PCA and natural selection

arXiv:1504.04543 [q-bio.PE]

Detecting genomic signatures of natural selection with principal component analysis: application to the 1000 Genomes data

Nicolas Duforet-Frebourg et al.

(Submitted on 8 Apr 2015)

Large-scale genomic data offers the perspective to decipher the genetic architecture of natural selection. To characterize natural selection, various analytical methods for detecting candidate genomic regions have been developed. We propose to perform genome-wide scans of natural selection using principal component analysis. We show that the common Fst index of genetic differentiation between populations can be viewed as a proportion of variance explained by the principal components. Looking at the correlations between genetic variants and each principal component provides a conceptual framework to detect genetic variants involved in local adaptation without any prior definition of populations. To validate the PCA-based approach, we consider the 1000 Genomes data (phase 1) after removal of recently admixed individuals resulting in 850 individuals coming from Africa, Asia, and Europe. The number of genetic variants is of the order of 36 millions obtained with a low-coverage sequencing depth (3X). The correlations between genetic variation and each principal component provide well-known targets for positive selection (EDAR, SLC24A5, SLC45A2, DARC), and also new candidate genes (APPBPP2, TP1A1, RTTN, KCNMA, MYO5C) and non-coding RNAs. In addition to identifying genes involved in biological adaptation, we identify two biological pathways involved in polygenic adaptation that are related to the innate immune system (beta defensins) and to lipid metabolism (fatty acid omega oxidation). PCA-based statistics retrieve well-known signals of human adaptation, which is encouraging for future whole-genome sequencing project, especially in non-model species for which defining populations can be difficult. Genome scan based on PCA is implemented in the open-source and freely available PCAdapt software.

Link

bioRxiv http://dx.doi.org/10.1101/018143

Fast principal components analysis reveals independent evolution of ADH1B gene in Europe and East Asia

Kevin J Galinsky et al.

Principal components analysis (PCA) is a widely used tool for inferring population structure and correcting confounding in genetic data. We introduce a new algorithm, FastPCA, that leverages recent advances in random matrix theory to accurately approximate top PCs while reducing time and memory cost from quadratic to linear in the number of individuals, a computational improvement of many orders of magnitude. We apply FastPCA to a cohort of 54,734 European Americans, identifying 5 distinct subpopulations spanning the top 4 PCs. Using a new test for natural selection based on population differentiation along these PCs, we replicate previously known selected loci and identify three new signals of selection, including selection in Europeans at the ADH1B gene. The coding variant rs1229984 has previously been associated to alcoholism and shown to be under selection in East Asians; we show that it is a rare example of independent evolution on two continents.

Link

Natural selection and ancient European DNA

A new preprint on the bioRxiv studies the same data as the recent Haak et al. paper, but focuses on natural selection in Europe. Until recently, selection could only be studied by looking at modern populations, but since selection is genetic change over time effected by the environment, it's possible that studies like this will be the norm in the future.

The new study seems to confirm the results of Wilde et al. on steppe groups, as the Yamnaya had a very low frequency of the HERC2 derived "blue eye" allele and a lower frequency of the SLC45A2 "light skin" allele than any modern Europeans. The Yamnaya seem to have been fixed for the other SLC24A5 "light skin" allele which seems to have been at high frequency in all ancient groups save the "Western Hunter Gatherers".

It seems that light pigmentation traits had already existed in pre-Indo-European Europeans (both farmers and hunter-gatherers) and so long-standing philological attempts to correlate them with the arrival of light-pigmented Indo-Europeans from the steppe (or indeed anywhere), and to contrast them with darker pre-Indo-European inhabitants of Europe were misguided. If anything, it seems that the "fairest of them all" were the Scandinavian hunter-gatherers, and a combination of light/dark pigmentation was also present in Neolithic farmers and Western Hunter Gatherers in various combinations.

It also seems that both the theory that lactose tolerance started with LBK farmers and the theory that it came to Europe from milk-drinking steppe Indo-Europeans were wrong, as this trait seems to be altogether absent in European hunter-gatherers, farmers, and Yamnaya, and make a very timid appearance in the Late neolithic/Bronze Age before shooting up in frequency to the present.

Another new development is the ability to predict "genetic height" from ancient DNA. I think this may be a little bit superfluous as you can predict "actual height" by measuring long bone lengths. On the other hand, actualized height depends not only on genetics but also on diet, disease, etc., so it's useful to look at genetic changes in such polygenic traits directly.

A big surprise was the presence of the derived EDAR allele in Swedish hunter-gatherers. This allele is very rare in modern Europeans and seems to have pleiotropic effects in East Asians. This raises the question why this allele (that was so successful in East Asians), never "took hold" in Europeans. One possibility is that it never provided an advantage to Europeans (I don't think anyone really knows what it's actually good for). Another is that Swedish hunter-gatherers simply didn't contribute much ancestry to modern Europeans and so the allele never got the chance to rise in frequency by much.

bioRxiv http://dx.doi.org/10.1101/016477

Eight thousand years of natural selection in Europe

Iain Mathieson et al.

The arrival of farming in Europe beginning around 8,500 years ago required adaptation to new environments, pathogens, diets, and social organizations. While evidence of natural selection can be revealed by studying patterns of genetic variation in present-day people, these pattern are only indirect echoes of past events, and provide little information about where and when selection occurred. Ancient DNA makes it possible to examine populations as they were before, during and after adaptation events, and thus to reveal the tempo and mode of selection. Here we report the first genome-wide scan for selection using ancient DNA, based on 83 human samples from Holocene Europe analyzed at over 300,000 positions. We find five genome-wide signals of selection, at loci associated with diet and pigmentation. Surprisingly in light of suggestions of selection on immune traits associated with the advent of agriculture and denser living conditions, we find no strong sweeps associated with immunological phenotypes. We also report a scan for selection for complex traits, and find two signals of selection on height: for short stature in Iberia after the arrival of agriculture, and for tall stature on the Pontic-Caspian steppe earlier than 5,000 years ago. A surprise is that in Scandinavian hunter-gatherers living around 8,000 years ago, there is a high frequency of the derived allele at the EDAR gene that is the strongest known signal of selection in East Asians and that is thought to have arisen in East Asia. These results document the power of ancient DNA to reveal features of past adaptation that could not be understood from analyses of present-day people.

Link (pdf)

Dark pigmentation of Eneolithic and Bronze Age kurgan groups from eastern Europe

This is a very exciting new study that seems to parallel some results from early west Europeans. The authors invoke selection as a possible cause for the massive change in frequency between the Bronze Age and present-day Ukrainians.

An invocation of selection as an explanation requires evidence population continuity, otherwise changes in allele frequency may involve migration of a new frequency-differentiated new population; for example, the massive change in pigmentation in North America over the last 500 years is not due to selection but to migration of Europeans. The authors cannot reject population continuity on the basis of mtDNA haplogroup frequencies, although autosomal data may be more informative for that purpose.

In any case, the fact that the limited sample from western Europe and the much more extensive sample from eastern Europe both show a darker pigmentation than modern Europeans does suggest that interesting changes happened in Europe over the last few thousand years and samples from more recent time periods may better determine the pace of this change.

From the paper:

In sum, a combination of selective pressures associated with living in northern latitudes, the adoption of an agriculturalist diet, and assortative mating may sufficiently explain the observed change from a darker phenotype during the Eneolithic/Early Bronze age to a generally lighter one in modern Eastern Europeans, although other selective factors cannot be discounted. The selection coefficients inferred directly from serially sampled data at these pigmentation loci range from 2 to 10% and are among the strongest signals of recent selection in humans.

UPDATE: 

The classical Greeks did of course notice that the inhabitants of the north Pontic hinterland, collectively known as Scythians, were extraordinarily light-pigmented. This would imply that major pigmentation change occurred in the steppe over a time span of Bronze Age-Classical Antiquity rather than Bronze Age-present; this would imply even higher selection coefficients (if selection over a population exhibiting continuity is at play).

The Scythians were also thought to be recent arrivals from the east so it is not clear if they were descended from the Bronze Age population of eastern Europe; the crazy selection coefficients that would need to be assumed if there was indeed population continuity might imply that Herodotus got it right again, and the Scythians did in fact arrive from elsewhere. That would of course also imply that people from Central Asia and Siberia (where the Scythians may have come from) were originally lighter than Europeans which does find support from an older study on southern Siberian remains. Ironically, if that is the case, it would mean that the famous light-pigmented mummies of different parts of Inner Asia may not be long-lost European descendants -- as it has sometimes been presumed on the basis of modern-day clines of pigmentation. As usual, ancient DNA continues to surprise.

PNAS doi: 10.1073/pnas.1316513111

Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y

Sandra Wilde et al.

Eye, hair, and skin pigmentation are highly variable in humans, particularly in western Eurasian populations. This diversity may be explained by population history, the relaxation of selection pressures, or positive selection. To investigate whether positive natural selection is responsible for depigmentation within Europe, we estimated the strength of selection acting on three genes known to have significant effects on human pigmentation. In a direct approach, these estimates were made using ancient DNA from prehistoric Europeans and computer simulations. This allowed us to determine selection coefficients for a precisely bounded period in the deep past. Our results indicate that strong selection has been operating on pigmentation-related genes within western Eurasia for the past 5,000 y.

Link

Brown-skinned, blue-eyed, Y-haplogroup C-bearing European hunter-gatherer from Spain (Olalde et al. 2014)

There is nothing like a little ancient DNA weirdness to start off 2014, which promises to be as exciting as 2013 was.

The new study La Brana 1 identifies it as ancestral in the SLC24A5 locus in which virtually all Europeans are derived. This comes in the heels of the Loschbour preprint which identified that sample from Luxembourg as also being ancestral. Taken together, it's now clear that hunter-gatherers from Mesolithic Western Europe were brown.

Curiously, it now seems that both Europe and India were (in part) inhabited by brown people and became lighter by a process of admixture + selection. The process went "all the way" in Europe, but a cline of pigmentation was sustained in India.

The other finding (not mentioned in the abstract) is that La Brana 1 belonged to Y-haplogroup C6! This is a low-frequency European clade of haplogroup C. So now, we have evidence that haplogroup C is not eastern Eurasian (as the presence of its subclades in Australia, India, East Asia, and the Americas might suggest), but a pan-Eurasian entity. It remains to be seen whether this C-in-Europe can be pushed further back in time, but finding it in Mesolithic Iberia reduces the chance that it's some random eastern Eurasian who made it to the outskirts of Europe recently.

Finally, La Brana 1 has derived alleles at loci associated with pathogen resistance. This might be important, because a common hypothesis is that Europeans developed this type of resistance during the Neolithic as they started interacting with the pathogens of domesticated species and started living in less-hygienic higher-density settlements.


Nature (2014) doi:10.1038/nature12960

Derived immune and ancestral pigmentation alleles in a 7,000-year-old Mesolithic European

Iñigo Olalde et al.

Ancient genomic sequences have started to reveal the origin and the demographic impact of farmers from the Neolithic period spreading into Europe1, 2, 3. The adoption of farming, stock breeding and sedentary societies during the Neolithic may have resulted in adaptive changes in genes associated with immunity and diet4. However, the limited data available from earlier hunter-gatherers preclude an understanding of the selective processes associated with this crucial transition to agriculture in recent human evolution. Here we sequence an approximately 7,000-year-old Mesolithic skeleton discovered at the La Braña-Arintero site in León, Spain, to retrieve a complete pre-agricultural European human genome. Analysis of this genome in the context of other ancient samples suggests the existence of a common ancient genomic signature across western and central Eurasia from the Upper Paleolithic to the Mesolithic. The La Braña individual carries ancestral alleles in several skin pigmentation genes, suggesting that the light skin of modern Europeans was not yet ubiquitous in Mesolithic times. Moreover, we provide evidence that a significant number of derived, putatively adaptive variants associated with pathogen resistance in modern Europeans were already present in this hunter-gatherer.

Link

GWAS study of pigmentation in four European countries

From the paper:

Males (M) have consistently lighter pigmentation (lower scored) than females (F) in all four countries. Among countries, the largest pigmentation difference is with Ireland, where, in our sample, individuals have lighter pigmentation or lower M index on average than in Poland, Italy, or Portugal. Hair pigmentation histogram (C) and boxplot by country (D) in 341 individuals showing the distribution of hair pigmentation and the differences among countries. In our sample, individuals from Northern European countries (Ireland, Poland) have on average lighter hair pigmentation than individuals from Southern European countries (Italy, Portugal). The distributions in males are similar to those in females in all countries except Ireland, where, in our sample, males have darker hair color than females (not shown). Eye pigmentation histogram (E) and boxplot by country (F) in 468 individuals showing the bimodal distribution of eye pigmentation and the differences among countries. Comparison with self-reported phenotypes shows that the two modes of the distribution correspond to blue and brown eye color, while individuals reporting green and hazel eye color have intermediate C’ values. As with hair pigmentation, in our sample, individuals from Northern European countries have on average lighter eye pigmentation than individuals from Southern European countries. 

...   

Interestingly, our analysis of variation in skin color in Europe demonstrates a consistent difference in skin color between the sexes. By the DermaSpectrometer M index measure, males are more lightly pigmented than females in each of the four European countries we studied. The same trend in M index was reported previously in a sample of European Americans [38]. Our results in populations of European ancestry contradict earlier anthropological studies that have concluded females are more lightly pigmented than males in most populations (reviewed in [2]). One potential reason for the conflicting results is the different instruments used. In early studies, which used the Evans Electric Limited (EEL) and Photovolt broad-spectrum spectrophotometers, skin pigmentation estimates may be confounded by the hemoglobin level to a greater extent than for the DermaSpectrometer used in the present study [46].

Some data (lower = lighter):

One thing of interest is that while Irish males/females are both lighter-eyed than other Europeans, including Poles from northern Europe, Irish females appear to be lighter-haired than Irish males (96.3 vs. 106.7), but no such substantial sex difference exists in the Poles in this trait (107.5 vs. 109.5). Sexual dimorphism seems to lean in the direction of lighter male skins and lighter female hair across the four countries.

Peter Frost has offered the theory that "gentlemen prefer blondes" because during the Ice Age boreal hunters lived a harsh lifestyle that killed many of them, but the remainder could not adopt a polygynous lifestyle, because provisioning for a wife was expensive. As a result, women had to compete for the remaining men, and men could be picky, preferring those with a "rare color advantage." It is not immediately clear to me how this might explain the Ireland vs. Poland differentiation, assuming it reflects a broader NW/NE trend, since NE Europeans are more likely to be descended from hunter-gatherers of the tundra-steppe.

PLoS ONE 7(10): e48294. doi:10.1371/journal.pone.0048294

Genome-Wide Association Studies of Quantitatively Measured Skin, Hair, and Eye Pigmentation in Four European Populations

Sophie I. Candille et al.

Pigmentation of the skin, hair, and eyes varies both within and between human populations. Identifying the genes and alleles underlying this variation has been the goal of many candidate gene and several genome-wide association studies (GWAS). Most GWAS for pigmentary traits to date have been based on subjective phenotypes using categorical scales. But skin, hair, and eye pigmentation vary continuously. Here, we seek to characterize quantitative variation in these traits objectively and accurately and to determine their genetic basis. Objective and quantitative measures of skin, hair, and eye color were made using reflectance or digital spectroscopy in Europeans from Ireland, Poland, Italy, and Portugal. A GWAS was conducted for the three quantitative pigmentation phenotypes in 176 women across 313,763 SNP loci, and replication of the most significant associations was attempted in a sample of 294 European men and women from the same countries. We find that the pigmentation phenotypes are highly stratified along axes of European genetic differentiation. The country of sampling explains approximately 35% of the variation in skin pigmentation, 31% of the variation in hair pigmentation, and 40% of the variation in eye pigmentation. All three quantitative phenotypes are correlated with each other. In our two-stage association study, we reproduce the association of rs1667394 at the OCA2/HERC2 locus with eye color but we do not identify new genetic determinants of skin and hair pigmentation supporting the lack of major genes affecting skin and hair color variation within Europe and suggesting that not only careful phenotyping but also larger cohorts are required to understand the genetic architecture of these complex quantitative traits. Interestingly, we also see that in each of these four populations, men are more lightly pigmented in the unexposed skin of the inner arm than women, a fact that is underappreciated and may vary across the world.

Link

When Eurasians got lighter skin

My default position is to doubt all molecular dates until I understand how they were derived. Nonetheless, these results seem broadly consistent with the idea that Eurasian modern humans got lighter as their ancestors moved into more northern latitudes of the Old World and replaced Neandertals and others earlier Eurasian occupants, and then they got really lighter post-LGM, and then some got really really lighter with mutations in genes such as SLC24A4 (not studied here).

I suppose we will really find out who got what mutation when only through ancient DNA.

Mol Biol Evol (2012) doi: 10.1093/molbev/mss207

The timing of pigmentation lightening in Europeans

Sandra Belezal et al.

The inverse correlation between skin pigmentation and latitude observed in human populations is thought to have been shaped by selective pressures favoring lighter skin in order to facilitate vitamin D synthesis in regions far from the equator. Several candidate genes for skin pigmentation have been shown to exhibit patterns of polymorphism that overlap the geospatial variation in skin color. However, little work has focused on estimating the timeframe over which skin pigmentation has changed and on the intensity of selection acting on different pigmentation genes. To provide a temporal framework for the evolution of lighter pigmentation, we used forward Monte Carlo simulations coupled with a rejection sampling algorithm to estimate the time of onset of selective sweeps and selection coefficients at four genes associated with this trait in Europeans: KITLG, TYRP1, SLC24A5, and SLC45A2. Using compound haplotype systems consisting of rapidly evolving microsatellites linked to one SNP in each gene, we estimate that the onset of the sweep shared by Europeans and East Asians at KITLG occurred about 30,000 years ago, after the out-of-Africa migration, while the selective sweeps for the European-specific alleles at TYRP1, SLC24A5, and SLC45A2 started much later, within the last 11,000-19,000 years, well after the first migrations of modern humans into Europe. We suggest that these patterns were influenced by recent increases in size of human populations, which favored the accumulation of advantageous variants at different loci.

Link

Selection for skin color: not so simple

Investigative Genetics 2011, 2:24 doi:10.1186/2041-2223-2-24

Contrasting signals of positive selection in genes involved in human skin color variation from tests based on SNP scans and resequencing

Johanna Maria de Gruijter et al.

Abstract (provisional)
Background
Numerous genome-wide scans conducted by genotyping previously-ascertained single nucleotide polymorphisms (SNPs) have provided candidate signatures of positive selection in various regions of the human genome, including in genes involved in pigmentation traits. However, it is unclear how well the signatures discovered by such haplotype-based test statistics can be reproduced in tests based on full resequence data. Four genes, OCA2, TYRP1, DCT and KITLG, implicated in human skin color variation, have shown evidence for positive selection in Europeans and East Asians in previous SNP-scan data. In the current study, we resequenced 4.7-6.7 kb of DNA from each of these genes in Africans, Europeans, East Asians and South Asians.

Results
Applying all commonly-used allele frequency distribution neutrality test statistics to the newly generated sequence data provided conflicting results in respect of evidence for positive selection. Previous haplotype-based findings could not be clearly confirmed. The application of Markov Chain Monte Carlo Approximate Bayesian Computation to these sequence data using a simple forward simulator revealed broad posterior distributions of the selective parameters for all four genes providing no support for positive selection. However, when we applied this approach to published sequence data on SLC45A2, another human pigmentation candidate gene, we could readily confirm evidence for positive selection as previously detected with sequence-based and some haplotype-based tests.

Conclusions
Overall, our data indicate that even genes that are strong biological candidates for positive selection and show reproducible signatures of positive selection in SNP scans do not always show the same replicability of selection signals in other tests, which should be considered in future studies on detecting positive selection in genetic data.

Link

Light-pigmented Caucasoids from prehistoric Siberia

This sample was previously tested for Y-chromosome and mtDNA polymorphisms.

The pigmentation-related loci tested can be seen in the labels of my post, which should lead you to some earlier studies on them.

Most individuals were found to be most similar to European than to East Asian or African individuals based on these loci, although some (2 from Andronovo) of them were more similar to East Asians or intermediate (1 from Tagar) between East Asians and Europeans.

Interestingly, 1 of the Andronovo Mongoloids (S07) was previously found to belong to Y chromosome haplogroup C(xC3), while the Caucasoid-Mongoloid individual from Tagar (S32) belonged to haplogroup R1a1.

It should be noted that the use of the term "European individual ancestry" does not mean that these individuals were from Europe, as no test to distinguish between European and Asian Caucasoids was performed, and we know from literary descriptions and occasional archaeological remains about the ancient presence of light-pigmented Caucasoids in Siberia.

From the paper:

The genotype for rs12913832 was obtained for 23 out of the 25 samples, and most had the G/G genotype (n=15), which indicates that at least 60% of ancient specimens were probably blue- or green-eyed individuals. The remaining samples had the A/G (n=5) or A/A (n=3) genotypes, which are predictive of brown eye color phenotype.

International Journal of Legal Medicine doi:10.1007/s00414-009-0348-5

Pigment phenotype and biogeographical ancestry from ancient skeletal remains: inferences from multiplexed autosomal SNP analysis

Caroline Bouakaze et al.

Abstract

In the present study, a multiplexed genotyping assay for ten single nucleotide polymorphisms (SNPs) located within six pigmentation candidate genes was developed on modern biological samples and applied to DNA retrieved from 25 archeological human remains from southern central Siberia dating from the Bronze and Iron Ages. SNP genotyping was successful for the majority of ancient samples and revealed that most probably had typical European pigment features, i.e., blue or green eye color, light hair color and skin type, and were likely of European individual ancestry. To our knowledge, this study reports for the first time the multiplexed typing of autosomal SNPs on aged and degraded DNA. By providing valuable information on pigment traits of an individual and allowing individual biogeographical ancestry estimation, autosomal SNP typing can improve ancient DNA studies and aid human identification in some forensic casework situations when used to complement conventional molecular markers.

Link

Selection in the human genome with HGDP samples

Genetic Future points me to a new paper on signatures of selection in the human genome. Also Gene Expression and John Hawks on the subject, in which he responds to criticism in the paper about his accelerated evolution theory. Go ahead and read these sources for commentary on the paper (which is open view anyway).

I would like to comment on this interesting bit:

In general, we find the evidence for selection on disease risk is not as conclusive as that for selection on pigmentation traits. One parsimonious explanation for this is that However, the role of the genetic architecture of a trait (the number of loci underlying a trait and their effect sizes and frequencies) in how it responds to selection remains largely unexplored. Since the genetic architecture of pigmentation is relatively simple (compared with other complex traits), perhaps a selection signal on this trait is more readily detected because it is selection on disease risk, assuming disease risk is under selection at all, is much weaker than selection on pigmentation.spread across fewer loci. On the other hand, this explanation may confuse cause and effect. Perhaps skin pigmentation has a simpler genetic architecture than other complex traits because it has been subject to recent strong selection—the first moves to a new phenotypic optimum are predicted to be on mutations of large fitness
effect (Orr 2002). So assuming a positive correlation between the effects of an allele on fitness and on a trait, it is also plausible that the relatively simple genetic architecture of skin pigmentation is actually a consequence of the strong selection that has acted on this phenotype. Further work on the interplay between genetic architecture and natural selection is needed to clarify these issues.

In my opinion, there is a fairly clear dependence of pigmentation with environment (exposure to solar radiation) and with geographical latitude. While disease load varied with time and social organization, natural selection for skin pigmentation has been fairly constant: it has always been "better" to possess a dark phenotype in Africa than it is in Europe or Asia.

Depigmentation of Caucasoids and Mongoloids was thus -in all likelihood- a continuous process which invariably resulted in lighter phenotypes compared to the original dark standard. This process initially involved response to reduced solar radiation, but may have been shaped at a later stage by other factors, such as ready access to vitamin D from milk products, or sexual selection for rare phenotypes that seems to have taken hold in northern Europe.

Genome Research doi:10.1101/gr.087577.108

Signals of recent positive selection in a worldwide sample of human populations

Joseph K. Pickrell et al.

Abstract

Genome-wide scans for recent positive selection in humans have yielded insight into the mechanisms underlying the extensive phenotypic diversity in our species, but have focused on a limited number of populations. Here, we present an analysis of recent selection in a global sample of 53 populations, using genotype data from the Human Genome Diversity-CEPH Panel. We refine the geographic distributions of known selective sweeps, and find extensive overlap between these distributions for populations in the same continental region but limited overlap between populations outside these groupings. We present several examples of previously unrecognized candidate targets of selection, including signals at a number of genes in the NRG–ERBB4 developmental pathway in non-African populations. Analysis of recently identified genes involved in complex diseases suggests that there has been selection on loci involved in susceptibility to type II diabetes. Finally, we search for local adaptation between geographically close populations, and highlight several examples.

Link

SLC45A2 and human hair color

Yann Klimentidis points me to this new article which shows a link between variations in the SLC45A2 gene and hair color.

Journal of Human Genetics doi: 10.1007/s10038-008-0338-3

Association of the SLC45A2 gene with physiological human hair colour variation

Wojciech Branicki et al.

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.

Link

More ASHG 2008 abstracts

The previous batch is here.

Analysis of East Asia Genetic Substructure: Population Differentiation and PCA Clusters Correlate with Geographic Distribution

Accounting for genetic substructure within European populations has been important in reducing type 1 errors in genetic studies of complex disease. As efforts to understand complex genetic disease are expanded to other continental populations an understanding of genetic substructure within these continents will be useful in design and execution of association tests. In this study, population differentiation(Fst) and Principal Components Analyses(PCA) are examined using >200K genotypes from multiple populations of East Asian ancestry(total 298 subjects). The population groups included those from the Human Genome Diversity Panel[Cambodian(CAMB), Yi, Daur, Mongolian(MGL), Lahu, Dai, Hezhen, Miaozu, Naxi, Oroqen, She, Tu, Tujia, Naxi, and Xibo], HapMap(CHB and JPT), and East Asian or East Asian American subjects of Vietnamese(VIET), Korean(KOR), Filipino(FIL) and Chinese ancestry. Paired Fst(Wei and Cockerham) showed close relationships between CHB and several large East Asian population groups(CHB/KOR, 0.0019; CHB/JPT, 00651; CHB/VIET, 0.0065) with larger separation with FIL(CHB/FIL, 0.014). Low levels of differentiation were also observed between DAI and VIET(0.0045) and between VIET and CAMB(0.0062). Similarly, small Fsts were observed among different presumed Han Chinese populations originating in different regions of mainland of China and Taiwan. For example, the four For PCA, the first two PCs showed a pattern of relationships that closely followed the geographic distribution of the different East Asian populations.corner groups were JPT, FIL, CAMB and MGL with the CHB forming the center group, and KOR was between CHB and JPT. Other small ethnic groups were also in rough geographic correlation with their putative origins. These studies have also enabled the selection of a subset of East Asian substructure ancestry informative markers(EASTASAIMS) that may be useful for future genetic association studies in reducing type 1 errors and in identifying homogeneous groups.

Worldwide Population Structure using SNP Microarray Genotyping

We genotyped 348 individuals sampled from 24 populations world-wide using the Affymetrix 250k NspI microarray chip. For context, we added matching genotypes from 210 HapMap individuals for a total of 250,823 loci genotyped in 543 individuals from 28 populations. We included populations from India and Daghestan to provide detail between the genetic poles of Western Europe, East Asia, and sub-Sahara Africa. With so many markers, principal components analyses reveal genetic differentiation between almost all identified populations in our sample. Northern and southern European populations (FST = 0.004, p <0.01) are statistically distinguishable, as are upper and lower caste groups in India (FST = 0.005, p <0.01). All individuals are accurately classified into continental groups, and even between closely-related populations, genetic- and self-classifications conflict for only a minority of individuals (e.g. ~2% between upper and lower Indian castes; k-means clustering.) As expected, the HapMap CHB+JPT, CEU, and YRI samples are most similar to our east Asian, west European, and African samples, respectively. The HapMap CEU samples and our northern European ancestry samples were both collected from Utah. Although individual samples cannot be reliably classified into their collection of origin, the groups are statistically distinguishable despite their high similarity (FST = 0.0005, n.s.). Our Japanese group is also statistically distinguishable from the HapMap JPT group (FST = 0.006, p <0.01), and in this comparison, most samples can be correctly classified. With such large numbers of genotypes, significant differences can be found even between very similar population samplings. Our results provide guidelines for researchers in selecting suitable control populations for case-control studies.

Frequency distribution and selection in 4 pigmentation genes in Europe

Pigmentation is one of the more obvious forms of variation in humans, particularly in Europeans where one sees more within group variation in hair and eye pigmentation than in the rest of the world. We studied 4 genes (SLC24A5, SLC45A2, OCA2 and MC1R) that are believed to contribute to the pigment phenotypes in Europeans. SLC24A5 has a single functional variant that leads to lighter skin pigmentation. Data on 83 populations worldwide (including 55 from our lab) show the variant (at rs1426654) has almost reached fixation in Europe, Southwest Asia, and North Africa, has moderate to high frequencies (.2-.9) throughout Central Asia, and has frequencies of .1-.3 in East and South Africa. The variant is essentially absent elsewhere. SLC45A2 also has a single functional variant (at rs16891982) associated with light skin pigmentation in Europe. Data on 84 populations worldwide show the light skin allele is nearly fixed in Northern Europe but has lower frequencies in Southern Europe, the Middle East and Northern Africa. In Central Asia the frequency of the SLC45A2 variant declines more quickly than the SLC24A5 variant. It is absent in both East and South Africa. In OCA2 we typed 4 SNPs (rs4778138, rs4778241, rs7495174, rs12913832) with a haplotype associated with blue eyes in Europeans. This haplotype shows a Southeastern to Northwestern pattern in Europe with frequencies of .25 (.05 homozygous) in the Adygei to .85 (.75 homozygous) in the Danes. In MC1R we typed 5 SNPs (rs3212345, rs3212357, rs3212363, C_25958294_10, rs7191944) that cover the entire MC1R gene and found a predominantly European haplotype that ranges in frequency from .35 to .65 in Europe, reaching its highest levels in Southwest Asia and Northwestern Europe. Extended Haplotype Heterozygosity (EHH) and normalized Haplosimilarity (nHS) show evidence of selection at SLC24A5 in not only our European and Southwest Asian populations but also our East African populations. Neither SLC45A2 or OCA2 showed evidence of selection in either test. MC1R did not show evidence of selection for our European specific haplotype but we did see some evidence both upstream and downstream in our nHS test in Europe.

Using principal components analysis to identify candidate genes for natural selection.

Genetic markers that differentiate populations are excellent candidates for natural selection due to local adaptation, and may shed light into physiological pathways that underlie disorders with varying frequencies around the world. Principal Components Analysis (PCA) has emerged as a powerful tool for the characterization and analysis of the structure of genomewide datasets. In prior work, we described an algorithm that can be used to select small subsets of genetic markers (SNPs) that correlate well with population structure, as captured by PCA. Our method can be used to detect SNPs that differentiate individuals from different geographic regions, or even neighboring subpopulations. We set out to explore the nature and properties of the genes where population-differentiating SNPs reside, by analyzing the publicly available Human Genome Diversity Panel dataset (650,000 SNPs for 1,043 individuals, 51 populations). Applying our SNP selection algorithms, we chose small subsets of SNPs that almost perfectly reproduce worldwide population structure as identified by PCA. We determined SNP panels both for population differentiation within seven geographic regions, as well as around the globe. We then explored the hypothesis that the selected SNPs attained their current worldwide allele frequency patterns as a response to the pressure of natural selection. Comparing our lists to recently published reports, we found a significant overlap with other genomewide scans for selection, thus validating our hypothesis. For example, EDAR (involved in the development of hair follicles) harbors the most differentiating SNPs in our world-wide panels. SNPs located in genes that are involved in skin and eye pigmentation (OCA2, MYO5C, HERC1, HERC2) are also among the top population differentiating markers. In East Asia, SNPs residing at the ADH cluster appear among the most important SNPs for population structure, while, in Europe, the same is true for genes that are involved in immune response to pathogens (CR1, DUOX2, TLR, and HLA). Finally, a comprehensive gene ontology analysis is presented.