Predicting pigmentation phenotypes with genetic information

This is a very short paper and their methods are fairly simplistic. They pick some SNPs from the literature, and count the number of homozygous SNPs related to various pigmentation phenotypes.
Henry Louis Gates and "Extinct Paleo-Eskimo" are both predicted to have red hair!

Predicting homo pigmentation phenotype through genomic data: From neanderthal to James Watson
Caio C S Cerqueira, Vanessa R Paixão-Côrtes, Francis M B Zambra, Francisco M Salzano, Tábita Hünemeier, Maria-Cátira Bortolini
American Journal of Human Biology. Early View

Abstract:

Background:Human pigmentation is regulated by several genes acting at different stages of melanin formation. Functional and association studies have elucidated the role of several of these genes in pigmentation phenotypes. Forensic and evolutionary studies can benefit from this knowledge.
Objectives:To evaluate the reliability of the prediction of pigmentation phenotypes using a large database of genetic markers in individuals with known phenotypes; and from this try to predict the pigmentation phenotype of prehistoric Homo specimens and of contemporary individuals whose visible phenotypes are not known.
Methods:We compared predicted and observed phenotypic data through an analysis of 124 single nucleotide polymorphisms in 33 genic and seven intergenic regions of 30 subjects, five of them prehistoric, whose complete nuclear genomes are available in UCSC and PSU UCSC public databases.
Results:For the molecular predicted versus observed phenotypes, the percentage of agreement was as follows: freckles: 91; skin: 64; hair: 44; eyes: 36; total: 59; while the molecular predicted versus probable (no visible observation available; inferences based on ethnic population characteristics) it was, respectively, 83, 60, 42, 67, and 63. The difference between two sets is statistically nonsignificant (P = 0.75).
Conclusion:To our knowledge, this is the first article to examine the effect of a large number of genetics markers for phenotype prediction. The approach could be useful for forensic applications, as well as for the determination of possible phenotypes of extinct prehistoric individuals.

Antagonistic pleiotropy - the case for BRCA mutations

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

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?

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"

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

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

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

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?

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?

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

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

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?

...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

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.