farmers vs. hunter-gatherers

2010-01-19T12:30:00.007-07:00

Continuing on the theme from the last post, here is a paper that just came out in PLoS Biology. It seems to come to the same conclusion as the Science one that used ancient mtDNA...sort of. The results conflict since the Bramanti one finds discontinuity in mtDNA lineages, while this paper doesn't. So the Bramanti paper finds little evidence for continuity in mtDNA lineages, while this one finds that there is some continuity in mtDNA lineages, at least compared to the Y-chromosome. The two papers use different sources of data and different methods, which could somehow explain the discrepancy.
Razib's already all over this.

A Predominantly Neolithic Origin for European Paternal Lineages
Patricia Balaresque, Georgina R. Bowden, Susan M. Adams, Ho-Yee Leung, Turi E. King, Zoë H. Rosser, Jane Goodwin, Jean-Paul Moisan, Christelle Richard, Ann Millward, Andrew G. Demaine, Guido Barbujani, Carlo Previderè, Ian J. Wilson, Chris Tyler-Smith, Mark A. Jobling
PLoS Biology 8(1): e1000285.

Abstract: The relative contributions to modern European populations of Paleolithic hunter-gatherers and Neolithic farmers from the Near East have been intensely debated. Haplogroup R1b1b2 (R-M269) is the commonest European Y-chromosomal lineage, increasing in frequency from east to west, and carried by 110 million European men. Previous studies suggested a Paleolithic origin, but here we show that the geographical distribution of its microsatellite diversity is best explained by spread from a single source in the Near East via Anatolia during the Neolithic. Taken with evidence on the origins of other haplogroups, this indicates that most European Y chromosomes originate in the Neolithic expansion. This reinterpretation makes Europe a prime example of how technological and cultural change is linked with the expansion of a Y-chromosomal lineage, and the contrast of this pattern with that shown by maternally inherited mitochondrial DNA suggests a unique role for males in the transition.

Genetics of hunter-gatherers and early farmers in Europe

2010-01-09T06:09:00.000-07:00

I'm back, and will try to be more regular about posting. This paper came out a few months ago in Science and I've been meaning to look at it for a while.
They examine the Fst in mtDNA sequence between hunter-gatherer samples (13,400 to 2,300 ago) in Central Europe, from more recent individuals (and modern Europeans). I guess they must use archaeological or other evidence to determine their subsistence pattern.
They get an Fst of 0.163, which is indeed remarkably high - although do we really know what to expect when comparing populations over time? To answer this, they perform some simulations, and reject the hypothesis that this Fst could have been due to a process of population continuity.
Along with their discussion of the haplotype differences betwee the hunter-gatherers and farmers, this result is pretty interesting and suggests a migration of early farmers into central Europe and replacement of hunter-gatherers.
Proto-Indo-Europeans?

Genetic discontinuity between local hunter-gatherers and central Europe's first farmers.
Bramanti B, Thomas MG, Haak W, Unterlaender M, Jores P, Tambets K, Antanaitis-Jacobs I, Haidle MN, Jankauskas R, Kind CJ, Lueth F, Terberger T, Hiller J, Matsumura S, Forster P, Burger J.
Science 2009 Oct 2;326(5949):137-40.

Abstract: After the domestication of animals and crops in the Near East some 11,000 years ago, farming had reached much of central Europe by 7500 years before the present. The extent to which these early European farmers were immigrants or descendants of resident hunter-gatherers who had adopted farming has been widely debated. We compared new mitochondrial DNA (mtDNA) sequences from late European hunter-gatherer skeletons with those from early farmers and from modern Europeans. We find large genetic differences between all three groups that cannot be explained by population continuity alone. Most (82%) of the ancient hunter-gatherers share mtDNA types that are relatively rare in central Europeans today. Together, these analyses provide persuasive evidence that the first farmers were not the descendants of local hunter-gatherers but immigrated into central Europe at the onset of the Neolithic.

Are Uyghurs a recent or ancient population?

2009-09-14T05:07:00.000-06:00

They are basically seeing whether there are many private haplotypes in the Uyghur population compared to East Asian and European populations. They don't find this to be the case, thus suggesting that Uyghurs are the result of a recent admixture process.

Haplotype-Sharing Analysis Showing Uyghurs Are Unlikely Genetic Donors
Shuhua Xu, Wenfei Jin and Li Jin
Molecular Biology and Evolution 2009 26(10):2197-2206

Abstract: The Uyghur (UIG) are a group of people primarily residing in Xinjiang of China, which is geographically located in Central Asia, from where modern humans were presumably spread in all directions reaching Europe, east, and northeast Asia about 40 kya. A recent study suggested that the UIG are ancestry donors of the East Asian (EAS) gene pool. However, an alternative hypothesis, that is, the UIG is an admixture population with both EAS and EUR ancestries is also supported by our previous studies. To test the two competing hypotheses, here we conducted a haplotype-sharing analysis (HSA) based on empirical and simulated data of high-density single nucleotide polymorphisms. Our results showed that more than 95% of UIG haplotypes could be found in either EAS or EUR populations, which contradicts the expectation of the null models assuming that UIG are donors. Simulation studies further indicated that the proportion of UIG private haplotypes observed in empirical data is only expected in alternative models assuming that UIG is an admixture population. Interestingly, the estimated ancestry contribution of 44%:56% (EAS:EUR) based on HSA is consistent with our previous estimation with STRUCTURE analysis. Although the history of UIGs could be complex, our method is explicit and conservative in rejecting the null hypothesis. We concluded that the gene pool of modern UIGs is more likely a sole recipient with contribution from both EAS and EUR.

Human mutation rate estimate

2009-09-01T12:35:00.002-06:00

via this story at Nature News, their estimate based on Y chromosome is 100-200 new mutations per genome per generation, or about one mutation in every 30 million bases, which is in agreement with previous indirect estimates. Apparently this is the first direct measurement of the human mutation rate.

Human Y Chromosome Base-Substitution Mutation Rate Measured by Direct Sequencing in a Deep-Rooting Pedigree
Yali Xue, Qiuju Wang, Quan Long, Bee Ling Ng, Harold Swerdlow, John Burton, Carl Skuce, Ruth Taylor, Zahra Abdellah, Yali Zhao, Asan, Daniel G. MacArthur, Michael A. Quail, Nigel P. Carter, Huanming Yang and Chris Tyler-Smith
Current Biology, 27 August 2009

Abstract: Understanding the key process of human mutation is important for many aspects of medical genetics and human evolution. In the past, estimates of mutation rates have generally been inferred from phenotypic observations or comparisons of homologous sequences among closely related species [1,2,3]. Here, we apply new sequencing technology to measure directly one mutation rate, that of base substitutions on the human Y chromosome. The Y chromosomes of two individuals separated by 13 generations were flow sorted and sequenced by Illumina (Solexa) paired-end sequencing to an average depth of 11 or 20, respectively [4]. Candidate mutations were further examined by capillary sequencing in cell-line and blood DNA from the donors and additional family members. Twelve mutations were confirmed in 10.15 Mb; eight of these had occurred invitro and four invivo. The latter could be placed in different positions on the pedigree and led to a mutation-rate measurement of 3.0x10-8 mutations/nucleotide/generation (95% CI: 8.9x10-9 7.0x10-8), consistent with estimates of 2.3x10-8 - 6.3x10-8 mutations/nucleotide/generation for the same Y-chromosomal region from published human-chimpanzee comparisons [5] depending on the generation and split times assumed.

Got some performance enhancing polymorphisms?

2009-08-30T16:54:00.004-06:00

First of all, gotta love the term "Performance Enhanding Polymorphisms" (PEPs). This is a review paper describing what we know about the genetics of athletic performance. They focus on ACE, ACTN3, MSTN, NOS3 and several other genes. In light of recent performances, and just out of curiosity, let's get some genotypes on these three people:
Usain Bolt
Lance Armstrong
Michael Phelps

Genetics of Athletic Performance
Elaine A. Ostrander, Heather J. Huson, and Gary K. Ostrander
Annual Review of Genomics and Human Genetics Vol. 10: 407-429

Abstract: Performance enhancing polymorphisms (PEPs) are examples of natural genetic variation that affect the outcome of athletic challenges. Elite athletes, and what separates them from the average competitor, have been the subjects of discussion and debate for decades. While training, diet, and mental fitness are all clearly important contributors to achieving athletic success, the fact that individuals reaching the pinnacle of their chosen sports often share both physical and physiological attributes suggests a role for genetics. That multiple members of a family often participate in highly competitive events, such as the Olympics, further supports this argument. In this review, we discuss what is known regarding the genes and gene families, including the mitochondrial genome, that are believed to play a role in human athletic performance. Where possible, we describe the physiological impact of the critical gene variants and consider predictions about other potentially important genes. Finally, we discuss the implications of these findings on the future for competitive athletics.

Geographical origin and dating of the lactase persistence allele

2009-08-28T07:40:00.004-06:00

See Dienekes' blog post about a new paper that purports the origin of the lactase persistence allele to be somewhere in the Austria/Czech Republic area, around 7,500 years ago.
From the abstract:

Using data on −13,910*T allele frequency and farming arrival dates across Europe, and approximate Bayesian computation to estimate parameters of interest, we infer that the −13,910*T allele first underwent selection among dairying farmers around 7,500 years ago in a region between the central Balkans and central Europe, possibly in association with the dissemination of the Neolithic Linearbandkeramik culture over Central Europe. Furthermore, our results suggest that natural selection favouring a lactase persistence allele was not higher in northern latitudes through an increased requirement for dietary vitamin D.

A set of AIMs that can distinguish within continents

2009-08-22T12:30:00.002-06:00

An ancestry informative marker set for determining continental origin: validation and extension using human genome diversity panels.
Nassir R, Kosoy R, Tian C, White PA, Butler LM, Silva G, Kittles R, Alarcon-Riquelme ME, Gregersen PK, Belmont JW, De La Vega FM, Seldin MF.
BMC Genet. 2009 Jul 24;10(1):39.

ABSTRACT: BACKGROUND: Case-control genetic studies of complex human diseases can be confounded by population stratification. This issue can be addressed using panels of ancestry informative markers (AIMs) that can provide substantial population substructure information. Previously, we described a panel of 128 SNP AIMs that were designed as a tool for ascertaining the origins of subjects from Europe, Sub-Saharan Africa, Americas, and East Asia. RESULTS: In this study, genotypes from Human Genome Diversity Panel populations were used to further evaluate a 93 SNP AIM panel, a subset of the 128 AIMS set, for distinguishing continental origins. Using both model-based and relatively model-independent methods, we here confirm the ability of this AIM set to distinguish diverse population groups that were not previously evaluated. This study included multiple population groups from Oceana, South Asia, East Asia, Sub-Saharan Africa, North and South America, and Europe. In addition, the 93 AIM set provides population substructure information that can, for example, distinguish Arab and Ashkenazi from Northern European population groups and Pygmy from other Sub-Saharan African population groups. CONCLUSION: These data provide additional support for using the 93 AIM set to efficiently identify continental subject groups for genetic studies, to identify study population outliers, and to control for admixture in association studies.

Epigenetics and disease causality

2009-08-04T10:07:00.000-06:00

Obviously this has a lot of important implications, one of which is the fact that we may be overestimating the heritability of traits like obesity and diabetes.

Epigenetic Inheritance and the Missing Heritability Problem
Montgomery Slatkin
Genetics July 2009; 182: 845

Abstract: Epigenetic phenomena, and in particularly heritable epigenetic changes, or transgenerational effects, are the subject of much discussion in the current literature. This paper presents a model of transgenerational epigenetic inheritance and explores the effect of epigenetic inheritance on the risk and recurrence risk of a complex disease. The model assumes that epigenetic modifications of the genome are gained and lost at specified rates and that each modification contributes multiplicatively to disease risk. The potentially high rate of loss of epigenetic modifications causes the probability of identity in state in close relatives to be smaller than is implied by their relatedness. As a consequence, the recurrence risk to close relatives is reduced. Although epigenetic modifications may contribute substantially to average risk, they will not contribute much to recurrence risk and heritability unless they persist on average for many generations. If they do persist for long times, they are equivalent to mutations and hence are likely to be in linkage disequilibrium with SNPs surveyed in genome-wide association studies. Thus epigenetic modifications are a potential solution to the problem of missing causality of complex diseases but not to the problem of missing heritability. The model highlights the need for empirical estimates of the persistence times of heritable epialleles.

Human mtDNA subject to selection by climate?

2009-07-09T08:06:00.004-06:00

Climate shaped the worldwide distribution of human mitochondrial DNA sequence variation
François Balloux, Lori-Jayne Lawson Handley, Thibaut Jombart, Hua Liu and Andrea Manica
Proceedings Royal Society B

Abstract: There is an ongoing discussion in the literature on whether human mitochondrial DNA (mtDNA) evolves neutrally. There have been previous claims for natural selection on human mtDNA based on an excess of non-synonymous mutations and higher evolutionary persistence of specific mitochondrial mutations in Arctic populations. However, these findings were not supported by the reanalysis of larger datasets. Using a geographical framework, we perform the first direct test of the relative extent to which climate and past demography have shaped the current spatial distribution of mtDNA sequences worldwide. We show that populations living in colder environments have lower mitochondrial diversity and that the genetic differentiation between pairs of populations correlates with difference in temperature. These associations were unique to mtDNA; we could not find a similar pattern in any other genetic marker. We were able to identify two correlated non-synonymous point mutations in the ND3 and ATP6 genes characterized by a clear association with temperature, which appear to be plausible targets of natural selection producing the association with climate. The same mutations have been previously shown to be associated with variation in mitochondrial pH and calcium dynamics. Our results indicate that natural selection mediated by climate has contributed to shape the current distribution of mtDNA sequences in humans.

Social brain hypothesis shot down twice in two days?!

2009-06-11T08:32:00.004-06:00

Why do some animals have bigger brains? There's several hypotheses out there, including the monogamy one which was tested in the first paper below, but the strongest one, in my mind, the social complexity (or Machiavellian intelligence) hypothesis, has been "shot down" twice in recent papers. These hypotheses are not necessarily mutually exclusive, and the ecological determinants of brain size are likely to differ by taxa/clade/lineage.

Sociality, ecology, and relative brain size in lemurs
Evan L. MacLean, Nancy L. Barrickman, Eric M. Johnson and Christine E. Wall
Journal of Human Evolution Volume 56, Issue 5, May 2009, Pages 471-478

Abstract: The social brain hypothesis proposes that haplorhine primates have evolved relatively large brains for their body size primarily as an adaptation for living in complex social groups. Studies that support this hypothesis have shown a strong relationship between relative brain size and group size in these taxa. Recent reports suggest that this pattern is unique to haplorhine primates; many nonprimate taxa do not show a relationship between group size and relative brain size. Rather, pairbonded social monogamy appears to be a better predictor of a large relative brain size in many nonprimate taxa. It has been suggested that haplorhine primates may have expanded the pairbonded relationship beyond simple dyads towards the evolution of complex social groups. We examined the relationship between group size, pairbonding, and relative brain size in a sample of 19 lemurs; strepsirrhine primates that last share a common ancestor with monkeys and apes approximately 75 Ma. First, we evaluated the social brain hypothesis, which predicts that species with larger social groups will have relatively larger brains. Secondly, we tested the pairbonded hypothesis, which predicts that species with a pairbonded social organization will have relatively larger brains than non-pairbonded species. We found no relationship between group size or pairbonding and relative brain size in lemurs. We conducted two further analyses to test for possible relationships between two nonsocial variables, activity pattern and diet, and relative brain size. Both diet and activity pattern are significantly associated with relative brain size in our sample. Specifically, frugivorous species have relatively larger brains than folivorous species, and cathemeral species have relatively larger brains than diurnal, but not nocturnal species. These findings highlight meaningful differences between Malagasy strepsirrhines and haplorhines, and between Malagasy strepsirrhines and nonprimate taxa, regarding the social and ecological factors associated with increases in relative brain size. The results suggest that factors such as foraging complexity and flexibility of activity patterns may have driven selection for increases in brain size in lemurs.

Brain-size evolution and sociality in Carnivora
John A. Finarelli, John J. Flynn
PNAS June 9, 2009 vol. 106 no. 23 9345-9349

Abstract: Increased encephalization, or larger brain volume relative to body mass, is a repeated theme in vertebrate evolution. Here we present an extensive sampling of relative brain sizes in fossil and extant taxa in the mammalian order Carnivora (cats, dogs, bears, weasels, and their relatives). By using Akaike Information Criterion model selection and endocranial volume and body mass data for 289 species (including 125 fossil taxa), we document clade-specific evolutionary transformations in encephalization allometries. These evolutionary transformations include multiple independent encephalization increases and decreases in addition to a remarkably static basal Carnivora allometry that characterizes much of the suborder Feliformia and some taxa in the suborder Caniformia across much of their evolutionary history, emphasizing that complex processes shaped the modern distribution of encephalization across Carnivora. This analysis also permits critical evaluation of the social brain hypothesis (SBH), which predicts a close association between sociality and increased encephalization. Previous analyses based on living species alone appeared to support the SBH with respect to Carnivora, but those results are entirely dependent on data from modern Canidae (dogs). Incorporation of fossil data further reveals that no association exists between sociality and encephalization across Carnivora and that support for sociality as a causal agent of encephalization increase disappears for this clade.

Hygiene hypothesis: exposure to parasites and autoimmune diseases

2009-06-01T08:01:00.002-06:00

They use re-sequencing data on interleukin genes retrieved from Seattle SNPs.

Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions
Matteo Fumagalli, Uberto Pozzoli, Rachele Cagliani, Giacomo P. Comi, Stefania Riva, Mario Clerici, Nereo Bresolin, and Manuela Sironi
The Journal of Experimental Medicine doi:10.1084/jem.20082779

Abstract: Many human genes have adapted to the constant threat of exposure to infectious agents; according to the "hygiene hypothesis," lack of exposure to parasites in modern settings results in immune imbalances, augmenting susceptibility to the development of autoimmune and allergic conditions. Here, by estimating the number of pathogen species/genera in a specific geographic location (pathogen richness) for 52 human populations and analyzing 91 interleukin (IL)/IL receptor genes (IL genes), we show that helminths have been a major selective force on a subset of these genes. A population genetics analysis revealed that five IL genes, including IL7R and IL18RAP, have been a target of balancing selection, a selection process that maintains genetic variability within a population. Previous identification of polymorphisms in some of these loci, and their association with autoimmune conditions, prompted us to investigate the relationship between adaptation and disease. By searching for variants in IL genes identified in genome-wide association studies, we verified that six risk alleles for inflammatory bowel (IBD) or celiac disease are significantly correlated with micropathogen richness. These data support the hygiene hypothesis for IBD and provide a large set of putative targets for susceptibility to helminth infections.

GWAS and fine mapping in Africans

2009-05-27T07:50:00.002-06:00

Genome-wide and fine-resolution association analysis of malaria in West Africa.
Jallow M, Teo YY, Small KS et al.
Nat Genet. 2009 May 24. [Epub ahead of print]

Abstract: We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 x 10(-7) to P = 4 x 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

Geography and genetics of p53 in E. Asia

2009-05-12T12:26:00.000-06:00

Winter Temperature and UV Are Tightly Linked to Genetic Changes in the p53 Tumor Suppressor Pathway in Eastern Asia
Hong Shi,Si-jie Tan,Hua Zhong,Wenwei Hu,Arnold Levine,Chun-jie Xiao,Yi Peng,Xue-bin Qi,Wei-hua Shou,Run-lin Z. Ma,Yi Li,Bing Su, andXin Lu
AJHG Volume 84, Issue 4, 534-541, 02 April 2009

Abstract: The tumor suppressor p53 is a master sensor of stress. Two human-specific polymorphisms, p53 codon 72 and MDM2 SNP309, influence the activities of p53. There is a tight association between cold winter temperature and p53 Arg72 and between low UV intensity and MDM2 SNP309 G/G in a cohort of 4029 individuals across Eastern Asia that suggests causative selection. Moreover, the two polymorphisms are not coselected. Haplotype-based selection analysis further suggests that this is a striking example of two functional polymorphisms being strongly selected for in human populations in response to environmental stresses.

GWAS articles in NEJM

2009-04-16T09:40:00.003-06:00

Razib's got the links.

Lumberjacks and obesity genes

2009-04-16T07:21:00.005-06:00

Thought I'd post on this one, because the title caught my eye, and because I was keen on finding a good lumberjack picture. They look for association between variants in 18 genes and obesity related phenotypes. I'm a bit perplexed by the choice of genes...

Association study between candidate genes and obesity-related phenotypes using a sample of lumberjacks.
Chamberland A, Tremblay N, Audet M, Gilbert B, Pérusse L, Vohl MC, Laprise C.

Public Health Genomics. 2009;12(4):253-8. Epub 2009 Feb 16.

INTRODUCTION: Complex traits such as obesity are modulated by genetic and environmental factors and lead to varied clinical presentations.The aim of this study was to investigate associations between candidate genes and obesity-related phenotypes using a sample of 252 lumberjacks issued from a founder population and sharing a common and circumscribed environment. METHODS: Thirty-seven variants in 18 genes were genotyped. The restriction fragment length polymorphism method and the template-directed dye-terminator incorporation assay with fluorescence polarization detection were employed for the genotyping assays. Multivariate logistic regression models were built in order to calculate the relative odds of exhibiting obesity-related phenotypes associated with the presence of the studied polymorphism. Among them, 21 single nucleotide polymorphisms were tested for associations with obesity phenotypes. RESULTS: Significant associations were found between carriers of the minor alleles of APOE-epsilon2, FABP2-A54T, UCP1-L229M, LPL-HindIII, LPL-S447X and LPL-T1973C, patients bearing a combination of LPL-D9N, LPL-N291S and LPL-P207L and obesity-related phenotypes. CONCLUSION: The present results suggest that a particular population such as lumberjacks, sharing the same environment, could help target genes involved in complex traits.

Answer to my question (sorta): heritability of melanoma

2009-04-12T08:06:00.000-06:00

I wondered about the heritability of tanning response in a recent post about a GWAS for tanning response. Albeit not a direct answer, according to this paper below, there is a relatively high degree of heritability (~55%) for variation in development of melanoma:

A Population-Based Study of Australian Twins with Melanoma Suggests a Strong Genetic Contribution to Liability.
Shekar SN, Duffy DL, Youl P, Baxter AJ, Kvaskoff M, Whiteman DC, Green AC, Hughes MC, Hayward NK, Coates M, Martin NG.
J Invest Dermatol. 2009 Apr 9.

Abstract: Melanoma runs within families, but this may be due to either shared genetic or shared environmental influences within those families. The concordance between pairs of non-identical twins compared to that between identical twins can be used to determine whether familial aggregation is due to genetic or environmental factors. Mandatory reporting of melanoma cases in the state of Queensland yielded approximately 12,000 cases between 1982 and 1990. Twins in this study and from the adjacent state of New South Wales (125 pairs in total) were used to partition variation in liability to melanoma into genetic and environmental factors. Identical twins were more concordant for melanoma (4 of 27 pairs) than non-identical twins (3 of 98 pairs; P-value approximately 0.04). Identical co-twins of affected individuals were 9.8 times more likely to be affected than by chance. However, non-identical co-twins of affected individuals were only 1.8 times more likely to be affected than by chance. An MZ:DZ recurrence risk ratio of 5.6 suggests that some of the genetic influences on melanoma are due to epistatic (gene-gene) interactions. Using these data and population prevalences, it was estimated that 55% of the variation in liability to melanoma is due to genetic influences.

Evolutionary medicine gaining ground

2009-04-10T07:34:00.004-06:00

Description of Evolutionary Medicine meeting in the current Science:
Apparently there is a growing trend of teaching medicine from an evolutionary perspective in medical schools. The figure here shows the increase in connections between ecology & evolution and Medicine as reflected in citations (look at connections between the two reddish dots).
Some interesting parts from Elizabeth Pennisi's article:

For instance, anthropologist Kathleen Barnes of Johns Hopkins University has evidence that for some asthmatics, this overly energetic inflammatory response may be a holdover from the body's successes in coping with parasitic disease.

...With genomic data in hand, "medical students are much more equipped to understand the connections between all organisms,"...

Barnes and her colleagues have found that asthma is associated with the defective Duffy gene in populations in Brazil, Columbia, and the Caribbean whose recent African ancestors lived where malaria was endemic.

Also, in this issue, from the same meeting, a piece about schizophrenia and autism by Constance Holden, arguing for the evolutionary connection between these two conditions (I think that an equally appropriate spectrum is: William's syndrome-Autism)

At the Sackler Colloquium on Evolution in Health and Medicine held last week at the National Academy of Sciences (NAS) in Washington, D.C., evolutionary geneticist Bernard Crespi of Simon Fraser University in Burnaby, Canada, threw some evolutionary firepower at the question. He proposes that both schizophrenia and autism are disorders of the "social brain"--but at opposite ends of the same spectrum.

A number of studies have shown some overlap in genomic "hot spots" for CNVs in schizophrenia and autism, with, in some cases, deletions in one condition just where there are duplications for the other

That would fit with their theory that psychotic disorders--including not only schizophrenia but also bipolar disorder and some major depression--result from "overdevelopment" of the social brain, and autism spectrum disorders reflect underdevelopment of that brain. Many scientists believe socialization is the main force behind the rapid expansion of human brains, said Crespi, pointing out that in primates the size of the cortex increases with size of social groups. The components of the social brain, according to Crespi, include language, self-awareness, "social emotions" such as pride and guilt, logical thinking, pursuit of goals, and awareness of the mental states of others.

Utility of GWAS prostate cancer risk alleles in other populations

2009-04-06T09:08:00.002-06:00

Generalizability of Associations from Prostate Cancer Genome-Wide Association Studies in Multiple Populations.
Waters KM, Le Marchand L, Kolonel LN, Monroe KR, Stram DO, Henderson BE, Haiman CA.
Cancer Epidemiol Biomarkers Prev. 2009 Mar 24. [Epub ahead of print]

Abstract: Genome-wide association studies have identified multiple common alleles associated with prostate cancer risk in populations of European ancestry. Testing these variants in other populations is needed to assess the generalizability of the associations and may guide fine-mapping efforts. We examined 13 of these risk variants in a multiethnic sample of 2,768 incident prostate cancer cases and 2,359 controls from the Multiethnic Cohort (African Americans, European Americans, Latinos, Japanese Americans, and Native Hawaiians). We estimated ethnic-specific and pooled odds ratios and tested for ethnic heterogeneity of effects using logistic regression. In ethnic-pooled analyses, 12 of the 13 variants were positively associated with risk, with statistically significant associations (P less than 0.05) noted with six variants: JAZF1, rs10486567 [odds ratio (OR), 1.23; 95% confidence interval (95% CI, 1.12-1.35); Xp11.2, rs5945572 (OR, 1.31; 95% CI, 1.13-1.51); HNF1B, rs4430796 (OR, 1.15; 95% CI, 1.06-1.25); MSMB, rs10993994 (OR, 1.13; 95% CI, 1.04-1.23); 11q13.2, rs7931342 (OR, 1.13; 95% CI, 1.03-1.23); 3p12.1, rs2660753 (OR, 1.11; 95% CI, 1.01-1.21); SLC22A3, rs9364554 (OR, 1.10; 95% CI, 1.00-1.21); CTBP2, rs12769019 (OR, 1.11; 95% CI, 0.99-1.25); HNF1B, rs11649743 (OR, 1.10; 95% CI, 0.99-1.22); EHBP1, rs721048 (OR, 1.08; 95% CI, 0.94-1.25); KLK2/3, rs2735839 (OR, 1.06; 95% CI, 0.97-1.16); 17q24.3, rs1859962 (OR, 1.04; 95% CI, 0.96-1.13); and LMTK2, rs6465657 (OR, 0.99; 95% CI, 0.89-1.09). Significant ethnic heterogeneity of effects was noted for four variants (EHBP1, Phet = 3.9 x 10(-3); 11q13, Phet = 0.023; HNF1B (rs4430796), Phet = 0.026; and KLK2/3, Phet = 2.0 x 10(-3)). Although power was limited in some ethnic/racial groups due to variation in sample size and allele frequencies, these findings suggest that a large fraction of prostate cancer variants identified in populations of European ancestry are global markers of risk. For many of these regions, fine-mapping in non-European samples may help localize causal alleles and better determine their contribution to prostate cancer risk in the population.

GWAS deluge

2009-04-03T13:08:00.002-06:00

I wonder how exactly they operationalize this phenotype...I don't have full text access, but I'll assume they control for constitutive skin color. I still think this is a bit weird. Is there a heritable component to skin burning that is really independent of constitutive skin color?

Genome-Wide Association Study of Tanning Phenotype in a Population of European Ancestry.
Nan H, Kraft P, Qureshi AA, Guo Q, Chen C, Hankinson SE, Hu FB, Thomas G, Hoover RN, Chanock S, Hunter DJ, Han J.
J Invest Dermatol. 2009 Apr 2

Abstract: We conducted a multistage genome-wide association study (GWAS) of tanning response after exposure to sunlight in over 9,000 men and women of European ancestry who live in the United States. An initial analysis of 528,173 single-nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified LOC401937 (rs966321) on chromosome 1 as a novel locus highly associated with tanning ability, and we confirmed this association in 870 women controls from a skin cancer case-control study with joint P-value=1.6 x 10(-9). We further genotyped this SNP in two subsequent replication studies (one with 3,750 women and the other with 2,405 men). This association was not replicated in either of these two studies. We found that several SNPs reaching the genome-wide significance level are located in or adjacent to the loci previously known as pigmentation genes: MATP, IRF4, TYR, OCA2, and MC1R. Overall, these tanning ability-related loci are similar to the hair color-related loci previously reported in the GWAS of hair color.

Blue eyes follow-up

2009-04-03T12:51:00.004-06:00

According to this paper, blue eyes in N. European humans is predicted very well by these variants:
HERC2 rs12913832
OCA2 rs1800407
SLC24A4 rs12896399
SLC45A2 rs16891982
TYR rs1393350
IRF4 rs12203592

It might be interesting to look at the five latter ones in the blue-eyed lemur... although, it looks like only one SNP (in HERC2, I assume) is sufficient to explain the majority of the variation in humans.

Convergent evolution via different genetic mechanism: blue eyes in lemurs and humans

2009-04-02T09:09:00.003-06:00

I guess we are to assume that the blue eye color is the same in humans and lemurs. From looking at some pictures, the color appears pretty similar. Haven't read the paper, but are all cases of blue eye color in humans explained by the same variation in HERC2? I might have a post on this somewhere.
I suppose we shouldn't be too surprised by this finding, given what we know about convergence of light skin color evolution in Europeans and E. Asians via different genes.

Brief communication: Blue eyes in lemurs and humans: Same phenotype, different genetic mechanism.
Bradley BJ, Pedersen A, Mundy NI.
Am J Phys Anthropol. 2009 Mar 10.

Almost all mammals have brown or darkly-pigmented eyes (irises), but among primates, there are some prominent blue-eyed exceptions. The blue eyes of some humans and lemurs are a striking example of convergent evolution of a rare phenotype on distant branches of the primate tree. Recent work on humans indicates that blue eye color is associated with, and likely caused by, a single nucleotide polymorphism (rs12913832) in an intron of the gene HERC2, which likely regulates expression of the neighboring pigmentation gene OCA2. This raises the immediate question of whether blue eyes in lemurs might have a similar genetic basis. We addressed this by sequencing the homologous genetic region in the blue-eyed black lemur (Eulemur macaco flavifrons; N = 4) and the closely-related black lemur (Eulemur macaco macaco; N = 4), which has brown eyes. We then compared a 166-bp segment corresponding to and flanking the human eye-color-associated region in these lemurs, as well as other primates (human, chimpanzee, orangutan, macaque, ring-tailed lemur, mouse lemur). Aligned sequences indicated that this region is strongly conserved in both Eulemur macaco subspecies as well as the other primates (except blue-eyed humans). Therefore, it is unlikely that this regulatory segment plays a major role in eye color differences among lemurs as it does in humans. Although convergent phenotypes can sometimes come about via the same or similar genetic changes occurring independently, this does not seem to be the case here, as we have shown that the genetic basis of blue eyes in lemurs differs from that of humans.

Disentangling genetic signatures of natural selection and demography among Native Americans and W. Beringians

2009-03-07T09:59:00.003-07:00

Haplotypic background of a private allele at high frequency in the Americas.
Schroeder KB, Jakobsson M, Crawford MH, Schurr TG, Boca SM, Conrad DF, Tito RY, Osipova LP, Tarskaia LA, Zhadanov SI, Wall JD, Pritchard JK, Malhi RS, Smith DG, Rosenberg NA.
Mol Biol Evol. 2009 Feb 17. [Epub ahead of print]

Abstract: Recently, the observation of a high-frequency private allele, the 9-repeat allele at microsatellite D9S1120, in all sampled Native American and Western Beringian populations has been interpreted as evidence that all modern Native Americans descend primarily from a single founding population. However, this inference assumed that all copies of the 9-repeat allele were identical by descent and that the geographic distribution of this allele had not been influenced by natural selection. To investigate whether these assumptions are satisfied, we genotyped 34 SNPs across approximately 500 kilobases (kb) around D9S1120 in 21 Native American and Western Beringian populations and 54 other worldwide populations. All chromosomes with the 9-repeat allele share the same haplotypic background in the vicinity of D9S1120, suggesting that all sampled copies of the 9-repeat allele are identical by descent. Ninety-one percent of these chromosomes share the same 76.26 kb haplotype, which we call the "American Modal Haplotype" (AMH). Three observations lead us to conclude that the high frequency and widespread distribution of the 9-repeat allele are unlikely to be the result of positive selection: 1) aside from its association with the 9-repeat allele, the AMH does not have a high frequency in the Americas, 2) the AMH is not unusually long for its frequency compared to other haplotypes in the Americas, and 3) in Latin American mestizo populations, the proportion of Native American ancestry at D9S1120 is not unusual compared to that observed at other genomewide microsatellites. Using a new method for estimating the time to the most recent common ancestor (MRCA) of all sampled copies of an allele on the basis of an estimate of the length of the genealogy descended from the MRCA, we calculate the mean time to the MRCA of the 9-repeat allele to be between 7,325 and 39,900 years, depending on the demographic model used. The results support the hypothesis that all modern Native Americans and Western Beringians trace a large portion of their ancestry to a single founding population which may have been isolated from other Asian populations prior to expanding into the Americas.

Discovery of rare variants in regions identified by GWASs

2009-03-07T09:43:00.004-07:00

P-ter at GNXP and Dan at Genetic Future discuss what seems to be an interesting and important recently published paper in Science (abstract below) that finds four rare variants with larger-than-usual effects for Type-1 Diabetes. The last line of the abstract pretty much says it all. The evolutionary interpretation is of course very interesting, especially since the rare variants reduce risk. Dan talks about this.

Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes
Sergey Nejentsev, Neil Walker , David Riches, Michael Egholm, John A. Todd
Science DOI: 10.1126/science.1167728

Abstract: Genome-wide association studies (GWAS) are widely used to map genomic regions contributing to common human diseases, but they often do not identify the precise causative genes and sequence variants. To identify causative type 1 diabetes (T1D) variants, we resequenced exons and splice sites of ten candidate genes in pools of DNA from 480 patients and 480 controls and tested their disease association in over 30,000 subjects. We discovered four rare variants that lowered T1D risk independently of each other (OR = 0.51 – 0.74; P = 1.3 x 10-3 – 2.1 x 10-16) in IFIH1, a gene located in a region previously associated with T1D by GWAS. These variants are predicted to alter the expression and structure of IFIH1 (MDA5), a cytoplasmic helicase that mediates induction of interferon response to viral RNA. This firmly establishes the role of IFIH1 in T1D and demonstrates that resequencing studies can pinpoint disease-causing genes in genomic regions initially identified by GWAS.

Introgression of black coat color into wolves from dogs

2009-03-06T07:25:00.002-07:00

Molecular and Evolutionary History of Melanism in North American Gray Wolves
Tovi M. Anderson, Bridgett M. vonHoldt, Sophie I. Candille, Marco Musiani, Claudia Greco, Daniel R. Stahler, Douglas W. Smith, Badri Padhukasahasram, Ettore Randi, Jennifer A. Leonard, Carlos D. Bustamante, Elaine A. Ostrander, Hua Tang, Robert K. Wayne, Gregory S. Barsh
Science 6 March 2009: Vol. 323. no. 5919, pp. 1339 - 1343

Abstract: Morphological diversity within closely related species is an essential aspect of evolution and adaptation. Mutations in the Melanocortin 1 receptor (Mc1r) gene contribute to pigmentary diversity in natural populations of fish, birds, and many mammals. However, melanism in the gray wolf, Canis lupus, is caused by a different melanocortin pathway component, the K locus, that encodes a beta-defensin protein that acts as an alternative ligand for Mc1r. We show that the melanistic K locus mutation in North American wolves derives from past hybridization with domestic dogs, has risen to high frequency in forested habitats, and exhibits a molecular signature of positive selection. The same mutation also causes melanism in the coyote, Canis latrans, and in Italian gray wolves, and hence our results demonstrate how traits selected in domesticated species can influence the morphological diversity of their wild relatives.

Predictive ability of SNPs for prostate cancer

2009-02-25T13:39:00.003-07:00

Utility of Incorporating Genetic Variants for the Early Detection of Prostate Cancer
Robert K. Nam, William W. Zhang, John Trachtenberg, Arun Seth, Laurence H. Klotz, Aleksandra Stanimirovic, Sanoj Punnen, Vasundara Venkateswaran, Ants Toi, D. Andrew Loblaw, Linda Sugar, Katherine A. Siminovitch, Steven A. Narod
Clinical Cancer Research, 10.1158/1078-0432

Abstract Purpose: Several single nucleotide polymorphisms (SNP) have been associated with the risk of prostate cancer. The clinical utility of using SNPs in the early detection of prostate cancer has not been evaluated.Experimental Design: We examined a panel of 25 SNPs from candidate genes and chromosomal regions in 3,004 unselected men who were screened for prostate cancer using serum prostate-specific antigen (PSA) and digital rectal examination. All underwent a prostate biopsy. We evaluated the ability of these SNPs to help predict the presence of prostate cancer at biopsy.Results: Of the 3,004 patients, 1,389 (46.2%) were found to have prostate cancer. Fifteen of the 25 SNPs studied were significantly associated with prostate cancer (P = 0.02-7 x 10-8). We selected a combination of 4 SNPs with the best predictive value for further study. After adjusting for other predictive factors, the odds ratio for patients with all four of the variant genotypes compared with men with no variant genotype was 5.1 (95% confidence interval, 1.6-16.5; P = 0.006). When incorporated into a nomogram, genotype status contributed more significantly than PSA, family history, ethnicity, urinary symptoms, and digital rectal examination (area under the curve = 0.74). The positive predictive value of the PSA test ranged from 42% to 94% depending on the number of variant genotypes carried (P = 1 x 10-15).Conclusions: SNP genotyping can be used in a clinical setting for the early detection of prostate cancer in a nomogram approach and by improving the positive predictive value of the PSA test.

Teaching material for evolution by natural selection

2009-02-18T19:44:00.003-07:00

In honor of Darwin's recent 200th birthday, Nature came up with a list of 15 Evolutionary Gems. My major complaint, and a pretty major one at that, is that none of the examples are related to human evolution - something that students could probably relate to a bit more easily, and might increase the chance that they actually pay attention.
Basically, what I'm getting at: Why is lactase persistence not there? or the several other well-documented and clear cut examples from human evolution?

Elucidating the genetics of eye color

2009-02-18T14:32:00.003-07:00

Getting closer to predicting not-so-complex "complex" phenotypes from genetic data?
Eye and skin color are great model phenotypes with which we can learn about the genetics of complex traits, as I've often argued. Here's another step in the process.

Interactions Between HERC2, OCA2 and MC1R May Influence Human Pigmentation Phenotype.
Branicki W, Brudnik U, Wojas-Pelc A.
Ann Hum Genet. 2009 Feb 4. [Epub ahead of print]

Abstract: Human pigmentation is a polygenic trait which may be shaped by different kinds of gene-gene interactions. Recent studies have revealed that interactive effects between HERC2 and OCA2 may be responsible for blue eye colour determination in humans. Here we performed a population association study, examining important polymorphisms within the HERC2 and OCA2 genes. Furthermore, pooling these results with genotyping data for MC1R, ASIP and SLC45A2 obtained for the same population sample we also analysed potential genetic interactions affecting variation in eye, hair and skin colour. Our results confirmed the association of HERC2 rs12913832 with eye colour and showed that this SNP is also significantly associated with skin and hair colouration. It is also concluded that OCA2 rs1800407 is independently associated with eye colour. Finally, using various approaches we were able to show that there is an interaction between MC1R and HERC2 in determination of skin and hair colour in the studied population sample.

Genetics of lipid profiles in European and African Americans

2009-01-24T08:28:00.003-07:00

Genetic Differences between the Determinants of Lipid Profile Phenotypes in African and European Americans: The Jackson Heart Study
Rahul C. Deo, David Reich, Arti Tandon, Ermeg Akylbekova, Nick Patterson, Alicja Waliszewska, Sekar Kathiresan, Daniel Sarpong, Herman A. Taylor, Jr., James G. Wilson
PLoS Genetics 5(1): e1000342.

Abstract: Genome-wide association analysis in populations of European descent has recently found more than a hundred genetic variants affecting risk for common disease. An open question, however, is how relevant the variants discovered in Europeans are to other populations. To address this problem for cardiovascular phenotypes, we studied a cohort of 4,464 African Americans from the Jackson Heart Study (JHS), in whom we genotyped both a panel of 12 recently discovered genetic variants known to predict lipid profile levels in Europeans and a panel of up to 1,447 ancestry informative markers allowing us to determine the African ancestry proportion of each individual at each position in the genome. Focusing on lipid profiles—HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), and triglycerides (TG)—we identified the lipoprotein lipase (LPL) locus as harboring variants that account for interethnic variation in HDL-C and TG. In particular, we identified a novel common variant within LPL that is strongly associated with TG (p = 2.7×10−6) and explains nearly 1% of the variability in this phenotype, the most of any variant in African Americans to date. Strikingly, the extensively studied “gain-of-function” S447X mutation at LPL, which has been hypothesized to be the major determinant of the LPL-TG genetic association and is in trials for human gene therapy, has a significantly diminished strength of biological effect when it is found on a background of African rather than European ancestry. These results suggest that there are other, yet undiscovered variants at the locus that are truly causal (and are in linkage disequilibrium with S447X) or that work synergistically with S447X to modulate TG levels. Finally, we find systematically lower effect sizes for the 12 risk variants discovered in European populations on the African local ancestry background in JHS, highlighting the need for caution in the use of genetic variants for risk assessment across different populations.

Gene importance and evolutionary rate

2009-01-09T09:02:00.002-07:00

Why Is the Correlation between Gene Importance and Gene Evolutionary Rate So Weak?
Zhi Wang, Jianzhi Zhang
PLoS Genetics 5(1): e1000329.

Abstract: One of the few commonly believed principles of molecular evolution is that functionally more important genes (or DNA sequences) evolve more slowly than less important ones. This principle is widely used by molecular biologists in daily practice. However, recent genomic analysis of a diverse array of organisms found only weak, negative correlations between the evolutionary rate of a gene and its functional importance, typically measured under a single benign lab condition. A frequently suggested cause of the above finding is that gene importance determined in the lab differs from that in an organism's natural environment. Here, we test this hypothesis in yeast using gene importance values experimentally determined in 418 lab conditions or computationally predicted for 10,000 nutritional conditions. In no single condition or combination of conditions did we find a much stronger negative correlation, which is explainable by our subsequent finding that always-essential (enzyme) genes do not evolve significantly more slowly than sometimes-essential or always-nonessential ones. Furthermore, we verified that functional density, approximated by the fraction of amino acid sites within protein domains, is uncorrelated with gene importance. Thus, neither the lab-nature mismatch nor a potentially biased among-gene distribution of functional density explains the observed weakness of the correlation between gene importance and evolutionary rate. We conclude that the weakness is factual, rather than artifactual. In addition to being weakened by population genetic reasons, the correlation is likely to have been further weakened by the presence of multiple nontrivial rate determinants that are independent from gene importance. These findings notwithstanding, we show that the principle of slower evolution of more important genes does have some predictive power when genes with vastly different evolutionary rates are compared, explaining why the principle can be practically useful despite the weakness of the correlation.

Genetic information doesn't add much for predicting diabetes

2009-01-02T13:47:00.003-07:00

Predicting type 2 diabetes based on polymorphisms from genome-wide association studies: a population-based study.
van Hoek M, Dehghan A, Witteman JC, van Duijn CM, Uitterlinden AG, Oostra BA, Hofman A, Sijbrands EJ, Janssens AC.
Diabetes. 2008 Nov;57(11):3122-8.

OBJECTIVE: Prediction of type 2 diabetes based on genetic testing might improve identification of high-risk subjects. Genome-wide association (GWA) studies identified multiple new genetic variants that associate with type 2 diabetes. The predictive value of genetic testing for prediction of type 2 diabetes in the general population is unclear. RESEARCH DESIGN AND METHODS: We investigated 18 polymorphisms from recent GWA studies on type 2 diabetes in the Rotterdam Study, a prospective, population-based study among homogeneous Caucasian individuals of 55 years and older (genotyped subjects, n = 6,544; prevalent cases, n = 686; incident cases during follow-up, n = 601; mean follow-up 10.6 years). The predictive value of these polymorphisms was examined alone and in addition to clinical characteristics using logistic and Cox regression analyses. The discriminative accuracy of the prediction models was assessed by the area under the receiver operating characteristic curves (AUCs). RESULTS: Of the 18 polymorphisms, the ADAMTS9, CDKAL1, CDKN2A/B-rs1412829, FTO, IGF2BP2, JAZF1, SLC30A8, TCF7L2, and WFS1 variants were associated with type 2 diabetes risk in our population. The AUC was 0.60 (95% CI 0.57-0.63) for prediction based on the genetic polymorphisms; 0.66 (0.63-0.68) for age, sex, and BMI; and 0.68 (0.66-0.71) for the genetic polymorphisms and clinical characteristics combined. CONCLUSIONS: We showed that 9 of 18 well-established genetic risk variants were associated with type 2 diabetes in a population-based study. Combining genetic variants has low predictive value for future type 2 diabetes at a population-based level. The genetic polymorphisms only marginally improved the prediction of type 2 diabetes beyond clinical characteristics.

The genetics of skin pigmentation in beach mice from different beaches

2008-12-23T10:38:00.004-07:00

A similar story to humans in East Asia and Europe...

The Genetic Basis of Phenotypic Convergence in Beach Mice: Similar Pigment Patterns but Different Genes Cynthia C. Steiner, Holger Römpler, Linda M. Boettger, Torsten Schöneberg and Hopi E. Hoekstra
Molecular Biology and Evolution 2009 26(1):35-45

Abstract: Convergent evolution is a widespread phenomenon seen in diverse organisms inhabiting similar selective environments. However, it is unclear if similar phenotypes are produced by the same or different genes and mutations. Here we analyze the molecular mechanisms underlying convergent pigment pattern among subspecies of the beach mouse (Peromyscus polionotus) inhabiting the Gulf and Atlantic coasts of Florida. In these two geographic regions, separated by more than 300 km, "beach mice" have lighter colored coats than do their mainland counterparts, produced by natural selection for camouflage against the pale coastal sand dunes. We measured color pattern in eight beach mouse subspecies and showed that three of the Gulf Coast subspecies are more phenotypically similar to an Atlantic coast subspecies than to their Gulf Coast neighbors. However, light-colored beach mice do not form a monophyletic group. Previous results implicated a single derived amino acid change in the melanocortin-1 receptor (Mc1r) as a major contributor to pigment pattern in the Gulf Coast beach mice; despite phenotypic similarities, the derived Mc1r allele was not found in the Atlantic coast beach mouse populations. Here we show that Atlantic coast beach mice have high levels of Mc1r polymorphism but they lack unique alleles. Functional assays revealed that single amino acid mutations segregating in Atlantic coast beach mice do not cause any change in Mc1r activity compared with the activity of Mc1r from dark-colored mice. These joint results show that convergent pigment patterns in recently diverged beach mouse subspecies—whose developmental constraints are presumably similar—have evolved through a diversity of genetic mechanisms.

Tradeoff between pathogen resistance and auto-immune response?

2008-12-11T10:57:00.001-07:00

I first read about this in one of the earlier papers on European genetic structure where they mention: "a north/south gradient in the incidence of autoimmune diseases has been noted for several continents," and give a reference to this paper which, if I remember correctly, shows differences in incidence of various diseases across Europe and discusses the potential tradeoff between pathogen resistance and auto-immune disorders.

Dan at Genetic Future points out a recent study where they find that the same genetic factors contribute to both celiac disease and type I diabetes (both auto-immune disorders). The study also finds that those with the delta-32 variant of CCR5 (protective of HIV infection) have a lower risk of type I diabetes and celiac disease.
These findings beg the questions: Given the distribution of these diseases across Europe, shouldn't they have controlled for ancestry stratification?, and more generally: Is there a unifying phenotype that can be measured which maps to the underlying factor contributing to all these auto-immune diseases? Why is this phenotype seemingly more prevalent among Northern Europeans? Is there some kind of tradeoff between between pathogen resistance and auto-immune "disorders"?
I must say I'm still unclear about the evidence, if any, for this tradeoff.

Slavery, fetal programming, and low birth weight among African Americans

2008-12-10T09:02:00.004-07:00

It doesn't look like any hypotheses are tested here. The proposal is not too surprising, but I think it's very important to fully consider it as we try to grasp the complete etiology of health disparities.

Low birth weight of contemporary African Americans: An intergenerational effect of slavery?
Grazyna Jasienska
American Journal of Human Biology 2008, 21: 16 - 24

Abstract: The average birth weight in the contemporary African-American population is about 250 g lower than the average birth weight of European Americans. Differences in genetic and socioeconomic factors present between these two groups can explain only part of birth weight variation. I propose a hypothesis that the low birth weight of contemporary African Americans not only results from the difference in present exposure to lifestyle factors known to affect fetal development but also from conditions experienced during the period of slavery. Slaves had poor nutritional status during all stages of life because of the inadequate dietary intake accompanied by high energetic costs of physical work and infectious diseases. The concept of fetal programming suggests that physiology and metabolism including growth and fat accumulation of the developing fetus, and, thus its birth weight, depend on intergenerational signal of environmental quality passed through generations of matrilinear ancestors. I suggest that several generations that have passed since the abolition of slavery in the United States (1865) has not been enough to obliterate the impact of slavery on the current biological and health condition of the African-American population.

Distance from Africa explains within-population cranial variation better than climate

2008-12-10T07:50:00.000-07:00

This paper is somewhat disappointingly deceptive (as Dienekes points out nicely). They are actually looking at within-population variation in cranial traits and how it varies across the globe. They could have put that in their title.
To be fair, I haven't looked too closely at the paper, and it does look interesting and informative as to the relative roles of demographic vs. selection forces in shaping within-population variation.

Distance from Africa, not climate explains human variation.

Lia Betti, François Balloux, William Amos, Tsunehiko Hanihara, Andrea Manica
Proc Roy Soc B Early online

Abstract: The relative importance of ancient demography and climate in determining worldwide patterns of human within-population phenotypic diversity is still open to debate. Several morphometric traits have been argued to be under selection by climatic factors, but it is unclear whether climate affects the global decline in morphological diversity with increasing geographical distance from sub-Saharan Africa. Using a large database of male and female skull measurements, we apply an explicit framework to quantify the relative role of climate and distance from Africa. We show that distance from sub-Saharan Africa is the sole determinant of human within-population phenotypic diversity, while climate plays no role. By selecting the most informative set of traits, it was possible to explain over half of the worldwide variation in phenotypic diversity. These results mirror those previously obtained for genetic markers and show that ‘bones and molecules’ are in perfect agreement for humans.

European ancestry associated with higher breast cancer risk?

2008-12-04T18:31:00.003-07:00

Latinas have been found to have a lower incidence of breast cancer than other ethnic groups. Indigenous Americans have the lowest incidence. This meta-review paper from a few months ago finds that ethnic disparities in breast cancer can be explained by SES, except for the lower incidence among African Americans.

So what do they find in this new paper (see abstract below)? It's a case control study with a pretty large sample size (440 cases and 597 controls, matched for age) of Latinas in the SF Bay area to determine whether genetic differences between groups account for differences in breast cancer incidence. They used 106 AIMs (ancestry informative markers). Interestingly:

"Breast cancer among Latinas presents a particularly
interesting case because the main ancestral components of the Latino population (European and Indigenous American) have the highest and lowest breast cancer incidence (1)."

They control for a suite of known breast cancer risk factors
(including education, but unfortunately, not income). Surprisingly the cases and controls differed significantly for many of the measured risk factors.

The main findings:

"In unadjusted models, we found a strong association between genetic ancestry (continuous) and breast cancer risk. Higher European ancestry was associated with increased risk, with an odds ratio (OR) of 1.79 [95% confidence intervals (95% CI), 1.28–2.79; P less than 0.001] for every 25% increase in European ancestry. When known risk factors and place of birth were adjusted for (Table 2), the association with European ancestry was somewhat attenuated but remained statistically significant (OR, 1.39; 95% CI, 1.06–2.11; P = 0.013). When African ancestry was included in the adjusted model, the association with European ancestry became stronger [OR for European ancestry, 1.54 (95% CI, 1.11–2.52; P = 0.004), and OR for African ancestry, 2.05 (95% CI, 1.00–7.56; P = 0.055)]."

They also looked at the association using genetic admixture and "using parent/grandparent European origin instead of genetic ancestry."

"We observed a significant association between the number of European-born parents/grandparents and breast cancer risk, with higher number of European ancestors being associated with increased risk (OR, 1.21; 95% CI, 1.02–1.44; P = 0.025, adjusted model)."

Although their results suggest that there may be some genetic risk factor specific to individuals with higher European ancestry, they are careful to acknowledge the possibility for residual confounders. It's too bad they didn't control for income and/or some other SES variables.

Genetic Ancestry and Risk of Breast Cancer among U.S. Latinas
Laura Fejerman, Esther M. John, Scott Huntsman, Kenny Beckman, Shweta Choudhry, Eliseo Perez-Stable, Esteban González Burchard and Elad Ziv
Cancer Research 2008;68(23):9723–8

Abstract: U.S. Latinas have a lower incidence of breast cancer compared with non-Latina White women. This difference is partially explained by differences in the prevalence of known risk factors. Genetic factors may also contribute to this difference in incidence. Latinas are an admixed population with most of their genetic ancestry from Europeans and Indigenous Americans. We used genetic markers to estimate the ancestry of Latina breast cancer cases and controls and assessed the association with genetic ancestry, adjusting for reproductive and other risk factors. We typed a set of 106 ancestry informative markers in 440 Latina women with breast cancer and 597 Latina controls from the San Francisco Bay area and estimated genetic ancestry using a maximum likelihood method. Odds ratios (OR) and 95% confidence intervals (95% CI) for ancestry modeled as a continuous variable were estimated using logistic regression with known risk factors included as covariates. Higher European ancestry was associated with increased breast cancer risk. The OR for a 25% increase in European ancestry was 1.79 (95% CI, 1.28–2.79; P less than 0.001). When knownrisk factors and place of birth were adjusted for, the associationwith European ancestry was attenuated but remained statisticallysignificant (OR, 1.39; 95% CI, 1.06–2.11; P = 0.013).Further work is needed to determine if the association is dueto genetic differences between populations or possibly due toenvironmental factors not measured.

Paralogous genes and disease alleles

2008-12-03T15:23:00.000-07:00

I don't quite fully get this, but the point of the method that they propose is to look at paralogous genes to more efficiently pinpoint the actual causal variants from among the many "hits" that pop up in GWASs.

Genome-Wide Analysis of Human Disease Alleles Reveals That Their Locations Are Correlated in Paralogous Proteins
Mark Yandell, Barry Moore, Fidel Salas, Chris Mungall, Andrew MacBride, Charles White, Martin G. Reese
PLoS Comput Biol 4(11): e1000218

Abstract: The millions of mutations and polymorphisms that occur in human populations are potential predictors of disease, of our reactions to drugs, of predisposition to microbial infections, and of age-related conditions such as impaired brain and cardiovascular functions. However, predicting the phenotypic consequences and eventual clinical significance of a sequence variant is not an easy task. Computational approaches have found perturbation of conserved amino acids to be a useful criterion for identifying variants likely to have phenotypic consequences. To our knowledge, however, no study to date has explored the potential of variants that occur at homologous positions within paralogous human proteins as a means of identifying polymorphisms with likely phenotypic consequences. In order to investigate the potential of this approach, we have assembled a unique collection of known disease-causing variants from OMIM and the Human Genome Mutation Database (HGMD) and used them to identify and characterize pairs of sequence variants that occur at homologous positions within paralogous human proteins. Our analyses demonstrate that the locations of variants are correlated in paralogous proteins. Moreover, if one member of a variant-pair is disease-causing, its partner is likely to be disease-causing as well. Thus, information about variant-pairs can be used to identify potentially disease-causing variants, extend existing procedures for polymorphism prioritization, and provide a suite of candidates for further diagnostic and therapeutic purposes.

NY Times article on testing kids for ACTN3 gene

2008-11-30T09:59:00.003-07:00

It was only a matter of time, but there is now a company in the US that is offering a test to determine a person's ACTN3 genotype. This is a locus for which there is some evidence of an association with muscle fiber composition (fast vs. slow twitch) and whether an elite athlete competes in sprint or endurance events.
This article in the New York Times describes the test, some of the evidence concerning the association, and some of the issues surrounding its costs/benefits.
My favorite line:

Dr. Foster suggested another way to determine if a child will be good at sprint and power sports. “Just line them up with their classmates for a race and see which ones are the fastest,” he said.

Dan MacArthur has done some of the primary work on this locus and its association with athletic performance. I'm surprised his name didn't show up in the article. Actually, I just noticed that he has also written a blog post about this article.
He discusses the tests' limitations and mentions that this test has been commercially offered in several countries for some time and is available through the personal genomics companies in the US.

There are indeed many limitations to this test. Given what goes into making a great athlete, I see no use for it whatsoever, except for giving some solace to a person wondering why, after years of training, he/she didn't become the great athlete he/she hoped to become. Given the predictive power of this test, I think that the costs (mostly psychological) of doing this test to see what you would be good at greatly outweigh the benefits.

GWAS of metabolite profiles

2008-11-27T17:02:00.001-07:00

This is great, and somewhat appropriate for Thanksgiving.

An important issue in deciphering the genetic basis for traits is appropriate phenotype definition. In this study, they look at the association between metabolic by-products in individuals and their genetic profile. These metabolites represent a better phenotype since they are more proximal to the genetic/biochemical pathways that happen within cells, compared to the clinically assessed symptoms of a "disease." Not only does this give us a more appropriate and well-defined phenotype, it's also a phenotype that can be measured on a continuous scale.

The subjects are from Germany and they briefly dismiss the possibility of population stratification: "Also, recent experimental assessment has found little population stratification to exist within and across Germany [33]". Ironically, the latest European genetic structure study, see my last blog post, showed some stratification within Germany - granted, probably not too big of a deal for this study, but it's just funny

Blood samples were obtained in the morning after overnight fasting. In the future, I can imagine collecting samples after feeding of some sugary or fatty meal to get even better measures of metabolic variation.

Genetics Meets Metabolomics: A Genome-Wide Association Study of Metabolite Profiles in Human Serum.
Gieger C, Geistlinger L, Altmaier E, Hrabe´ de Angelis M, Kronenberg F, et al.
PLoS Genet (2008)4(11): e1000282. doi:10.1371/journal.pgen.1000282

Abstract: The rapidly evolving field of metabolomics aims at comprehensive measurement of ideally all endogenous metabolites in a cell or body fluid. It thereby provides a functional readout of the physiological state of the human body. Genetic variants that associate with changes in the homeostasis of key lipids, carbohydrates, or amino acids are not only expected to display much larger effect sizes due to their direct involvement in metabolite conversion modification, but should also provide access to the biochemical context of such variations, in particular when enzyme coding genes are concerned. To test this hypothesis, we conducted what is, to the best of our knowledge, the first GWA study with metabolomics based on the quantitative measurement of 363 metabolites in serum of 284 male participants of the KORA study. We found associations of frequent single nucleotide polymorphisms (SNPs) with considerable differences in the metabolic homeostasis of the human body, explaining up to 12% of the observed variance. Using ratios of certain metabolite concentrations as a proxy for enzymatic activity, up to 28% of the variance can be explained (p-values 10216 to 10221). We identified four genetic variants in genes coding for enzymes (FADS1, LIPC, SCAD, MCAD) where the corresponding metabolic phenotype (metabotype) clearly matches the biochemical pathways in which these enzymes are active. Our results suggest that common genetic polymorphisms induce major differentiations in the metabolic make-up of the human population. This may lead to a novel approach to personalized health care based on a combination of genotyping and metabolic characterization. These genetically determined metabotypes may subscribe the risk for a certain medical phenotype, the response to a given drug treatment, or the reaction to a nutritional intervention or environmental challenge.

European genetic structure, study du jour

2008-11-26T16:25:00.000-07:00

Yet another one.
As usual, Dienekes and Razib have talked about this one on their blogs.

Anything new or particularly interesting?

within-Germany resolution (see figure, labeled by Razib)
big sample, of nearly 6000
LCT (lactase), HERC2 (eye color and hair color) and HLA (immune function) regions stood out as most highly correlated to the North-South gradient.
they frame the importance of this in relation to picking appropriately matched controls in case-control studies

Ethnicity/country origin of subjects is taken as where the sample was obtained. This is unfortunate since more detailed information on the origin of each subject could have enabled better resolution.

Do big brains call for special milk?

2008-11-25T10:21:00.001-07:00

Apparently not...
I can't believe no one has already studied this.

Evolutionary modifications of human milk composition: evidence from long-chain polyunsaturated fatty acid composition of anthropoid milks
Lauren A. Milligan and Richard P. Bazinet
Journal of Human Evolution 55: 6, December 2008, 1086-1095

Abstract: Brain growth in mammals is associated with increased accretion of long-chain polyunsaturated fatty acids (LCPUFA) in brain phospholipids. The period of maximum accumulation is during the brain growth spurt. Humans have a perinatal brain growth spurt, selectively accumulating docosahexaenoic acid (DHA) and other LCPUFA from the third trimester through the second year of life. The emphasis on rapid postnatal brain growth and LCPUFA transfer during lactation has led to the suggestion that human milk LCPUFA composition may be unique. Our study tests this hypothesis by determining fatty acid composition for 11 species of captive anthropoids (n = 53; Callithrix jacchus, Cebus apella, Gorilla gorilla, Hylobates lar, Leontopithecus rosalia, Macaca mulatta, Pan troglodytes, Pan paniscus, Pongo pygmaeus, Saimiri boliviensis, and Symphalangus syndactylus). Results are compared to previously published data on five species of wild anthropoids (n = 28; Alouatta paliatta, Callithrix jacchus, Gorilla beringei, Leontopithecus rosalia, and Macaca sinica) and human milk fatty acid profiles. Milk LCPUFA profiles of captive anthropoids (consuming diets with a preformed source of DHA) are similar to milk from women on a Western diet, and those of wild anthropoids are similar to milk from vegan women. Collectively, the range of DHA percent composition values from nonhuman anthropoid milks (0.03–1.1) is nearly identical to that from a cross-cultural analysis of human milk (0.06–1.4). Humans do not appear to be unique in their ability to secrete LCPUFA in milk but may be unique in their access to dietary LCPUFA.

Determining the genetic composition of an unknown founder population

2008-11-25T07:32:00.001-07:00

Using the HLA system, they describe a method to determine the haplotypes of an unknown founder population given information on the haplotypes of the admixed population and those of the other founder population.

Re-creation of the genetic composition of a founder population.

Klitz W, Maiers M, Gragert L.
Human Genetics 2008 Nov;124(4):417-21.

Abstract: Human ethnic groups are frequently comprised of two or more founder populations. One of these founding populations is often available for contemporary sampling. We describe a method for reconstructing the composition of a missing founder population using the highly informative haplotypes comprising the HLA system. An application of the method is demonstrated using bone marrow registry samples of African Americans. We use contemporary samples of African Americans and European Americans to derive haplotypes of the West African founder populations. This approach may also be useful for reconstructing ancestral haplotypes for regions elsewhere in the genome.

Review paper on the importance of considering sex for genotype-phenotype relationships

2008-11-19T07:53:00.001-07:00

Sex-specific genetic architecture of human disease
Carole Ober, Dagan A. Loisel & Yoav Gilad
Nature Reviews Genetics 9, 911-922 (December 2008)

Abstract: Sexual dimorphism in anatomical, physiological and behavioural traits are characteristics of many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course and severity of many common diseases, including cardiovascular diseases, autoimmune diseases and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid-responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.

Demonstration of epigenetic changes due to early stress, and how do you measure methylation?

2008-11-14T10:36:00.001-07:00

An interesting paper showing epigenetic changes caused by early stress has recently come out in PNAS (see below). Siblings who were in utero during the Dutch Famine in the winter of '44 - '45 had less methylation on the IGF2 gene compared to their same-sex siblings who were not in utero during the famine.

So, how exactly does one measure methylation?
According to the paper, and a Wikipedia entry:
First, methylation usually occurs on CpG cytosines, and when you treat your piece of DNA with bisulfite, the methylated cytosines becomes reduced to uracil. Then a variety of PCR methods and/or sequencing methods can be applied. In this paper they use a mass-spectroscopy based method called Epityper.

Persistent epigenetic differences associated with prenatal exposure to famine in humans
Bastiaan T. Heijmansa, Elmar W. Tobia, Aryeh D. Stein, Hein Putter, Gerard J. Blauw, Ezra S. Susser, P. Eline Slagboom, and L. H. Lumeye
PNAS 2008 105:17046-17049

Abstract: Extensive epidemiologic studies have suggested that adult disease risk is associated with adverse environmental conditions early in development. Although the mechanisms behind these relationships are unclear, an involvement of epigenetic dysregulation has been hypothesized. Here we show that individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944–45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings. The association was specific for periconceptional exposure, reinforcing that very early mammalian development is a crucial period for establishing and maintaining epigenetic marks. These data are the first to contribute empirical support for the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life.

Updated refresher course on genes

2008-11-14T09:52:00.000-07:00

There's an article in the NYT by Carl Zimmer called "Now: The Rest of the Genome" that discusses some of the new findings about how genes work:
Here are some of the more interesting nuggets:

"the average protein-coding region produces 5.7 different transcripts"
"cells often toss exons into transcripts from other genes. Those exons may come from distant locations, even from different chromosomes."
"When an embryo begins to develop, the epigenetic marks that have accumulated on both parents’ DNA are stripped away. The cells add a fresh set of epigenetic marks in the same pattern that its parents had when they were embryos."
"As an embryo matures, epigenetic marks in different cells are altered, and as a result they develop into different tissues. Once the final pattern of epigenetic marks is laid down, it clings stubbornly to cells. When cells divide, their descendants carry the same set of marks."
"Although only 1.2 percent of the human genome encodes proteins, the Encode scientists estimate that a staggering 93 percent of the genome produces RNA transcripts."
"Dr. Prohaska argues that a gene should be the smallest unit underlying inherited traits. It may include not just a collection of exons, but the epigenetic marks on them that are inherited as well."

Facilitated Variation: How the genetic code hedges its bets on a variable environment

2008-11-10T15:55:00.001-07:00

Haven't had the chance to look very closely at the details, but this paper looks very interesting. Evolution thrives on variation, and according to them, the genomes of organisms can accumulate a sort of stored memory of past adaptation to varying environments that as they say "makes it more likely that random genetic changes will result in organisms with novel shapes that can survive."

Facilitated Variation: How Evolution Learns from Past Environments To Generalize to New Environments
Merav Parter, Nadav Kashtan, Uri Alon
PLoS Comput Biol 4(11): e1000206.

Abstract: One of the striking features of evolution is the appearance of novel structures in organisms. Recently, Kirschner and Gerhart have integrated discoveries in evolution, genetics, and developmental biology to form a theory of facilitated variation (FV). The key observation is that organisms are designed such that random genetic changes are channeled in phenotypic directions that are potentially useful. An open question is how FV spontaneously emerges during evolution. Here, we address this by means of computer simulations of two well-studied model systems, logic circuits and RNA secondary structure. We find that evolution of FV is enhanced in environments that change from time to time in a systematic way: the varying environments are made of the same set of subgoals but in different combinations. We find that organisms that evolve under such varying goals not only remember their history but also generalize to future environments, exhibiting high adaptability to novel goals. Rapid adaptation is seen to goals composed of the same subgoals in novel combinations, and to goals where one of the subgoals was never seen in the history of the organism. The mechanisms for such enhanced generation of novelty (generalization) are analyzed, as is the way that organisms store information in their genomes about their past environments. Elements of facilitated variation theory, such as weak regulatory linkage, modularity, and reduced pleiotropy of mutations, evolve spontaneously under these conditions. Thus, environments that change in a systematic, modular fashion seem to promote facilitated variation and allow evolution to generalize to novel conditions.

Post-admixture selection among Mexican Americans?

2008-11-05T09:09:00.002-07:00

This paper examines the variation in admixture proportions across the genome at 284 microsatellite markers among 392 Mexican Americans. They find increased European ancestry on a region of chromosome 1, and decreased African ancestry on Chromosomes 2 and 9 (see figure on right: "Genome-wide distribution of African (bottom line), European (top line) and Native American (middle line) ancestry. The dashed vertical lines correspond to chromosome boundaries. Chromosomes are listed in numerical order from 1 to 22")
Since the markers are widely spaced out, they couldn't pinpoint any specific genes. Interestingly, these results differ pretty dramatically compared to a previous similar study among Puerto Ricans. Also, interestingly, since they had people who were hypertensive or had diabetes, and people who didn't, they were able to determine that the identified regions were not associated with these health outcomes, since the local ancestry at those areas was no different between cases and controls.
They do make some mention at the end that they might expect selection at infectious-disease related genes given that the ancestral parental populations that had adapted to specific environments were suddenly faced with different environments.

Genome-wide distribution of ancestry in Mexican Americans
Analabha Basu, Hua Tang, Xiaofeng Zhu, C. Charles Gu, Craig Hanis, Eric Boerwinkle and Neil Risch
Human Genetics Volume 124, Number 3 / October, 2008

Abstract Migrations to the new world brought together individuals from Europe, Africa and the Americans. Inter-mating between these migrant and indigenous populations led to the subsequent formation of new admixed populations, such as African and Latino Americans. These unprecedented events brought together genomes that had evolved independently on different continents for tens of thousands of years and presented new environmental challenges for the indigenous and migrant populations, as well as their offspring. These circumstances provided novel opportunities for natural selection to occur that could be reflected in deviations at specific locations from the genome-wide ancestry distribution. Here we present an analysis examining European, Native American and African ancestry based on 284 microsatellite markers in a study of Mexican Americans from the Family Blood Pressure Program. We identified two genomic regions where there was a significant decrement in African ancestry (at 2p25.1, p less than 10⁻⁸ and 9p24.1, p less than 2 × 10⁻⁵) and one region with a significant increase in European ancestry (at 1p33, p less than 2 × 10⁻⁵). These locations may harbor genes that have been subjected to natural selection after the ancestral mixing giving rise to Mexicans.

Another EDAR - hair thickness association study

2008-11-02T10:56:00.003-07:00

A SNP in EDAR has been found to be associated with hair thickness among SE Asians and increased expression of this gene results in mice with thicker hair (via p-ter at GNXP). This study looks at the association among a Japanese sample and compare it to the Southeast Asian sample. Interestingly, there are considerable differences in hair thickness between Japanese and Southeast Asians:

"JPN individuals have more than 30% larger mean cross-sectional area (6,518 'units') than SEA (4,957 'units') and more than 50% larger than Africans (4,274 'units') and Caucasians (3,857 'units') (12)."

Since population origin also explains variation in hair thickness, the EDAR SNP "1540T/C by itself cannot explain all the differentiation of hair fiber thickness between JPN and SEA" and other genetic and environmental factors must be responsible.

They do a control for population stratification, but it would have been interesting to see a STRUCTURE output of their sample. I assume there wasn't that much stratification in terms of the 23 markers that they chose to look at (those with high 'JPN+CHN vs. the rest of the HapMap pops' differentiation)

A replication study confirmed the EDAR gene to be a major contributor to population differentiation regarding head hair thickness in Asia
Akihiro Fujimoto, Jun Ohashi, Nao Nishida, Taku Miyagawa, Yasuyuki Morishita, Tatsuhiko Tsunoda, Ryosuke Kimura and Katsushi Tokunaga
Human Genetics V. 124, Number 2 / September, 2008

Abstract Hair morphology is a highly divergent phenotype among human populations. We recently reported that a nonsynonymous SNP in the ectodysplasin A receptor (EDAR 1540T/C) is associated with head hair fiber thickness in an ethnic group in Thailand (Thai-Mai) and an Indonesian population. However, these Southeast Asian populations are genetically and geographically close, and thus the genetic contribution of EDAR to hair morphological variation in the other Asian populations has remained unclear. In this study, we examined the association of 1540T/C with hair morphology in a Japanese population (Northeast Asian). As observed in our previous study, 1540T/C showed a significant association with hair cross-sectional area (P = 2.7 × 10−6) in Japanese. When all populations (Thai-Mai, Indonesian, and Japanese) were combined, the association of 1540T/C was stronger (P = 3.8 × 10−10) than those of age, sex, and population. These results indicate that EDAR is the genetic determinant of hair thickness as well as a strong contributor to hair fiber thickness variation among Asian populations.

Gene-language co-evolution in Melanesia

2008-11-01T10:36:00.003-06:00

This paper, authored by fellow UNM anthropologists, looks at the nature of the relationship between genetic and linguistic variation in Melanesia.
Kambiz and Razib have both commented on this paper.

Genetic and Linguistic Coevolution in Northern Island Melanesia
Keith Hunley, Michael Dunn, Eva Lindström, Ger Reesink, Angela Terrill, Meghan E. Healy, George Koki, Françoise R. Friedlaender, Jonathan S. Friedlaender
PLoS Genetics

Abstract: Recent studies have detailed a remarkable degree of genetic and linguistic diversity in Northern Island Melanesia. Here we utilize that diversity to examine two models of genetic and linguistic coevolution. The first model predicts that genetic and linguistic correspondences formed following population splits and isolation at the time of early range expansions into the region. The second is analogous to the genetic model of isolation by distance, and it predicts that genetic and linguistic correspondences formed through continuing genetic and linguistic exchange between neighboring populations. We tested the predictions of the two models by comparing observed and simulated patterns of genetic variation, genetic and linguistic trees, and matrices of genetic, linguistic, and geographic distances. The data consist of 751 autosomal microsatellites and 108 structural linguistic features collected from 33 Northern Island Melanesian populations. The results of the tests indicate that linguistic and genetic exchange have erased any evidence of a splitting and isolation process that might have occurred early in the settlement history of the region. The correlation patterns are also inconsistent with the predictions of the isolation by distance coevolutionary process in the larger Northern Island Melanesian region, but there is strong evidence for the process in the rugged interior of the largest island in the region (New Britain). There we found some of the strongest recorded correlations between genetic, linguistic, and geographic distances. We also found that, throughout the region, linguistic features have generally been less likely to diffuse across population boundaries than genes. The results from our study, based on exceptionally fine-grained data, show that local genetic and linguistic exchange are likely to obscure evidence of the early history of a region, and that language barriers do not particularly hinder genetic exchange. In contrast, global patterns may emphasize more ancient demographic events, including population splits associated with the early colonization of major world regions.

Evolutionary perspective on the genetics of osteoporosis

2008-10-31T10:41:00.000-06:00

This review paper in Human Genetics discusses osteoporosis from an evolutionary and genetic perspective, and sometimes reads like a list of personal health guidelines (which is ok, I guess). I'm usually pretty reserved when it comes to criticizing papers on my blog, but I'm going to make an exception and say that this paper was somewhat disappointing, especially given that it was published in a high level journal: Human Genetics.
Ok, so first the obligatory point about how we are "stone age bodies living in a novel, modern world":

" ... current demographic trends will have the effect of altering what was once a positive adaptation for distinctive human bipedality into a serious set of “collateral” pathology among the modern elderly (Latimer 2005)."

...then a brief mention on the source of population differences: (I don't like the "Africans" generalization)

"Therefore, Africans more frequently have lactose intolerance, probably because they do not need as much vitamin D and calcium to maintain their (relatively strong) skeletons. On the contrary, skin depigmentation and high consumption of dairy products do not seem to protect Northern Europeans from fractures."

They also go on to explain the mechanism by which consumption of whole grain and milk products likely aggravates the risk of osteoporosis, which is pretty interesting.

He then briefly moves on to the genetics of osteoporosis with this statement which I find a bit hard to swallow, maybe just because I'm a too much of a hard-core adaptationist:

"It seems accurate to assume that if osteoporosis has a genetic determinant, its genetics will share peculiarity with the aging per se, being an example of “post-reproductive” genetics (Capri et al. 2008), which is difficult to explain by a selection process."

He argues that there would have been no selection against osteoporotic phenotypes since these cause problems later in life and would have no effect early in life, an argument which leaves me unconvinced:

"Therefore, children with a “pro-osteoporotic” bone architecture and lower bone mineralization were not selected against—which means, they were able to transfer their genes further on."

At the end of the paper are statements about the future of evolution in humans (which generally make me cringe):

"Is natural selection still a driving force in humans, given that our survival is often less dependent on genes than on technology?"

Osteoporosis: an evolutionary perspective
David Karasik
Human Genetics early online

Abstract: Increased life expectancy has led to an overall aging of the population and greater numbers of elderly people. Therefore, the number of people with osteoporosis has increased substantially, accompanied with an epidemic of hip fractures. Osteoporosis is an age-related systemic condition that naturally occurs, among mammals, only in humans. Osteoporosis is known to be highly heritable. However, assuming a genetic determinant for this post-reproductive disease to be transmitted from one generation to the next is counter-intuitive, based on the principles of human evolution, I will attempt to provide an explanation of the phenomenon from the point of view of evolution, selection, and changed environment in humans, which contributed to human longevity, while on other hand, contribute to diseases of civilization, including osteoporosis. There is a need to delve into evolution of human species in search for adaptive patterns to a specific environment that humans are operating in the last couple of millennia, to clarify whether “good” and “bad” genes exist, and how to find and correct them. The answer to the above questions will help us to identify causes of the current epidemic of osteoporosis and to pin-point a tailored treatment.

Predicting unobserved phenotypes from genotypic data

2008-10-28T09:07:00.006-06:00

This looks really interesting. The goal is to use whole genome SNP data to predict three phenotypes in mice (coal color, % of CD8+ cells, cellular hemoglobin), using "reversible jump MCMC". According to this website this is how RJMCMC works:

"– RJMCMC randomly “walks around” the space of possible model structures by changing one edge at a time – called structurallearning.
– At each step in its “walk”, all of the model parameters are updated
– called parametrical learning.
– At the end, you have a list of all of the model structures it visited at each step and their corresponding set of parameters."

They cite this recent paper that I posted about a few months ago that proposes a different way of looking simultaneously at the association between a collection of SNPs and some trait.
So, in this paper, they seem to be able to make decent predictions about these traits using about 12,000 SNPs in each of 2,300 mice. The correlations between observed and expexted phenotypes, using only genotype data, are in the range of .33 to .85.
There's really a lot of interesting things in this paper and I don't have to go over all of them.
I'll just end by mentioning that, as the authors state, if we were to do this in humans we would probably need many more markers and more individuals since the mice used in this experiment were from inbred lines with extended LD.

Predicting Unobserved Phenotypes for Complex Traits from Whole-Genome SNP Data
Sang Hong Lee, Julius H. J. van der Werf, Ben J. Hayes, Michael E. Goddard, Peter M. Visscher
PLoS Genet 4(10): e1000231.

Abstract: Genome-wide association studies (GWAS) for quantitative traits and disease in humans and other species have shown that there are many loci that contribute to the observed resemblance between relatives. GWAS to date have mostly focussed on discovery of genes or regulatory regions habouring causative polymorphisms, using single SNP analyses and setting stringent type-I error rates. Genome-wide marker data can also be used to predict genetic values and therefore predict phenotypes. Here, we propose a Bayesian method that utilises all marker data simultaneously to predict phenotypes. We apply the method to three traits: coat colour, %CD8 cells, and mean cell haemoglobin, measured in a heterogeneous stock mouse population. We find that a model that contains both additive and dominance effects, estimated from genome-wide marker data, is successful in predicting unobserved phenotypes and is significantly better than a prediction based upon the phenotypes of close relatives. Correlations between predicted and actual phenotypes were in the range of 0.4 to 0.9 when half of the number of families was used to estimate effects and the other half for prediction. Posterior probabilities of SNPs being associated with coat colour were high for regions that are known to contain loci for this trait. The prediction of phenotypes using large samples, high-density SNP data, and appropriate statistical methodology is feasible and can be applied in human medicine, forensics, or artificial selection programs.

Another study on European genetic structure

2008-10-24T09:25:00.001-06:00

...this time focused on Northern Europe, and especially Finland, using 250,000 SNPs, STRUCTURE, MDS plots and other measures of population differentiation.
see Dienekes' post for STRUCTURE output, and other comments.

I wanted to do this!! - Eating behavior at Chinese buffets

2008-10-22T16:28:00.000-06:00

Dang!!, I've always wanted to do a study like this, but these researchers beat me to the punch. The things they look at here are pretty interesting (and frankly, pretty funny), but they could have looked at the types of foods people were eating (ex: meat vs. other), SES, ethnicity etc.... Of course that would entail more complicated data collection... This reminds me of this great study.

Eating behavior and obesity at Chinese buffets.
Wansink B, Payne CR.
Obesity 2008 Aug;16(8):1957-60.

Abstract: The aim of this study was to investigate whether the eating behaviors of people at all-you-can-eat Chinese buffets differs depending upon their body mass. The resulting findings could confirm or disconfirm previous laboratory research that has been criticized for being artificial. METHODS AND PROCEDURES: Trained observers recorded the height, weight, sex, age, and behavior of 213 patrons at Chinese all-you-can-eat restaurants. Various seating, serving, and eating behaviors were then compared across BMI levels. RESULTS: Patrons with higher levels of BMI were more likely to be associated with using larger plates vs. smaller plates (OR 1.16, P less than 0.01) and facing the buffet vs. side or back (OR 1.10, P less than 0.001). Patrons with higher levels of BMI were less likely to be associated with using chopsticks vs. forks (OR 0.90,P less than 0.05), browsing the buffet before eating vs. serving themselves immediately (OR 0.92, P less than 0.001), and having a napkin on their lap vs. not having a napkin on their lap (OR 0.92, P less than 0.01). Patrons with lower BMIs left more food on their plates (10.6% vs. 6.0%, P less than 0.05) and chewed more per bite of food (14.8 vs. 11.9, P less than 0.001). DISCUSSION: These observational findings of real-world behavior provide support for laboratory studies that have otherwise been dismissed as artificial.

Hispanics and Alzheimer's: article in New York Times

2008-10-21T10:29:00.000-06:00

It looks like Hispanics have a disproportionately high prevalence of Alzheimer's and tend to develop it earlier, according to research cited in this New York Times article.
Genetic reasons are not favored, at least according to what the author of the article, Pam Belluck has gleaned:

"It is not that Hispanics are more genetically predisposed to Alzheimer’s, say experts, who say the diversity of ethnicities that make up Hispanics or Latinos make a genetic explanation unlikely."

...and what this researcher has found:

Dr. Rafael A. Lantigua, a professor of clinical medicine at Columbia University Medical School, said, “There’s no gene at this point that we can say this is just for Latinos.” Dr. Lantigua added that one gene that increased Alzheimer’s risk was less prevalent in Latinos than non-Hispanic whites.

More favored explanations are SES, "cultural dislocation", and depression.
The author goes on to describe several studies that have examined the etiology of population differences in Alzheimer's, one of them finding that higher acculturation to American society among Mexican Americans was associated with higher Alzheimer's risk.

Selection may not be responsible for worldwide variation in circadian clock genes

2008-10-19T17:23:00.000-06:00

some suggestive evidence, at most (look here for related post about PER2 gene variation):

Genetic differences in human circadian clock genes among worldwide populations.
Ciarleglio CM, Ryckman KK, Servick SV, Hida A, Robbins S, Wells N, Hicks J, Larson SA, Wiedermann JP, Carver K, Hamilton N, Kidd KK, Kidd JR, Smith JR, Friedlaender J, McMahon DG, Williams SM, Summar ML, Johnson CH.
J Biol Rhythms. 2008 Aug;23(4):330-40.

Abstract: The daily biological clock regulates the timing of sleep and physiological processes that are of fundamental importance to human health, performance, and well-being. Environmental parameters of relevance to biological clocks include (1) daily fluctuations in light intensity and temperature, and (2) seasonal changes in photoperiod (day length) and temperature; these parameters vary dramatically as a function of latitude and locale. In wide-ranging species other than humans, natural selection has genetically optimized adaptiveness along latitudinal clines. Is there evidence for selection of clock gene alleles along latitudinal/photoperiod clines in humans? A number of polymorphisms in the human clock genes Per2, Per3, Clock, and AANAT have been reported as alleles that could be subject to selection. In addition, this investigation discovered several novel polymorphisms in the human Arntl and Arntl2 genes that may have functional impact upon the expression of these clock transcriptional factors. The frequency distribution of these clock gene polymorphisms is reported for diverse populations of African Americans, European Americans, Ghanaians, Han Chinese, and Papua New Guineans (including 5 subpopulations within Papua New Guinea). There are significant differences in the frequency distribution of clock gene alleles among these populations. Population genetic analyses indicate that these differences are likely to arise from genetic drift rather than from natural selection.

Lipid profiles and African ancestry

2008-10-16T16:08:00.001-06:00

Previous research has found that African ancestry is associated with healthier lipid profiles, compared to European ancestry, and that people of African descent in the UK have lower coronary heart disease compared to whites. Since sex also mediates the risk of cardiovascular disease, this study investigates four variants on the Y-chromosome, in "579 men of different ethnic groups (blacks, South Asians, and whites) from UK and in 301 whites in Italy." All Black and South Asian men were first generation immigrants, so that might be why they don't do any kind of adjustment for differing admixture proportions. Given their conclusion:

"In our study, the men of black African origin carrying the A alleles of both TBL1Y and USP9Y had a more favorable lipoprotein profile, characterized by lower levels of serum triglycerides and higher levels of HDL-cholesterol, thus indicating the existence of a “cardio-protective haplotype.” In contrast, in white men, both from the UK and Italy, and in people of South Asian origin, the lipoprotein profiles were not affected by these genotypes."

...they then have a pretty good discussion of the weaknesses and alternative explanations of their findings. They don't really discuss any kind of adaptive or evolutionary explanation for the population differences, other than to mention, regarding which alleles are ancestral, that:

"The data presented here suggest that G allele of TBL1Y and T allele of USP9Y, reported as the wild-type alleles in whites (http://www.ncbi.nlm.nih.gov/SNP) may be derived from the A alleles of both genes, which are the most frequent in black people of African origin."

Genetic Variants of Y Chromosome Are Associated With a Protective Lipid Profile in Black Men
Paola Russo; Alfonso Siani; Michelle A. Miller; Sharada Karanam; Teresa Esposito; Fernando Gianfrancesco; Gianvincenzo Barba; Fabio Lauria; Pasquale Strazzullo;Francesco P. Cappuccio
Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1569.

Abstract Objective— Gender and ethnicity modulate the phenotypic expression of cardiovascular risk factors. In particular, men are at higher risk of developing cardiovascular diseases compared to women, whereas black populations of African origin display reduced mortality from coronary heart disease (CHD) as compared to both whites and South Asians. Because the male-specific region (MSY) of the human Y chromosome is an obvious candidate for gender-related differences in the development of cardiovascular diseases, we aimed to identify genetic variants of MSY influencing cardiovascular risk profile in different ethnic groups. Methods and Results— We genotyped 4 polymorphisms of MSY (HindIII±, rs768983 of TBL1Y, rs3212292 of USP9Y, and rs9341273 of UTY genes) in 579 men of different ethnic groups (blacks, South Asians, and whites) from UK and in 301 whites in Italy. We found that the TBL1YA USP9YA haplotype, present only in blacks in whom it represents the most frequent allelic combinations (AA: n=125; all other combinations: n=45), was associated with lower levels of triglycerides (P=0.025) and higher levels of HDL-cholesterol (P=0.005) as compared to the other haplotypes. Conclusion— The TBL1YA USP9YA haplotype of the Y chromosome, present only in black people of African origin, attributes a favorable lipoprotein pattern, likely to contribute to their reduced susceptibility to coronary heart disease. The study evaluated the association of genetic variants of the male-specific region of the Y chromosome with cardiovascular risk factors in different ethnic groups. The most frequently observed haplotype in black people was associated with a favorable lipoprotein pattern, thus contributing to the lower rate of cardiovascular diseases in blacks.

Baldness genetics

2008-10-15T11:00:00.001-06:00

Dan at Genetic Future has a great post on a couple of recent genome-wide association studies on male pattern baldness.

Genetic determinants of Vitamin D levels among Hispanics and African Americans

2008-10-14T09:23:00.001-06:00

This study has a large diverse sample and they look at the association between variants in three vitamin D related genes and vitamin D levels in the blood. They find an association between variants in the DBP (vitamin D Binding Protein gene) and plasma levels of 25(OH)D and 1,25(OH)2D in all three populations. I wonder how these polymorphisms differ in frequency and haplotype structure between groups.
Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans.
Corinne D. Engelman, Tasha E. Fingerlin, Carl D. Langefeld, Pamela J. Hicks, Stephen S. Rich, Lynne E. Wagenknecht, Donald W. Bowden and Jill M. Norris
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 9 3381-3388

Context: Vitamin D deficiency is associated with many adverse health outcomes, yet little is known about the genetic epidemiology of vitamin D or its metabolites. Objective: Our objective was to examine the relationship among three vitamin D-related genes and levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] in Hispanics (HAs) and African Americans (AAs). Design and Setting: The cross-sectional Insulin Resistance Atherosclerosis Family Study recruited and examined subjects in: Los Angeles, California (AAs; 513 individuals from 42 families); San Luis Valley (SLV), Colorado (HAs; 513 individuals from 30 families); and San Antonio (SA), Texas (HAs; 504 individuals from 58 families). Main Outcome Measures: Plasma levels of 25(OH)D and 1,25(OH)2D were measured. Results: Levels of 25(OH)D were highest in SLV-HAs [18.3 ± 7.7 ng/ml (45.7 ± 19.2 nmol/liter)], lower in SA-HAs [14.6 ± 6.4 ng/ml (36.4 ± 16.0 nmol/liter)], and lowest in AAs [11.0 ± 5.4 ng/ml (27.5 ± 13.5 nmol/liter)]. Levels of 1,25(OH)2D were similar in AAs [43.5 ± 13.9 pg/ml (113.1 ± 36.1 pmol/liter)] and SLV-HAs [43.2 ± 13.3 pg/ml (112.3 ± 34.6 pmol/liter)], but higher in SA-HAs [48.6 ± 17.0 pg/ml (126.4 ± 44.2 pmol/liter)]. After adjusting for gender and age within the site, two single nucleotide polymorphisms (SNPs) in the vitamin D binding protein gene (DBP), rs4588 and rs7041, were associated with 25(OH)D, and one SNP in the DBP, rs4588, was associated with 1,25(OH)2D at all three study centers. Conclusions: SNPs in the DBP are associated with levels of 25(OH)D and 1,25(OH)2D in HA and AA participants in the Insulin Resistance Atherosclerosis Family Study.

Why was lactase persistence selected for?

2008-10-09T09:17:00.001-06:00

This paper has been discussed by Razib at GNXP, and probably others. I thought I would take a closer look at it myself.
One of the main findings here is the north-south gradient within England in the frequency of the lactase persistence allele.
But they also examine relationships between this genotype and health measures in order to uncover the mechanism by which lactase persistence may have been selected for.
For example, did lactase persistence arise due to the benefits (sugar, protein, fat) or because it enabled one to avoid the ill effects of lactose non-persitence (adverse health reactions)? In this paper, they test for associations between the LCT genotype and various health-related measures.
They also have a good discussion about the selection pressures that may have led to the lactase persistence trait being favored. Among the hypotheses, many of which I had never heard of, as outlined in the paper:

1) "nutritional (and survival) advantage of milk consumption in populations that have milk availability"

2) "the calcium absorption hypothesis which considers the ability to use milk as of particular importance for high latitude
populations with low ultraviolet light exposure who are thus subject to potential vitamin D deficiency and poor calcium absorption and for whom the calcium absorption-stimulating effect of lactose would increase fitness."

3) "a reduced diarrhoeal disease mortality hypothesis that considers that, in populations that have become high consumers of milk, this consumption will increase risk of diarrhoeal disease in individuals who are not lactase persistent and thus select for lactase persistence"

4) specifically for African populations: "in arid regions with animal husbandry practices allowing access to milk, the ability to use milk has a selective advantage through the provision of water and electrolytes"

5) "the enhanced fertility by early weaning hypothesis that postulates that lactase persistence leads to earlier weaning and that earlier cessation of breastfeeding reduces the infertile period following each birth"

It doesn't seem like this study provides any conclusive or even suggestive evidence in favor or against any of these hypotheses, although there is some data that does goes against the diarrhea hypothesis:

"the consequences of prolonged childhood diarrhoeal disease that might be expected in survivors – shorter body height, leg length and perhaps higher blood pressure – were not seen in our data"

Lactase persistence-related genetic variant: population substructure and health outcomes
George Davey Smith, Debbie A Lawlor, Nic J Timpson, Jamil Baban, Matt Kiessling, Ian N M Day and Shah Ebrahim
European Journal of Human Genetics advance online

Abstract: Lactase persistence is an autosomal-dominant trait that is common in European-derived populations. A basic tendency for lactase persistence to increase from the southeast to the northwest across European populations has been noted, but such trends within countries have not been extensively studied. We genotyped the C/T-13910 variant (rs4988235) that constitutes the putatively causal allele for lactase persistence (T allele representing persistence) in a general population sample of 3344 women aged 60–79 years from 23 towns across Britain. We found an overall frequency of 0.253 for the C (lactase non-persistence) allele, but with considerable gradients of decreasing frequency from the south to the north and from the east to the west of Britain for this allele. Daily sunlight was positively related to C (non-persistence) allele prevalence. However, sunlight exposure and latitude are strongly correlated, and it was not possible to identify which is the primary factor statistically underlying the distribution of lactase persistence. The C/T-13910 variant (rs4988235) was not related to drinking milk or bone health (although drinking milk itself was protective of bone health), and was essentially unrelated to a wide range of other lifestyle, health and demographic characteristics. One exception was general health being rated as being poor or fair, for which there was an odds ratio of 1.38 (1.04, 1.84) for women homozygous for the C allele; on adjustment for latitude and longitude of place of birth, this attenuated to 1.19 (0.87, 1.64). The lactase persistence variant could contribute to the examination of data for the existence of, and then statistical control for, population substructure in genetic association studies.

Adipose tissue expandability explains onset of metabolic syndrome?

2008-10-08T15:28:00.000-06:00

When studying disease traits it is always preferable to understand all elements of the etiological pathway.
A recent paper in PLoS Biology titled "It's Not How Fat You Are, It's What You Do with It That Counts" describes the "Adipose Expandability Hypothesis" as a way of explaining why some individuals develop metabolic syndrome and why others don't, regardless of how obese they are. What matters is your ability to store fat. If you're good at it you can stave off further health complications. If you're not good at it, you start storing fat in organ tissue, leading to further health complications even if you have no excess body fat.

Predicting hair color from genes

2008-10-05T10:08:00.005-06:00

It seems like we're getting closer to understanding the genetic basis of traits like skin, hair and eye pigmentation. Although it is generally assumed that it will be difficult to fully grasp the genetics of complex traits, it could be within reach in the near-term for these types of traits. Understanding the genetic basis of these traits will provide some guiding principles for uncovering the genetic basis of more 'complex' complex traits, as well as about the evolutionary genetic process, population histories, and interactions with environmental factors.
So what do we learn from this paper (see abstract below) on the association between SLC45A2 variants and hair color among Polish subjects?
First, from the intro, with respect to predicting red hair color:

"Nowadays, red hair phenotype is being predicted using
assays that rely on examination of the single MC1R gene, and this allows correct inference in more than 90% of cases (Grimes et al. 2001; Branicki et al. 2007)."

Back to this study, they basically find a rare variant in SLC45A2 that increases a person's odds of having black hair by about seven.

Interestingly:

"However, in the present study, 3.6% of red-haired individuals were found to have the L374 allele associated with darker pigmentation. All of them had two MC1R alterations, which are considered as major function mutations strongly affecting receptor performance (data not present). All these individuals had fair skin and blue eyes. This indicates a predominant role of the MC1R gene."

Association of the SLC45A2 gene with physiological human hair colour variation
Wojciech Branicki, Urszula Brudnik, Jolanta Draus-Barini, Tomasz Kupiec and Anna Wojas-Pelc
Journal of Human Genetics Early online

Abstract: Pigmentation is a complex physical trait with multiple genes involved. Several genes have already been associated with natural differences in human pigmentation. The SLC45A2 gene encoding a transporter protein involved in melanin synthesis is considered to be one of the most important genes affecting human pigmentation. Here we present results of an association study conducted on a population of European origin, where the relationship between two non-synonymous polymorphisms in the SLC45A2 gene — rs26722 (E272K) and rs16891982 (L374F) — and different pigmentation traits was examined. The study revealed a significant association between both variable sites and normal variation in hair colour. Only L374F remained significantly associated with hair colour when both SNPs were included in a logistic regression model. No association with other pigmentation traits was detected in this population sample. Our results indicate that the rare allele L374 significantly increases the possibility of having black hair colour (OR = 7.05) and thus may be considered as a future marker for black hair colour prediction.

Ancient origin of genes associated with human genetic disease

2008-10-01T11:18:00.000-06:00

via Dienekes, an interesting paper on the temporal origin of disease-related genes.

An ancient evolutionary origin of genes associated with human genetic diseases
Tomislav Domazet-Loo and Diethard Tautz
Molecular Biology and Evolution

Abstract: Several thousand genes in the human genome have been linked to a heritable genetic disease. The majority of these appear to be non-essential genes (i.e. are not embryonically lethal when inactivated) and one could therefore speculate that they are late additions in the evolutionary lineage towards humans. Contrary to this expectation, we find that they are in fact significantly over-represented among the genes that have emerged during the early evolution of the metazoa. Using a phylostratigraphic approach, we have studied the evolutionary emergence of such genes at 19 phylogenetic levels. The majority of disease genes was already present in the eukaryotic ancestor and the second largest number has arisen around the time of evolution of multicellularity. Conversely, genes specific to the mammalian lineage are highly underrepresented. Hence, genes involved in genetic diseases are not simply a random subset of all genes in the genome, but are biased towards ancient genes.

Ethnicity, genetic variant at KCNMB1, sex, and asthma

2008-10-01T09:46:00.000-06:00

An african-specific functional polymorphism in KCNMB1 shows sex-specific association with asthma severity.
Seibold MA, Wang B, Eng C, Kumar G, Beckman KB, Sen S, Choudhry S, Meade K, Lenoir M, Watson HG, Thyne S, Williams LK, Kumar R, Weiss KB, Grammer LC, Avila PC, Schleimer RP, Burchard EG, Brenner R.
Hum Mol Genetics 2008 Sep 1;17(17):2681-90.

Abstract: A highly heritable and reproducible measure of asthma severity is baseline pulmonary function. Pulmonary function is largely determined by airway smooth muscle (ASM) tone and contractility. The large conductance, voltage and calcium-activated potassium (BK) channel negatively regulates smooth muscle tone and contraction in ASM. The modulatory subunit of BK channels, the beta1-subunit, is critical for proper activation of BK channels in smooth muscle and has shown sex hormone specific regulation. We hypothesized that KCNMB1 genetic variants in African Americans may underlie differences in bronchial smooth muscle tone and thus pulmonary function, possibly in a sex-specific manner. Through resequencing of the KCNMB1 gene we identified several common variants including a novel African-specific coding polymorphism (C818T, R140W). The C818T SNP and four other KCNMB1 variants were genotyped in two independent groups of African American asthmatics (n = 509) and tested for association with the pulmonary function measure--forced expiratory volume (FEV(1)) % of predicted value. The 818T allele is associated with a clinically significant decline (-13%) in FEV(1) in both cohorts of asthmatics among males but not females (P(combined) = 0.0003). Patch clamp electrophysiology studies of the BK channel expressed with the 140Trp variant of the beta1-subunit demonstrated significantly reduced channel openings, predicted by the loss of pulmonary function observed. African American male asthmatics carrying the 818T allele (10% of population) are potentially at risk for greater airway obstruction and increased asthma morbidity. Female asthmatics may be insulated from the deleterious effects of the 818T allele by estrogen-mediated upregulation in BK channel activity.

Is ethnic self-identification a good predictor of health risks?

2008-10-01T08:43:00.000-06:00

Ability of Ethnic Self-Identification to Partition Modifiable Health Risk Among US Residents of Mexican Ancestry.
Barger SD, Gallo LC.
Am J Public Health. 2008 Sep 17

Objectives. We examined the relationship between ethnic self-identification and the partitioning of health risk within a Mexican American population. Methods. We combined data from the 2000 to 2002 National Health Interview Surveys to obtain a large (N=10044) sample of US residents of Mexican ancestry. We evaluated health risk, defined as self-reported current smoking, overweight, and obesity, and compared the predictive strength of health risk correlates across self-identified Mexican and Mexican American participants. Results. Self-identified Mexican participants were less likely to smoke (odds ratio [OR]=0.70; 95% confidence interval[CI] = 0.60, 0.83; P<.001) and to be obese (OR=0.66; 95% CI=0.56, 0.77; P<.001) than were self-identified Mexican American participants. Within-group analyses found that sociodemographic predictors had inconsistent and even contradictory patterns of association with health risk across the 2 subgroups. Health risk was consistently lower among immigrants relative to US-born participants. Ethnic self-identification effects were independent of socioeconomic status. Conclusions. US residents of Mexican ancestry showed substantial within-group differences in health risk and risk correlates. Ethnic self-identification is a promising strategy to clarify differential risk and may help resolve apparent discrepancies in health risk correlates in this literature.

Protective factor against breast cancer in Black women?

2008-09-25T10:43:00.002-06:00

Breast cancer incidence has been found to be higher in those with higher SES, and incidence is highest among Whites, followed by Blacks, then Asians and Hispanics. Using several previous studies, this study finds that the disparity in breast cancer risk between ethnic groups can be accounted for by differences in SES, except for the disparity between Blacks and others.

"In contrast, for the black population, seven of the eight
analyzed datasets showed no difference in the incidence
of breast cancer at highest level of SES compared to the
lowest level, with only one dataset demonstrating a statistically significant disparity (data set 1: IRR 1.39, lower limit of 95% CI=1.04). This suggests that, as opposed to the apparent contributory effect of high SES on breast cancer risk in white, Hispanic and Asian/Pacific-Islander women, the risk of breast cancer in black women may not be significantly modified by SES."

in the conclusion:

"As for black women, the overall lack of statistically significant incidence rate ratios in Table 1 suggests that SES effects do not play an important role in modifying the risk of breast cancer in this population. This suggestion is supported by Chlebowski’s analysis, in which adjustment for SES-correlated breast cancer risk factors failed to eliminate the differencein hazard ratio of between black women and women of other races. Taken together, these findings imply the presence of a protective factor, which is not modified by SES, against breast cancer in black women."

There's a brief mention at the end about the grade and aggressiveness of breast cancer among Black women.

Disparities in breast cancer incidence across racial/ethnic strata and socioeconomic status: a systematic review
Vainshtein J.
J Natl Med Assoc. 2008 Jul;100(7):833-9.

OBJECTIVES: A higher incidence of breast cancer has been reported both in white women and women of higher socioeconomic status (SES) compared to women of other races and lower SES, respectively. We explored whether differences in SES can account for disparities in breast cancer incidence between races. METHODS: We identified several studies published between 1990 and 2007 that addressed disparities in breast cancer incidence across racial and socioeconomic strata. For each study, we calculated incidence rate ratios (IRRs) for breast cancer incidence in the highest strata to lowest strata of SES for white, black, Hispanic and Asian/Pacific-Islander populations. We then used these IRRs to compare trends in SES and breast cancer incidence between races and across studies. RESULTS: The studies we identified revealed that the magnitude of the disparity in breast cancer incidence between races decreases with increasing SES. While individual census-tract based studies' methods of assessing the association between SES and breast cancer incidence did not identify consistent trends between races, adjustment for risk factors closely correlated with SES eliminated the statistical differences in breast cancer incidence between women of white, Hispanic and Asian/Pacific-Islander, but not black, ethnicity. CONCLUSION: We found that racial differences in breast cancer incidence can largely be accounted for by ethnic differences in SES among white, Hispanic and Asian/Pacific-Islander women, but not between these populations and black women. We further highlight important differences in methodology between previously published studies that may account for their disparate findings.

Four Stone Hearth Anthropology Blog Carnival

2008-09-24T08:55:00.001-06:00

I'm happy to be hosting the 50th edition of the Four Stone Hearth Anthropology Blog Carnival!
We've got a wide array of Anthropology topics. I'll go from social/cultural anthropology, then into archaeology, and then into biological anthropology.

Daniel at Neuroanthropology shares with us Alesha Sivartha's collection of drawings representing the domains of life and culture that brains might be devoted to dealing with. This is interesting in the sense that evolutionary psychologists have argued that the brain is not like a general purpose computer, but rather like a Swiss army knife with domain specific mechanisms evolved to deal with specific problems such as face recognition, social relationships, mental maps, etc..

Daniel has another interesting post about Race in the Race for President of the US, which reminds us that racial dynamics are never far from the lived experience of Americans.

Magnus Reuterdahl at Testimony at the Spade discusses Mark Twain's visit to Jonkoping, Sweden.

Terry Toohill, guest blogger at Remote Central, discusses the evidence and misconceptions surrounding the processes of evolution, and might I add, provides plenty of references.

Martin at Aardvarchaeology shares his experience with the trials and tribulations of archaeological digs in Sweden.

At the Southeast Asian Archaeology Newblog, we see that six new Neolithic burials from Sarawak from the Niah cave complex have been recently put on display.

"More significantly, the skeletons are of the Australomelanasoid affinity, which means they were natives of Sundaland (the geological land shelf on which much of island Southeast Asia sits on) and possibly represent the continuous habitation of the cave site rather part of the migratory group originating from Southern China that is thought to populate Southeast Asia in this period" (from 2-3 thousand years ago)

The past couple of weeks has seen several stories about Neanderthals.
As usual, John Hawks has a wealth of information and insight:

on the marine diet of Neanderthals
the complete mtDNA sequence of a Neanderthal
the new National Geographic series called "Neanderthal Code"

Still on the Neanderthal topic, Julien at A Very Remote Period Indeed reviews the new National Geographic series on Neanderthals. He focuses on the evidence for whether there were hostile or peaceful relations between modern Humans and Neanderthals, on the relative (and complementary) merit of fossil, archaeological and genetic data in interpreting what happened in the past. He closes with a discussion about the reconstruction of a face of a Neanderthal female, discussed on other blogs as well.

Afarensis also discusses a paper about Neanderthal brain size and maturation which argues that Neanderthals grew quickly but matured later than modern humans, suggesting that their overall life history was perhaps slower paced than that of modern humans. Afarensis also discusses the use of marine food resources by Neanderthals, before the most recent piece of evidence came out in PNAS.

Dienekes has his usual dizzying array of posts from a wide variety of topics in evolutionary and molecular anthropology.
I'll just point out the post on Stonehenge and how it has been dated more accurately, and how it has been suggested that it was a healing center.

Razib at GNXP has a great post on a recent NYT article about David Goldstein on the HapMap, selection and race. Many other bloggers (John Hawks, Genetic Future etc...) have also commented on this article. In this article David Goldstein questions the efficiency of the process by which we currently look for the genetic basis for disease (and intelligence).

Finally, let me point you to Kambiz's always excellent and thorough Anthropology.net blog. He has recently posted about a new study published in PLoS Genetics that examines how genes involved in the immune system can predict human mating patterns.

Calling for Four Stone Hearth Anthropology Blog Carnival submissions

2008-09-22T10:25:00.001-06:00

It's time for the 50th edition of the Four Stone Hearth Anthropology Blog Carnival, so please email your submissions to me at yannatunmdotedu.

The Fourth Stone Hearth is a blog carnival that specializes in anthropology in the widest (American) sense of that word. Here, anthropology is the study of humankind, throughout all times and places, focusing primarily on four lines of research:

archaeology
socio-cultural anthropology
bio-physical anthropology
linguistic anthropology

Each one of these subfields is a stone in our hearth.

You need not be a blogger that specializes in anthropology to host or participate, but the posts submitted should relate to some aspect of anthropology.

Are Indians destined to be diabetic?

2008-09-22T07:02:00.000-06:00

I came across this interesting commentary paper that discusses whether there any particularities about diabetes risk among Indians (in India that is; living in New Mexico forces me to make that clarification). It discusses diabetes from an evolutionary perspective, as well as the link between mitochondrial function and the etiology of diabetes.

Comparing genetic admixture methods

2008-09-21T20:25:00.000-06:00

Comparison of Statistical Methods for Estimating Genetic Admixture in a Lung Cancer Study of African Americans and Latinos.
Aldrich MC, Selvin S, Hansen HM, Barcellos LF, Wrensch MR, Sison JD, Quesenberry CP, Kittles RA, Silva G, Buffler PA, Seldin MF, Wiencke JK.
Am J Epidemiol. 2008 Sep 12. [Epub ahead of print]

Abstract: A variety of methods are available for estimating genetic admixture proportions in populations; however, few investigators have conducted detailed comparisons using empirical data. The authors characterized admixture proportions among self-identified African Americans (n = 535) and Latinos (n = 412) living in the San Francisco Bay Area who participated in a lung cancer case-control study (1998-2003). Individual estimates of genetic ancestry based on 184 informative markers were obtained from a Bayesian approach and 2 maximum likelihood approaches and were compared using descriptive statistics, Pearson correlation coefficients, and Bland-Altman plots. Case-control differences in individual admixture proportions were assessed using 2-sample t tests and logistic regression analysis. Results indicated that Bayesian and frequentist approaches to estimating admixture provide similar estimates and inferences. No difference was observed in admixture proportions between African-American cases and controls, but Latino cases and controls significantly differed according to Amerindian and European genetic ancestry. Differences in admixture proportions between Latino cases and controls were not unexpected, since cases were more likely to have been born in the United States. Genetic admixture proportions provide a quantitative measure of ancestry differences among Latinos that can be used in analyses of genetic risk factors.

Admixed EUR-EAS population

2008-09-15T09:44:00.001-06:00

Apparently, an admixed population where the admixture event happened 120 generations ago can be useful for admixture mapping, and for studying diseases that differ in prevalence between Europeans and East Asians. For some reason, my university is not giving me full text access which is frustrating.

A Genome-wide Analysis of Admixture in Uyghurs and a High-Density Admixture Map for Disease-Gene Discovery.

Am J Hum Genet. 2008 Aug 27. [Epub ahead of print]
Xu S, Jin L.

Abstract: Following up on our previous study, we conducted a genome-wide analysis of admixture for two Uyghur population samples (HGDP-UG and PanAsia-UG), collected from the northern and southern regions of Xinjiang in China, respectively. Both HGDP-UG and PanAsia-UG showed a substantial admixture of East-Asian (EAS) and European (EUR) ancestries, with an empirical estimation of ancestry contribution of 53:47 (EAS:EUR) and 48:52 for HGDP-UG and PanAsia-UG, respectively. The effective admixture time under a model with a single pulse of admixture was estimated as 110 generations and 129 generations, or admixture events occurred about 2200 and 2580 years ago for HGDP-UG and PanAsia-UG, respectively, assuming an average of 20 yr per generation. Despite Uyghurs' earlier history compared to other admixture populations, admixture mapping, holds promise for this population, because of its large size and its mixture of ancestry from different continents. We screened multiple databases and identified a genome-wide single-nucleotide polymorphism panel that can distinguish EAS and EUR ancestry of chromosomal segments in Uyghurs. The panel contains 8150 ancestry-informative markers (AIMs) showing large frequency differences between EAS and EUR populations (F(ST) greater than 0.25, mean F(ST) = 0.43) but small frequency differences (7999 AIMs validated) within both populations (F(ST) less than 0.05, mean F(ST) less than 0.01). We evaluated the effectiveness of this admixture map for localizing disease genes in two Uyghur populations. To our knowledge, our map constitutes the first practical resource for admixture mapping in Uyghurs, and it will enable studies of diseases showing differences in genetic risk between EUR and EAS populations.

New issue of Annual Review of Genomics and Human Genetics

2008-09-10T10:10:00.003-06:00

There's several interesting review papers in this new issue:

Genetic Predisposition to Breast Cancer: Past, Present, and Future
Clare Turnbull and Nazneen Rahman

In recent years, our understanding of genetic predisposition to breast cancer has advanced significantly. Three classes of predisposition factors, categorized by their associated risks of breast cancer, are currently known. BRCA1 and BRCA2 are high-penetrance breast cancer predisposition genes identified by genome-wide linkage analysis and positional cloning. Mutational screening of genes functionally related to BRCA1 and/or BRCA2 has revealed four genes, CHEK2, ATM, BRIP1, and PALB2; mutations in these genes are rare and confer an intermediate risk of breast cancer. Association studies have further identified eight common variants associated with low-penetrance breast cancer predisposition. Despite these discoveries, most of the familial risk of breast cancer remains unexplained. In this review, we describe the known genetic predisposition factors, expound on the methods by which they were identified, and consider how further technological and intellectual advances may assist in identifying the remaining genetic factors underlying breast cancer susceptibility.

African Genetic Diversity: Implications for Human Demographic History, Modern Human Origins, and Complex Disease Mapping
Michael C. Campbell and Sarah A. Tishkoff

Comparative studies of ethnically diverse human populations, particularly in Africa, are important for reconstructing human evolutionary history and for understanding the genetic basis of phenotypic adaptation and complex disease. African populations are characterized by greater levels of genetic diversity, extensive population substructure, and less linkage disequilibrium (LD) among loci compared to non-African populations. Africans also possess a number of genetic adaptations that have evolved in response to diverse climates and diets, as well as exposure to infectious disease. This review summarizes patterns and the evolutionary origins of genetic diversity present in African populations, as well as their implications for the mapping of complex traits, including disease susceptibility.

this one looks especially good:
Positive Selection in the Human Genome: From Genome Scans to Biological Significance

Joanna L. Kelley and Willie J. Swanson
Vol. 9: 143-160

Here we review the evidence for positive selection in the human genome and its role in human evolution and population differentiation. In recent years, there has been a dramatic increase in the use of genome-wide scans to identify adaptively evolving loci in the human genome. Attention is now turning to understanding the biological relevance and adaptive significance of the regions identified as being subject to recent positive selection. Examples of adaptively evolving loci are discussed, specifically LCT and FOXP2. Comprehensive studies of these loci also provide information about the functional relevance of the selected alleles. We discuss current studies examining the role of positive selection in shaping copy number variation and noncoding genomic regions and highlight challenges presented by the study of positive selection in the human genome.

Evolutionary ecology of "hot" in chilies

2008-09-03T17:09:00.000-06:00

Green chile season is underway here in New Mexico, so this paper is fitting.
They find that variation in production of Capsaicinoids (hot stuff) is explained by variation in the damage caused by a fungal pathogen of chili seeds...so the hot stuff protects the plants from pathogens. I assume they discuss other ecological factors (climate, maybe) that explain why other species of plants don't do this also. I bet green chile farmers in New Mexico would know a lot about this since they maintain lines of varying hotness (hot, medium, mild) and have to deal with "pests".

Evolutionary ecology of pungency in wild chilies
Joshua J. Tewksbury, Karen M. Reagan, Noelle J. Machnicki, Tomás A. Carlo, David C. Haak, Alejandra Lorena Calderón Peñaloza, and Douglas J. Levey
PNAS 2008 105:11808-11811

Abstract: The primary function of fruit is to attract animals that disperse viable seeds, but the nutritional rewards that attract beneficial consumers also attract consumers that kill seeds instead of dispersing them. Many of these unwanted consumers are microbes, and microbial defense is commonly invoked to explain the bitter, distasteful, occasionally toxic chemicals found in many ripe fruits. This explanation has been criticized, however, due to a lack of evidence that microbial consumers influence fruit chemistry in wild populations. In the present study, we use wild chilies to show that chemical defense of ripe fruit reflects variation in the risk of microbial attack. Capsaicinoids are the chemicals responsible for the well known pungency of chili fruits. Capsicum chacoense is naturally polymorphic for the production of capsaicinoids and displays geographic variation in the proportion of individual plants in a population that produce capsaicinoids. We show that this variation is directly linked to variation in the damage caused by a fungal pathogen of chili seeds. We find that Fusarium fungus is the primary cause of predispersal chili seed mortality, and we experimentally demonstrate that capsaicinoids protect chili seeds from Fusarium. Further, foraging by hemipteran insects facilitates the entry of Fusarium into fruits, and we show that variation in hemipteran foraging pressure among chili populations predicts the proportion of plants in a population producing capsaicinoids. These results suggest that the pungency in chilies may be an adaptive response to selection by a microbial pathogen, supporting the influence of microbial consumers on fruit chemistry.

European genetic structure

2008-09-01T08:20:00.001-06:00

There's been two recent papers that look at the relationship between geography/ethnicity and genetics in Europe. Dienekes has some excellent posts and pictures of these two papers (here, here), as well as at GNXP (here, here, here).

from the Nature paper:
an individual's DNA can be used to infer their geographic origin with surprising accuracy--often to within a few hundred kilometres.
and from a news story:

The map was so accurate that when Novembre's team placed a geopolitical map over their genetic "map", half of the genomes landed within 310 kilometres of their country of origin, while 90% fell within 700 km.

Long term cultural selection for male dominance traits?

2008-08-30T10:05:00.001-06:00

Male dominance rarely skews the frequency distribution of Y chromosome haplotypes in human populations
J. Stephen Lansing, Joseph C. Watkins, Brian Hallmark, Murray P. Cox, Tatiana M. Karafet, Herawati Sudoyo, and Michael F. Hammer
PNAS August 19, 2008 vol. 105 no. 33 11645-11650

Abstract: A central tenet of evolutionary social science holds that behaviors, such as those associated with social dominance, produce fitness effects that are subject to cultural selection. However, evidence for such selection is inconclusive because it is based on short-term statistical associations between behavior and fertility. Here, we show that the evolutionary effects of dominance at the population level can be detected using noncoding regions of DNA. Highly variable polymorphisms on the nonrecombining portion of the Y chromosome can be used to trace lines of descent from a common male ancestor. Thus, it is possible to test for the persistence of differential fertility among patrilines. We examine haplotype distributions defined by 12 short tandem repeats in a sample of 1269 men from 41 Indonesian communities and test for departures from neutral mutation-drift equilibrium based on the Ewens sampling formula. Our tests reject the neutral model in only 5 communities. Analysis and simulations show that we have sufficient power to detect such departures under varying demographic conditions, including founder effects, bottlenecks, and migration, and at varying levels of social dominance. We conclude that patrilines seldom are dominant for more than a few generations, and thus traits or behaviors that are strictly paternally inherited are unlikely to be under strong cultural selection.

Why look at genetic association one locus at a time when you can do several loci at a time?

2008-08-28T08:33:00.002-06:00

This looks pretty cool. They propose a method of doing association studies by considering several SNPs at once instead of one SNP at a time. Even though this makes biological sense, it seems like the analysis would get messy and cumbersome. They seem to address these issues and analyze their method on previous data sets. They use a "Bayesian inspired" method called: stochastic search maximisation algorithm.
I'll need to read this paper more closely to see exactly how this method compares to previous single-SNP analyses, one of which, they describe in the paper, is on T2D.

S imultaneous Analysis of All SNPs in Genome-Wide and Re-Sequencing Association Studies
Clive J. Hoggart, John C. Whittaker, Maria De Iorio, David J. Balding
PLoS Genetics 4(7)

Abstract: Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants, which is a plausible scenario for many complex diseases. We show that simultaneous analysis of the entire set of SNPs from a genome-wide study to identify the subset that best predicts disease outcome is now feasible, thanks to developments in stochastic search methods. We used a Bayesian-inspired penalised maximum likelihood approach in which every SNP can be considered for additive, dominant, and recessive contributions to disease risk. Posterior mode estimates were obtained for regression coefficients that were each assigned a prior with a sharp mode at zero. A non-zero coefficient estimate was interpreted as corresponding to a significant SNP. We investigated two prior distributions and show that the normal-exponential-gamma prior leads to improved SNP selection in comparison with single-SNP tests. We also derived an explicit approximation for type-I error that avoids the need to use permutation procedures. As well as genome-wide analyses, our method is well-suited to fine mapping with very dense SNP sets obtained from re-sequencing and/or imputation. It can accommodate quantitative as well as case-control phenotypes, covariate adjustment, and can be extended to search for interactions. Here, we demonstrate the power and empirical type-I error of our approach using simulated case-control data sets of up to 500 K SNPs, a real genome-wide data set of 300 K SNPs, and a sequence-based dataset, each of which can be analysed in a few hours on a desktop workstation.

Cultured melanocytes, genotypes and gene expression of skin color genes

2008-08-27T08:08:00.001-06:00

Analysis of Cultured Human Melanocytes Based on Polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P Loci
Anthony L Cook, Wei Chen, Amy E Thurber, Darren J Smit, Aaron G Smith, Timothy G Bladen, Darren L Brown, David L Duffy, Lorenza Pastorino, Giovanna Bianchi-Scarra, J Helen Leonard, Jennifer L Stow and Richard A Sturm
Journal of Investigative Dermatology advance online publication 24 July 2008;

Abstract: Single nucleotide polymorphisms (SNPs) within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P genes have been associated with natural variation of pigmentation traits in human populations. Here, we describe the characterization of human primary melanocytic cells genotyped for polymorphisms within the MATP, NCKX5, or OCA2 loci. On the basis of genotype, these cultured cells reflect the phenotypes observed by others in terms of both melanin content and tyrosinase (TYR) activity when comparing skin designated as either "White" or "Black". We found a statistically significant association of MATP-374L (darker skin) with higher TYR protein abundance that was not observed for any NCKX5-111 or OCA2 rs12913832 allele. MATP-374L/L homozygous strains displayed significantly lower MATP transcript levels compared to MATP-374F/F homozygous cells, but this did not reach statistical significance based on NCKX5 or OCA2 genotype. Similarly, we observed significantly increased levels of OCA2 mRNA in rs12913832-T (brown eye) homozygotes compared to rs12913832-C (blue eye) homozygous strains, which was not observed for MATP or NCKX5 gene transcripts. In genotype–phenotype associations performed on a collection of 226 southern European individuals using these same SNPs, we were able to show strong correlations in MATP-L374F, OCA2, and melanocortin-1 receptor with skin, eye, and hair color variation, respectively.

Genetics of T2D among Ashkenazi Jews: Replication and predictive value of genetic information

2008-08-25T08:04:00.002-06:00

Last year 10 loci associated with type-2 Diabetes (T2D) were identified in a WGAS (whole genome association study) and replicated in various large samples (Scott et al. 2007). Here, they assess the association between these 10 loci and T2D among Ashkenazi Jews in Israel (all four grandparents are Ashkenazi Jews). They find that most markers show similar ORs as the Scott et al. meta-analysis, and p-values lower than 0.1 for 7 out of the 10 loci. They then look at the predictive power of information on these 10 loci on the risk of developing T2D, and find that it is rather limited (at least among Ashkenazi Jews):

"Consistent with the previous findings showing that such set of SNPs may explain only a small fraction (2–3%) ofthe trait variation (Saxena et al. 2007), we have also found that the predictive value of these findings is relatively limited.
For most individuals, the genotypic information will only modestly alter their baseline risk to develop T2D. Only for a small fraction of the population (about 3%), the genetic information may indicate a decrease or increase of the baseline risk by twofold (upwards or downwards). Consequently, at present, the use of genetic information by clinicians for the identification of patients at risk to develop T2D does not seem too relevant. Nevertheless, it is important to emphasize that the value of gene discovery lies primarily in the understanding of the disease as a means to develop efficient therapies."

Type 2 diabetes susceptibility loci in the Ashkenazi Jewish population.
Bronstein M, Pisanté A, Yakir B, Darvasi A.
Human Genetics 2008 Aug;124(1):101-4.

Abstract: Until last year, type 2 diabetes (T2D) susceptibility loci have hardly been identified, despite great effort. Recently, however, several whole-genome association (WGA) studies jointly uncovered 10 robustly replicated loci. Here, we examine these loci in the Ashkenazi Jewish (AJ) population in a sample of 1,131 cases versus 1,147 controls. Genetic predisposition to T2D in the AJ population was found similar to that established in the previous studies. One SNP, rs7754840 in the CDKAL1 gene, presented a significantly stronger effect in the AJ population as compared to the general Caucasian population. This may possibly be due to the increased homogeneity of the AJ population. The use of the SNPs considered in this study, to identify individuals at high (or low) risk to develop T2D, was found of limited value. Our study, however, strongly supports the robustness of WGA studies for the identification of genes affecting complex traits in general and T2D in particular.

Olfactory receptor genetics in humans and chimpanzees

2008-08-22T16:45:00.001-06:00

Several studies of genetic signatures of selection in humans have found something going on with olfactory receptor genes, which has been difficult to interpret. Why would there be strong selection for smelling related traits in the lineage leading to humans (smelling rotting meat, tracking animals??).
In this paper, the authors look at OR (olfactory receptor) genes in humans, chimps and macaques, and finds that:

The pseudogenization rates and the numbers of genes affected by positive selection are also similar between humans and chimpanzees.

and

...approximately 25% of their functional gene repertoires are species specific due to massive gene losses. These findings suggest that the tempo of evolution of OR [olfactory receptor] genes is similar between humans and chimpanzees, but the OR gene repertoires are quite different between them.

Similar Numbers but Different Repertoires of Olfactory Receptor Genes in Humans and Chimpanzees
Yasuhiro Go, and Yoshihito Niimura
Molecular Biology and Evolution 2008 25(9):1897-1907

Abstract: Animals recognize their external world through the detection of tens of thousands of chemical odorants. Olfactory receptor (OR) genes encode proteins for detecting odorant molecules and form the largest multigene family in mammals. It is known that humans have fewer OR genes and a higher fraction of OR pseudogenes than mice or dogs. To investigate whether these features are human specific or common to all higher primates, we identified nearly complete sets of OR genes from the chimpanzee and macaque genomes and compared them with the human OR genes. In contrast to previous studies, here we show that the number of OR genes (810) and the fraction of pseudogenes (51%) in chimpanzees are very similar to those in humans, though macaques have considerably fewer OR genes. The pseudogenization rates and the numbers of genes affected by positive selection are also similar between humans and chimpanzees. Moreover, the most recent common ancestor between humans and chimpanzees had a larger number of functional OR genes (>500) and a lower fraction of pseudogenes (41%) than its descendents, suggesting that the OR gene repertoires are in a phase of deterioration in both lineages. Interestingly, despite the close evolutionary relationship between the 2 species, approximately 25% of their functional gene repertoires are species specific due to massive gene losses. These findings suggest that the tempo of evolution of OR genes is similar between humans and chimpanzees, but the OR gene repertoires are quite different between them. This difference might be responsible for the species-specific ability of odor perception.

BRCA1 mutation among Yorubans

2008-08-21T16:34:00.001-06:00

They seem to have found the second of 2 known BRCA1 founder mutations in individuals of African descent. Four out of 365 breast cancer patients have this BRCA1 Y101X mutation. Although BRCA1 mutations probably account for a small proportion of breast cancer cases, these mutations are highly penetrant and therefore strong predictors of breast cancer. They discuss how the identification of these population-specific mutations can be used for genetic screening strategies for breast cancer.
Evidence for an ancient BRCA1 mutation in breast cancer patients of yoruban ancestry.

Local recent selection in humans

2008-08-11T18:15:00.001-06:00

In this paper the authors use a combined Fst and haplotype block length approach to finding genes/areas that have been under strong recent selection in different populations: about 24 individuals each, of African American, European American, and Han Chinese descent, with 1.6 milion SNPs typed in each.
After identifying haplotype blocks, they compared the average Fst for all SNPs in each block between populations.
Genes involved in skin pigmentation for which they find evidence of positive selection:RAB27A, DCT, EGFR, ATRN, MATP.
They also find that many of the areas under selection are in non-genic locations. They mention the example of the lactase gene is an example of the functional variant being in a regulatory region -- see this recent, interesting article in Science regarding the issue of the importance of genic vs. nongenic variation in evolutionary change (which this picture refers to).
Another interesting finding which they discuss is the small amount of overlap between loci that they find and the loci that other groups have found to be under recent positive selection.

Identification of local selective sweeps in human populations since the exodus from Africa
Åsa Johansson and Ulf Gyllensten,
Hereditas Volume 145, Issue 3, Pages 126-1372008

ABSTRACT: Selection on the human genome has been studied using comparative genomics and SNP architecture in the lineage leading to modern humans. In connection with the African exodus and colonization of other continents, human populations have adapted to a range of different environmental conditions. Using a new method that jointly analyses haplotype block length and allele frequency variation (FST) within and between populations, we have identified chromosomal regions that are candidates for having been affected by local selection. Based on 1.6 million SNPs typed in 71 individuals of African American, European American and Han Chinese descent, we have identified a number of genes and non-coding regions that are candidates for having been subjected to local positive selection during the last 100 000 years. Among these genes are those involved in skin pigmentation (SLC24A5) and diet adaptation (LCT). The list of genes implicated in these local selective sweeps overlap partly with those implicated in other studies of human populations using other methods, but show little overlap with those postulated to have been under selection in the 5–7 myr since the divergence of the ancestors of human and chimpanzee. Our analysis provides focal points in the genome for detailed studies of evolutionary events that have shaped human populations as they explored different regions of the world.

Religious diversity driven by disease prevalence

2008-08-05T07:09:00.000-06:00

They find that countries with more diseases have more religions, presumably due to some kind of selection (individual, multi-level??) against out-group contact. This would seem to be a complex topic with plenty of potential confounds, many of which they seem to control for.
They invoke the optimal outbreeding hypothesis as to why out-group contact would be costly, but there is very scant evidence for this in humans. Then again, there's the paper I just posted about a few days ago that showed higher rates of obesity among multi-racial individuals, but I don't think that really counts in this context... Razib touches on some other potential examples here, ...as well on this paper.

Assortative sociality, limited dispersal, infectious disease and the genesis of the global pattern of religion diversity

Corey L. Fincher, Randy Thornhill
Proceedings of the Royal Society, B First Cite

Abstract: Why are religions far more numerous in the tropics compared with the temperate areas? We propose, as an answer, that more religions have emerged and are maintained in the tropics because, through localized coevolutionary races with hosts, infectious diseases select for three anticontagion behaviours: in-group assortative sociality; out-group avoidance; and limited dispersal. These behaviours, in turn, create intergroup boundaries that effectively fractionate, isolate and diversify an original culture leading to the genesis of two or more groups from one. Religion is one aspect of a group's culture that undergoes this process. If this argument is correct then, across the globe, religion diversity should correlate positively with infectious disease diversity, reflecting an evolutionary history of antagonistic coevolution between parasites and hosts and subsequent religion genesis. We present evidence that supports this model: for a global sample of traditional societies, societal range size is reduced in areas with more pathogens compared with areas with few pathogens, and in contemporary countries religion diversity is positively related to two measures of parasite stress.

Prevalence of obesity in multi-racial vs. mono-racial individuals

2008-08-02T10:25:00.005-06:00

Despite the weird sounding title (why "ethnic admixture adults "? ... why not: "ethnically admixed adults" or something like that?) this paper (see below) examines quite an interesting question.
Do mixed-race individuals have a higher prevalence of obesity than single-race individuals?
First off, they mention that there is a high proportion (20%) of individuals who report two or more ethnicities in Hawaii, compared to the rest of the US (2%).
The introduction does not state why they expect to see the difference that they are looking for.
They have a humongous sample size (n=215,000), but the data is based on self-report which may bias the results.

The highest prevalence of overweight was for Hawaiian/Latino men (88%,) and black/Latina women (74.5%). The highest prevalence of obesity occurred in Hawaiian/Latino men (53.7%) and Hawaiian women (39.2%). The prevalence of obesity in men and women with Asian/white, Hawaiian/white, Hawaiian/Asian, Latina/white, and Hawaiian/Asian/white ethnic admixtures was significantly higher (P less than 0.0001) than the average prevalence of the ethnic groups with whom they share a common ethnicity/race.

and the money line:

Across all of the ethnic admixtures, the prevalences for both overweight and obesity were similar to or higher than the average of the prevalence estimates for their shared ethnicities; in contrast, none of the admixture prevalences were less than the average of their component ethnicities.

I can't believe they don't provide very much discussion about some of the potential mechanisms that would underlie their findings. They do find that:

"a high caloric intake (e.g., calories from fat and alcohol) and exercise did modestly decrease this difference" (referring to difference in prevalence between ethnic admixturesand monorace adults)"

There might be social and psychological factors that bi-racials experience more often than mono-racials, and this may negatively influence their health.
Nevertheless, this study is interesting and the finding merits future exploration.

The Prevalence of Obesity in Ethnic Admixture Adults
Cheryl L. Albright, Alana D. Steffen, Lynne R. Wilkens, Brian E. Henderson and Laurence N. Kolonel
Obesity (2008) 16 5, 1138–1143. doi:10.1038/oby.2008.31

Abstract: Objective: To determine whether the prevalence of obesity in ethnic admixture adults varies systematically from the average of the prevalence estimates for the ethnic groups with whom they share a common ethnicity.Methods and Procedures: The sample included 215,000 adults who reported one or more ethnicities, height, weight, and other characteristics through a mailed survey.Results: The highest age-adjusted prevalence of overweight (BMI 25) was in Hawaiian/Latino men (88% ; n = 41) and black/Latina women (74.5% ; n = 79), and highest obesity (BMI 30) rates were in Hawaiian/Latino men (53.7% ; n = 41) and Hawaiian women (39.2% , n = 1,247). The prevalence estimates for most admixed groups were similar to or higher than the average of the prevalences for the ethnic groups with whom they shared common ethnicities. For instance, the prevalence of overweight/obesity in five ethnic admixtures—Asian/white, Hawaiian/white, Hawaiian/Asian, Latina/white, and Hawaiian/Asian/white ethnic admixtures—was significantly higher (P less than 0.0001) than the average of the prevalence estimates for their component ethnic groups.Discussion: The identification of individuals who have a high-risk ethnic admixture is important not only to the personal health and well-being of such individuals, but could also be important to future efforts in order to control the epidemic of obesity in the United States.

Polynesian chickens in the pre-Columbian Americas...maybe not, after all

2008-07-31T17:20:00.002-06:00

see here for the post about this from last year.

Indo-European and Asian origins for Chilean and Pacific chickens revealed by mtDNA
Jaime Gongora, Nicolas J. Rawlence, Victor A. Mobegi§, Han Jianlin, Jose A. Alcalde, Jose T. Matus, Olivier Hanotte, Chris Moran, Jeremy J. Austin, Sean Ulm, Atholl J. Anderson, Greger Larson, and Alan Cooper
PNAS

Abstract: European chickens were introduced into the American continents by the Spanish after their arrival in the 15th century. However, there is ongoing debate as to the presence of pre-Columbian chickens among Amerindians in South America, particularly in relation to Chilean breeds such as the Araucana and Passion Fowl. To understand the origin of these populations, we have generated partial mitochondrial DNA control region sequences from 41 native Chilean specimens and compared them with a previously generated database of ≈1,000 domestic chicken sequences from across the world as well as published Chilean and Polynesian ancient DNA sequences. The modern Chilean sequences cluster closely with haplotypes predominantly distributed among European, Indian subcontinental, and Southeast Asian chickens, consistent with a European genetic origin. A published, apparently pre-Columbian, Chilean specimen and six pre-European Polynesian specimens also cluster with the same European/Indian subcontinental/Southeast Asian sequences, providing no support for a Polynesian introduction of chickens to South America. In contrast, sequences from two archaeological sites on Easter Island group with an uncommon haplogroup from Indonesia, Japan, and China and may represent a genetic signature of an early Polynesian dispersal. Modeling of the potential marine carbon contribution to the Chilean archaeological specimen casts further doubt on claims for pre-Columbian chickens, and definitive proof will require further analyses of ancient DNA sequences and radiocarbon and stable isotope data from archaeological excavations within both Chile and Polynesia.

Diabetes and African admixture

2008-07-30T08:28:00.002-06:00

several interesting things in this paper:
- comparison of three admixture estimation methods and using various number of markers
- looking at the effect of admixture on association between diabetes and variants in diabetes candidate genes.

Probably the most important finding is the high proportion of African ancestry in females with diabetes, compared to female controls, male cases and controls.
Their interpretation:

If AA females with T2DM have genes of “African descent” that are involved in energy storage and expenditure, but also influence or are influenced by gender-specific pathways, when exposed to a westernized lifestyle, these individuals will be at an increased risk of obesity and subsequently developing T2DM.

also, their finding makes sense in terms of:

the unexplained increase in risk for having a family history of ESRD that is present among African American women, relative to men (Freedman et al. 2005; McClellan et al. 2007)

Exploration of the utility of ancestry informative markers for genetic association studies of African Americans with type 2 diabetes and end stage renal disease.
Keene KL, Mychaleckyj JC, Leak TS, Smith SG, Perlegas PS, Divers J, Langefeld CD, Freedman BI, Bowden DW, Sale MM.
Hum Genetics Online First 2008 Jul 25.

Abstract: Admixture and population stratification are major concerns in genetic association studies. We wished to evaluate the impact of admixture using empirically derived data from genetic association studies of African Americans (AA) with type 2 diabetes (T2DM) and end-stage renal disease (ESRD). Seventy ancestry informative markers (AIMs) were genotyped in 577 AA with T2DM-ESRD, 596 AA controls, 44 Yoruba Nigerian (YRI) and 39 European American (EA) controls. Genotypic data and association results for eight T2DM candidate gene studies in our AA population were included. Ancestral estimates were calculated using FRAPPE, ADMIXMAP and STRUCTURE for all AA samples, using varying numbers of AIMs (25, 50, and 70). Ancestry estimates varied significantly across all three programs with the highest estimates obtained using STRUCTURE, followed by ADMIXMAP; while FRAPPE estimates were the lowest. FRAPPE estimates were similar using varying numbers of AIMs, while STRUCTURE estimates using 25 AIMs differed from estimates using 50 and 70 AIMs. Female T2DM-ESRD cases showed higher mean African proportions as compared to female controls, male cases, and male controls. Age showed a weak but significant correlation with individual ancestral estimates in AA cases (r (2) = 0.101; P = 0.019) and in the combined set (r (2) = 0.131; P = 3.57 x 10(-5)). The absolute difference between frequencies in parental populations, absolute delta, was correlated with admixture impact for dominant, additive, and recessive genotypic models of association. This study presents exploratory analyses of the impact of admixture on studies of AA with T2DM-ESRD and supports the use of ancestral proportions as a means of reducing confounding effects due to admixture.