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.

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

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

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!

...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

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

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

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?

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

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?

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

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

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

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?

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?!

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

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

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.