More selection on the X than in autosomes in humans

Mol Biol Evol (2014) doi: 10.1093/molbev/msu166

Evidence for Increased Levels of Positive and Negative Selection on the X Chromosome versus Autosomes in Humans

Krishna R. Veeramah et al.

Partially recessive variants under positive selection are expected to go to fixation more quickly on the X chromosome as a result of hemizygosity, an effect known as faster-X. Conversely, purifying selection is expected to reduce substitution rates more effectively on the X chromosome. Previous work in humans contrasted divergence on the autosomes and X chromosome, with results tending to support the faster-X effect. However, no study has yet incorporated both divergence and polymorphism to quantify the effects of both purifying and positive selection, which are opposing forces with respect to divergence. In this study, we develop a framework that integrates previously developed theory addressing differential rates of X and autosomal evolution with methods that jointly estimate the level of purifying and positive selection via modeling of the distribution of fitness effects (DFE). We then utilize this framework to estimate the proportion of nonsynonymous substitutions fixed by positive selection (α) using exome sequence data from a West African population. We find that varying the female to male breeding ratio (β) has minimal impact on the DFE for the X chromosome, especially when compared with the effect of varying the dominance coefficient of deleterious alleles (h). Estimates of α range from 46% to 51% and from 4% to 24% for the X chromosome and autosomes, respectively. While dependent on h, the magnitude of the difference between α values estimated for these two systems is highly statistically significant over a range of biologically realistic parameter values, suggesting faster-X has been operating in humans.

Link

An excess of X-chromosomal diversity in Africans

A new study provides important new data for African-Eurasian differences in the X-to-autosomal ratio of nucleotide diversity.

In my opinion, an explanation for this phenomenon might be found in the back-migration into Africa of Eurasian males (belonging to Y-haplogroup E). If a Eurasian man has offspring with an African woman, then the autosomal diversity of his offspring will be more than his and less than hers (*). For the pairing's daughters, 1 X chromosome will be contributed by the Eurasian man and 1 from the African woman. But, for its sons, 1 X chromosome will be contributed by the African woman only. Thus, X chromosomal diversity in descendants of such a mixed population will be higher because Africans will contribute 2/3 of the X chromosomes but only 1/2 of the autosomes.

(*) It will probably not be halfway between them, because some increase in diversity will be contributed by mutations (or equivalently archaic introgressions) that occured in the Eurasian and African lineages since their separation.

AJHG doi:10.1016/j.ajhg.2014.04.011

Contrasting X-Linked and Autosomal Diversity across 14 Human Populations

Leonardo Arbiza et al.

Contrasting the genetic diversity of the human X chromosome (X) and autosomes has facilitated understanding historical differences between males and females and the influence of natural selection. Previous studies based on smaller data sets have left questions regarding how empirical patterns extend to additional populations and which forces can explain them. Here, we address these questions by analyzing the ratio of X-to-autosomal (X/A) nucleotide diversity with the complete genomes of 569 females from 14 populations. Results show that X/A diversity is similar within each continental group but notably lower in European (EUR) and East Asian (ASN) populations than in African (AFR) populations. X/A diversity increases in all populations with increasing distance from genes, highlighting the stronger impact of diversity-reducing selection on X than on the autosomes. However, relative X/A diversity (between two populations) is invariant with distance from genes, suggesting that selection does not drive the relative reduction in X/A diversity in non-Africans (0.842 ± 0.012 for EUR-to-AFR and 0.820 ± 0.032 for ASN-to-AFR comparisons). Finally, an array of models with varying population bottlenecks, expansions, and migration from the latest studies of human demographic history account for about half of the observed reduction in relative X/A diversity from the expected value of 1. They predict values between 0.91 and 0.94 for EUR-to-AFR comparisons and between 0.91 and 0.92 for ASN-to-AFR comparisons. Further reductions can be predicted by more extreme demographic events in excess of those captured by the latest studies but, in the absence of these, also by historical sex-biased demographic events or other processes.

Link

Neandertal admixture in modern humans: some of it adaptive, some selected-against (Sankararaman et al. 2014)

From this paper, this should be of interest for those who argue if they are .1 or .2% more/less Neandertal than others based on commercial testing results:

Fourth, the standard deviation in Neanderthal ancestry among individuals from within the same population is 0.06–0.10%, in line with theoretical expectation (Supplementary Information section 3), showing that Neanderthal ancestry calculators that estimate differences on the order of a per cent18 are largely inferring statistical noise.

Also of interest, showing that while overall Neandertal ancestry in Eurasians is low (1+%), this average includes region where it is much higher, and indeed the majority:

The Neanderthal introgression map reveals locations where Neanderthal ancestry is inferred to be as high as 62% in east-Asian and 64% in European populations (Fig. 1b and Extended Data Fig. 2).

Finally:

We have shown that interbreeding of Neanderthals and modern humans introduced alleles onto the modern human genetic background that were not tolerated, which probably resulted in part from their contributing to male hybrid sterility. The resulting reduction in Neanderthal ancestry was quantitatively large: in the fifth of the genome with highest B, Neanderthal ancestry is 1.5460.15 times the genomewide average (Extended Data Table 4 and Supplementary Information section 9)22. If we assume that this subset of the genome was unaffected by selection, this implies that the proportion of Neanderthal ancestry shortly after introgression must have been >3%rather than the approximately 2% seen today. 

One of the lingering questions about Neandertal admixture is why there are no Neandertal Y-chromosomes or mtDNA in modern Eurasians. The disappearance of Neandertal mtDNA seems unlikely according to one study, but might be explained if negative selection was at play.

A different question is whether hybrid sterility was actually noticed by modern humans/Neandertals during the period of admixture. Modern societies have historically frowned upon mixture between diverged sapiens populations, even though there is no evidence that the offspring of, say, an African and a European are biologically disadvantaged. But, in the case of sapiens-Neandertal crossings, the offspring would have been biologically disadvantaged, a fact that may have been noticed over the span of a few generations.

Regardless of the historical dynamics of the admixture process, some of the Neandertal genome proved itself useful in its new sapiens hosts, and while the process may have been painful for the people involved, evolution found a way to use at least some of the material introduced to our species by our Neandertal cousins.

Nature (2014) doi:10.1038/nature12961

The genomic landscape of Neanderthal ancestry in present-day humans

Sriram Sankararaman

Genomic studies have shown that Neanderthals interbred with modern humans, and that non-Africans today are the products of this mixture1, 2. The antiquity of Neanderthal gene flow into modern humans means that genomic regions that derive from Neanderthals in any one human today are usually less than a hundred kilobases in size. However, Neanderthal haplotypes are also distinctive enough that several studies have been able to detect Neanderthal ancestry at specific loci1, 3, 4, 5, 6, 7, 8. We systematically infer Neanderthal haplotypes in the genomes of 1,004 present-day humans9. Regions that harbour a high frequency of Neanderthal alleles are enriched for genes affecting keratin filaments, suggesting that Neanderthal alleles may have helped modern humans to adapt to non-African environments. We identify multiple Neanderthal-derived alleles that confer risk for disease, suggesting that Neanderthal alleles continue to shape human biology. An unexpected finding is that regions with reduced Neanderthal ancestry are enriched in genes, implying selection to remove genetic material derived from Neanderthals. Genes that are more highly expressed in testes than in any other tissue are especially reduced in Neanderthal ancestry, and there is an approximately fivefold reduction of Neanderthal ancestry on the X chromosome, which is known from studies of diverse species to be especially dense in male hybrid sterility genes10, 11, 12. These results suggest that part of the explanation for genomic regions of reduced Neanderthal ancestry is Neanderthal alleles that caused decreased fertility in males when moved to a modern human genetic background.

Link

More on geographical divide between Asian and Melanesian types in Indonesia (Cox et al. 2010)

I had previously posted about a paper showing a sharp divide in Indonesia between "Asian" and "Melanesian" Y chromosomes. A reader alerts me to another paper from this year, which discovers this divide using autosomal and X chromosome polymorphisms.

From the paper:

this transition is shifted eastward relative to Wallace’s line—a boundary that separates the biogeographic regions of Asia and Wallacea. At its southern limit, Wallace’s line falls between the islands of Bali and Lombok (figure 1), which are separated by a deep-water sea channel that marks the southern edge of the Sunda
Shelf. During ice-age glacial advances, the Sunda land mass included Borneo, Bali, Java and Sumatra, together with mainland Southeast Asia. However, even in periods
of low sea level, deep water in Wallacea separated the Sunda shelf from the eastern landmass of Sahul (connecting New Guinea and Australia). While the distribution of
many flora and fauna conforms to Wallace’s line, the seafaring capabilities of human settlers to this region undoubtedly overcame this barrier to dispersal. Indeed, Asian ancestry exceeds 50 per cent as far east as the island of Alor, which is well within Wallacea and approximately 1000 km east of Bali, as well as on the island of Sulawesi, which is located east of Wallace’s line in the north (figure 1). Curiously, Wallace himself noted this difference, positing a second line in eastern Indonesia corresponding to changes in human phenotype (Wallace 1869; Cox 2008). Wallace’s second ‘phenotypic’ line broadly parallels the rapid decline in Asian admixture identified here. It is refreshing to see (for once) a paper which acknowledges that modern genetics did not discover the wheel but has to a large extent confirmed what previous generations of scientists, working with their eyes (and later their calipers) could plainly see.

A visually interesting figure from the paper illustrates what a "cline" actually is.

We can see how west of 120 degrees longitude there is a uniform area of Asian ancestry, then a sharp transition zone and then a fairly uniform area of Melanesian ancestry.

The above figure illustrates one of the arguments of those (like me) who assert that racial variation in humans is real: the fact that it geographically punctuated (no smooth cline). The smooth areas of uniformity east/west of 120deg deserve to be recognized as real entities.

For visual illustration, three examples from Deniker's The races of man: a New Caledonian woman representing an "eastern" Melanesian type, a group of people from Flores (where, according to the current paper Asian admixture runs at 62%), and finally a Javan man representing a "western" Indonesian Mongoloid type.

Proc. R. Soc. B (2010) 277, 1589–1596

doi:10.1098/rspb.2009.2041

Autosomal and X-linked single nucleotide polymorphisms reveal a steep Asian–Melanesian ancestry cline in eastern Indonesia and a sex bias in admixture rates

Murray P. Cox

Abstract

The geographical region between mainland Asia and New Guinea is characterized by numerous small islands with isolated human populations. Phenotypically, groups in the west are similar to their neighbours in mainland Southeast Asia, eastern groups near New Guinea are similar to Melanesians, and intervening populations are intermediate in appearance. A long-standing question is whether this pattern primarily reflects mixing between groups with distinct origins or whether natural selection has shaped this range of variation by acting differentially on populations across the region. To address this question, we genotyped a set of 37 single nucleotide polymorphisms that are evolutionarily independent, putatively neutral and highly informative for Asian–Melanesian ancestry in 1430 individuals from 60 populations spanning mainland Asia to Melanesia. Admixture analysis reveals a sharp transition from Asian to Melanesian genetic variants over a narrow geographical region in eastern Indonesia. Interestingly, this admixture cline roughly corresponds to the human phenotypic boundary noted by Alfred Russell Wallace in 1869. We conclude that this phenotypic gradient probably reflects mixing of two long-separated ancestral source populations—one descended from the initial Melanesian-like inhabitants of the region, and the other related to Asian groups that immigrated during the Paleolithic and/or with the spread of agriculture. A higher frequency of Asian X-linked markers relative to autosomal markers throughout the transition zone suggests that the admixture process was sex-biased, either favouring a westward expansion of patrilocal Melanesian groups or an eastward expansion of matrilocal Asian immigrants. The matrilocal marriage practices that dominated early Austronesian societies may be one factor contributing to this observed sex bias in admixture rates.

Link

Female-to-Male Breeding Ratio in Modern Humans (Labuda et al. 2010)

Related: Gender differences in reproductive success (Brown et al. 2009)

The American Journal of Human Genetics, 25 February 2010
doi:10.1016/j.ajhg.2010.01.029

Female-to-Male Breeding Ratio in Modern Humans—an Analysis Based on Historical Recombinations

Damian Labuda et al.

Abstract

Was the past genetic contribution of women and men to the current human population equal? Was polygyny (excess of breeding women) present among hominid lineages? We addressed these questions by measuring the ratio of population recombination rates between the X chromosome and the autosomes, ρX/ρA. The X chromosome recombines only in female meiosis, whereas autosomes undergo crossovers in both sexes; thus, ρX/ρA reflects the female-to-male breeding ratio, β. We estimated β from ρX/ρA inferred from genomic diversity data and calibrated with recombination rates derived from pedigree data. For the HapMap populations, we obtained β of 1.4 in the Yoruba from West Africa, 1.3 in Europeans, and 1.1 in East Asian samples. These values are consistent with a high prevalence of monogamy and limited polygyny in human populations. More mutations occur during male meiosis as compared to female meiosis at the rate ratio referred to as α. We show that at α ≠ 1, the divergence rates and genetic diversities of the X chromosome relative to the autosomes are complex functions of both α and β, making their independent estimation difficult. Because our estimator of β does not require any knowledge of the mutation rates, our approach should allow us to dissociate the effects of α and β on the genetic diversity and divergence rate ratios of the sex chromosomes to the autosomes.

Link

X-chromosome variation in global populations

The frappe analysis for K=7 using ~16k and ~19k X chromosome (top) and Chromosome 16 (bottom) SNPs is shown. The pattern is almost identical.

This showcases the fallacy of a common objection to the concept of "race", namely that it is "trait-specific" and by looking at one trait (or locus) we will arrive at one racial classification, while looking at another wew will arrive at another.

The fact that by looking at two completely independently inherited pieces of DNA we arrive at the same conclusion is strong visual evidence that race is neither (a) a subjective property which depends on which part of the genome we look at, nor (b) a holistic property that can only be inferred by looking at the individual in toto.

Genome Biology doi:10.1186/gb-2010-11-1-r10

Characterization of X-Linked SNP genotypic variation in globally-distributed human populations

Amanda M Casto et al.

Abstract

Background
The transmission pattern of the human X chromosome reduces its population size relative to the autosomes, subjects it to disproportionate influence by female demography, and leaves X-linked mutations exposed to selection in males. As a result, the analysis of X-linked genomic variation can provide insights into the influence of demography and selection on the human genome. Here we characterize the genomic variation represented by 16,297 X-linked SNPs genotyped in the CEPH human genome diversity project samples.

Results
We found that X chromosomes tend to be more differentiated between human populations than autosomes with several notable exceptions. Comparisons between genetically distant populations also showed an excess of X-linked SNPs with large allele frequency differences. Combining information about these SNPs with results from tests designed to detect selective sweeps, we identified two regions that were clear outliers from the rest of the X chromosome for haplotype structure and allele frequency distribution. We were also able to more precisely define the geographical extent of some previously described X-linked selective sweeps.

Conclusions
The relationship between male and female demographic histories is likely to be complex as evidence supporting different conclusions can be found in the same dataset. Although demography may have contributed to the excess of SNPs with large allele frequency differences observed on the X chromosome, we believe that selection is at least partially responsible. Finally, our results reveal the geographical complexities of selective sweeps on the X chromosome and argue for the use of diverse populations in studies of selection.

Link

ESHG 2009 abstracts

ESHG 2009 is in two weeks, and there are some very interesting abstracts, including a tantalizing new study on Y-chromosome haplogroup R1b1b2 (R-M269).

Phylogeography of human Y chromosome haplogroup R1b1b2 (R-M269) in Europe

F. Cruciani et al.

The human Y chromosome haplogroup R1b1b2 (R-M269) displays an extremely wide geographic distribution within Europe, with a decreasing frequency cline from Iberia (frequencies up to 90%) towards the Balkans (usually less than 10%). Previous studies have proposed that the observed R1b1b2 frequency cline is due to a population expansion from an Iberian Ice-age refugium after the LGM (Malaspina et al. 1998; Semino et al. 2000).

In this study, we explored the phylogeography of the human Y chromosome haplogroup R1b1b2 by analyzing more than 2,000 males from Europe. The haplogroup-defining marker M269 (Cruciani et al. 2002), and two additional internal markers (U106 and U152, Sims et al 2007) which identify internal branches (R1b1b2g and R1b1b2h) were analyzed. The paragroup R1b1b2*(xR1b1b2g, R1b1b2h) and the haplogroups R1b1b2g and R1b1b2h showed quite different frequency distribution patterns within Europe, with frequency peaks in the Iberian Peninsula, northern Europe and northern Italy/France, respectively. The overall frequency pattern of R1b1b2 haplogroup is suggestive of multiple events of migration and expansion within Europe rather than a single and uniform spread of people from an Iberian Ice-age refugium.

References:

Malaspina et al. (1998) Am J Hum Genet 63:847-860
Semino et al. (2000) Science 290:1155-1159
Cruciani et al. (2002) Am J Hum Genet 70:1197-1214
Sims et al. (2007) Hum Mutat 28:97

Note that in the abstract below, the authors refer to Slavopaionians, not Macedonians.

Y chromosome haplogroup R1a is associated with prostate cancer risk among Macedonian males

D. Plaseska-Karanfilska et al.

Prostate cancer (PC) is one of the most common male-specific cancers. Its incidence varies considerably between populations. Recent surveys suggest that PC is influenced by both genetic and environmental factors, although the etiology of the disease remains unknown in the majority of cases. Certain Y chromosomal lineages have been suggested to predispose individuals to prostate cancer in Japanese population, but no association has been found among Korean and Swedish patients. The aim of this study was to investigate the association between Y chromosomal haplogroups and predisposition to prostate cancer in Macedonian men. We studied 84 PC patients and 126 males from the general population of Macedonian ethnic origin. A total of 28 markers have been studied by multiplex PCR and SNaPshot analysis. Nineteen different Y haplogroups were determined; the most frequent being I1b-P37b, E3b1-M78, R1a-SRY 1532, R1b-P25 and J2b1a-M241. The frequency of R1a was significantly higher in PC patients (20.2%) in comparison with the controls (9.5%) [p=0.027; OR=2.41 (1.09-5.36)]. When stratified according to age, even stronger association was observed between haplogroup R1a and prostate cancer in patients of >65 years of age [p=0.004; OR=3.24 (1.41-7.46)]. Our results suggest that Y chromosome haplogroup R1a is associated with an increased prostate cancer risk in Macedonian men.

The genetic position of Western Brittany (Finistère, France) in the Celtic Y chromosome landscape

K. Rouault et al.

Brittany, a large peninsula located at the western part of France, is of particular interest because of its historical settlement and its relative geographic and cultural isolation. Brittany was invaded by waves of migration from Britain and Ireland between the 4th and 7th centuries and, therefore, belongs to the Brythonic branch of the Insular Celtic language. We have focused our study on the department of Finistère, the most western territorial unit of Brittany, and its administrative and historical areas. To explore the diversity of the Y-chromosome, we analyzed a total of 348 unrelated males using a combination of 23 biallelic markers and 12 microsatellite loci. The molecular analysis revealed that 82.2% of the Y chromosomes fell into haplogroup R1b, placing Finistère within the Western European landscape. Interestingly, at a microgeographical level, differences were detected by the haplogroup R1a* being confined to the south of the department, while haplogroups E3b, F, G, J2, K and R1a1 were found in the north. Nevertheless, geographical distribution of haplogroups and haplotypes suggested territorial homogeneity inside Finistère. Most of the Y-chromosomal gene pool in Finistère is shared with European, especially British, populations, thus corroborating the historical reports of ancient migrations to Brittany. Finally, the results are consistent with those obtained from classic genetic markers and support the Celtic paternal heritage of the Finistère population.

Mitochondrial Genome Diversity in Tungusic-speaking Populations (Even and Evenki) and Resettlement of Arctic Siberia After the Last Glacial Maximum

I. O. Mazunin et al.

The present study includes the Even/Evenki, hunters and reindeer-breeders, sampled from a few localities scattered across their vast geographic range encompassing low Yana-Indigirka-Kolyma in the west and the Sea of Okhotsk coast in the east. The mtDNA data show a very close affinity of the Even/Evenki with the Yukaghir, typical reindeer hunters, dominating in extreme northeastern Siberia until the middle of 18th century but now being on the brink of extinction. We found that the majority of mtDNA diversity in the Tungusic-speaking populations was accounted for by Siberian-East Eurasian lineages C2, C3, D2, D3, D4-D9 and G1. The similarity in the haplogroup C and D mtDNA intrinsic variation between the Even and Yukaghir populations is pronounced and indicates that the Even/Evenki harbor an essential portion of the ancestral Yukaghir pool. The phylogeography of the D4-D9 point to an early Neolithic phase expansion initiated northward to the northern and eastern perimeters of former Beringia. Concerning unique D2* lineage (Volodko et al. 2008), the network analysis encompassing four complete sequences, three of the Yukaghir from the low Indigirka-Kolyma region and one of the Evenk from the upper reaches of the Aldan River would suggest that the founding haplotype (1935-8683-14905) for D2* originated within western part of former Beringia. In the meanwhile, the core of the Even/Evenki mtDNA pool residing in the midst of the Yukaghir ancient territory would represent a recent amalgamation of the remnants of the Yukaghir and northern Tungusic-speakers (Even/Evenki) originated in the mid-Amur region.

X-chromosomal haplotypes in global human populations

V. A. Stepanov, I. Y. Khitrinskaya;

To reconstruct the origin and evolution of X-chromosomal lineages in global human populations we investigated the genetic diversity in 23 population samples (about 1500 individuals totally) using SNP markers in a single linkage disequilibrium region of ZFX gene. About sixty haplotypes belonging to 3 phylogenetic branches (A, B, and F) originated from the single African root were found in the total sample. Branch A includes mostly African haplotypes, whereas four major haplotypes belonging to different sub-branches of B (haplotype E8) and F (haplotypes H4, I3 and I11) were present in Eurasia. Major haplotype of the older branch B (E8) is almost evenly distributed among Eurasian populations. Haplotypes of the younger phylogenetic branches demonstrates clinal distribution with the sharp frequency changes from East to West. Haplotype H4 is presumably “Eastern-Eurasian”. It reaches the highest frequency in Eastern and South-Eastern Asians. Haplotypes I3 and I11 in the contrary show the clear frequency gradient from West to East with the highest frequency in Europeans, moderate frequency in Central Asia, and the minimal frequency in North-East and South-East Asia. The total level of genetic differentiation of global human populations estimated by the analysis of molecular variance of X-chromosomal haplotypes (Fst = 9.1%) is quite high and roughly corresponds to those measured for most other types of genetic markers except Y-chromosomal haplogroups which are characterized by the much higher level of between-population differences.

Dissecting the genetic make-up of Central Eastern Sardinia using a high density set of sex and autosomal markers

L. M. Pardo

Genetic isolates are valuable for identifying genetic variations underlying complex traits. However, prior knowledge of the genetic structure of the isolate is fundamental for carrying-out genome-wide association studies (GWAS) in these populations. The Sardinian population is currently the target of GWAS because of its ancient origin and long-standing isolation. To perform GWAS in Sardinia, we aim to characterize a subpopulation from the archaic area of Central-Eastern Sardinia at the genomic level. We used sex-specific markers (Y-chromosome and mtDNA) to assess the heterogeneity of the founder lineages and the divergence from other populations. In addition, we used a dense set of autosomal markers (SNP 5.0 array, Affymetrix) to investigate genome-wide Linkage Disequilibrium, to construct a Copy Number Variation map and to estimate pair-wise kinship and inbreeding.We first determined Y-chromosome lineages in 256 unrelated Sardinians using biallelic and microsatellite markers. Our analysis showed that the frequency of the major Y haplogroups clearly sets this population apart from other European haplogroups. The analysis of microsatellite markers revealed a high degree of gene diversity. Pairwise kinship and inbreeding were estimated in 113 subjects using 77709 autosomal SNP markers. We found that 16% of the subject pairs shared identical-by descent alleles more often than expected by chance. Furthermore, 60% of the subjects had low inbreeding coefficient values. Our preliminary results confirm that Sardinia is genetically different from other populations, as shown by Y-chromosome markers. The kinship and inbreeding estimates indicate some degree of relatedness among Sardinians, as expected for an isolated population.

Genetic differences between four European populations

V. Moskvina et al.

Population stratification can distort the results of genome-wide association studies (GWAS). One approach to deal with this inflation of the statistic is to estimate the inflation factor and adjust the detection statistic accordingly. However, the evolutionally forces work with different strength in some regions of the human genome, e.g. around the lactase gene (LCT) and the HLA region, making such an adjustment inappropriate.

We examined the population differences in four European populations (Scotland, Ireland, Sweden and Bulgaria) using data from GWAS performed with the Affymetrix 6.0 array at the Broad Institute. We show that there are >20,000 SNPs which are highly (p less than 10-6) significantly stratified between the four populations, after genome wide Bonferroni correction for multiple testing. We then examined the top 20 stratified regions to see what genes might have caused the top differences, using a highly conservative cut-off of p less than 10-40. Some of the loci span genes reported before: hair colour and pigmentation (HERC2, EXOC2), the LCT gene, genes involved in NAD metabolism, and genes involved in immunity (HLA and the Toll-like receptor genes TLR10, TLR 1, TLR 6). Among the top hits were several genes which have not yet been reported as stratified within European populations, indicating that they might also provide a selective advantage. Some involve other immunity genes (CD99, ILT6), but others show no obvious effect on positive selection: several zinc fingers, and most intriguingly, FOXP2, implicated in speech development. Future GWAS should take into consideration any positive associations with these genes.

Genomic runs of homozygosity: population history and disease

R. McQuillan

Runs of homozygosity (ROH), resulting from the inheritance from both parents of identical haplotypes, are abundant in the human genome. ROH length is determined partly by the number of generations since the common ancestor: offspring of cousin matings have long ROH, while the numerous shorter ROH reflect shared ancestry tens and hundreds of generations ago. In studies of European populations we show that Froh, a multipoint estimate of individual autozygosity derived from genomic ROH, distinguishes clearly between subpopulations classified in terms of demographic history and correlates strongly with pedigree-derived inbreeding coefficients. In a global population dataset, analysis of ROH allows categorisation of individuals into four major groups, inferred to have (a) parental relatedness in the last 150 years (many south and west Asians), (b) shared parental ancestry arising hundreds to thousands of years ago through population isolation and restricted effective population size (Ne), but little recent inbreeding (Oceanians, African hunter-gatherers, some European and south Asian isolates), (c) both ancient and recent parental relatedness (Native Americans), and (d) only the background level of shared ancestry relating to continental Ne (east Asians, urban Europeans; African agriculturalists). Long runs of homozygosity are therefore a widespread and underappreciated characteristic of our genomes which record past consanguinity and population isolation and provide a unique record of individual demographic history. Individual ROH measures also allow quantification of the disease risk arising from polygenic recessive effects. We present preliminary data from a survey of the effects of ROH on quantitative disease-related traits and disease risk.

European Lactase Persistence Allele is Associated With Increase in Body Mass Index

J. A. Kettunen et al.

The global prevalence of obesity, usually indexed by body mass index (BMI) cut-offs, has increased significantly in the recent decades, mainly due to positive energy balance. However, the impact of a selection for specific genes cannot be excluded. Here we have tested the association between BMI and one of the best known genetic variants showing strong selective pressure: the functional variant in the cis-regulatory element of the lactase gene. We tested this variant since it is presumed to provide nutritional advantage in specific physical and cultural environments. We found that the variant responsible for lactase persistence among Europeans was also associated with higher BMI in a Nordic population sample (p = 1.3*10-5) of 15 209 individuals, the size of the effect being close to that of FTO. We tested the effect of population stratification and concluded that the association was not due to population substructure.

X chromosomes and settling of Americas

Related:

• Concurrent but distinctive migrations into the Americas
• Three-stage colonization model for Americas reconsidered
• Craniofacial shape variation and Native American origins
• New synthesis on the first arrivals into the New World

American Journal of Physical Anthropology doi:10.1002/ajpa.21084

X-chromosome lineages and the settlement of the Americas

Stephane Bourgeois et al.

Abstract

Most genetic studies on the origins of Native Americans have examined data from mtDNA and Y-chromosome DNA. To complement these studies and to broaden our understanding of the origin of Native American populations, we present an analysis of 1,873 X-chromosomes representing Native American (n = 438) and other continental populations (n = 1,435). We genotyped 36 polymorphic sites, forming an informative haplotype within an 8-kb DNA segment spanning exon 44 of the dystrophin gene. The data reveal continuity from a common Eurasian ancestry between Europeans, Siberians, and Native Americans. However, the loss of two haplotypes frequent in Eurasia (18.8 and 7%) and the rise in frequency of a third haplotype rare elsewhere, indicate a major population bottleneck in the peopling of the Americas. Although genetic drift appears to have played a greater role in the genetic differentiation of Native Americans than in the latitudinally distributed Eurasians, we also observe a signal of a differentiated ancestry of southern and northern populations that cannot be simply explained by the serial southward dilution of genetic diversity. It is possible that the distribution of X-chromosome lineages reflects the genetic structure of the population of Beringia, itself issued from founder effects and a source of subsequent southern colonization(s).

Link

X chromosome diversity in Africans and non-Africans

From the paper:

The ratio of the tMRCA between chromosome X and the autosomes in West Africans, 0.763 ± 0.026, is consistent with the expected 3/4, but it is lower than 3/4 in non-African populations: 0.635 ± 0.024 in North Europeans and 0.613 ± 0.026 in East Asians (Table 2, Supplementary Note and Supplementary Table 2 online).

I am fairly allergic to explanations invoking genetic drift, and I think that both selection and demography might play a role in the observed discrepancy.

Nature Genetics doi:10.1038/ng.303

Accelerated genetic drift on chromosome X during the human dispersal out of Africa

Alon Keinan et al.

Abstract

Comparisons of chromosome X and the autosomes can illuminate differences in the histories of males and females as well as shed light on the forces of natural selection. We compared the patterns of variation in these parts of the genome using two datasets that we assembled for this study that are both genomic in scale. Three independent analyses show that around the time of the dispersal of modern humans out of Africa, chromosome X experienced much more genetic drift than is expected from the pattern on the autosomes. This is not predicted by known episodes of demographic history, and we found no similar patterns associated with the dispersals into East Asia and Europe. We conclude that a sex-biased process that reduced the female effective population size, or an episode of natural selection unusually affecting chromosome X, was associated with the founding of non-African populations.

Link

Isolation-with-migration model

From the paper:

Reconstructing human history requires an accurate picture of global human population structure [1]. However, methods currently used to describe structure among human groups typically rely on very simple demographic models that make unrealistic biological assumptions. Two commonly used models include the island model, which assumes that populations have no shared ancestry and are related only through gene flow (Figure 1A), and the phylogenetic branching or splitting model, which assumes that populations diverged at some time in the past and have remained completely isolated ever since (i.e., no gene flow) (Figure 1B). Despite increasingly sophisticated genetic datasets, most contemporary studies still assume these unrealistic models to infer aspects of human demographic history [2-8].

BMC Genetics doi: 10.1186/1471-2156-9-76

Intergenic DNA sequences from the human X chromosome reveal high rates of global gene flow

Murray P. Cox et al.

Abstract (provisional)

Background

Despite intensive efforts devoted to collecting human polymorphism data, little is known about the role of gene flow in the ancestry of human populations. This is partly because most analyses have applied one of two simple models of population structure, the island model or the splitting model, which make unrealistic biological assumptions.

Results

Here, we analyze 98-kb of DNA sequence from 20 independently evolving intergenic regions on the X chromosome in a sample of 90 humans from six globally diverse populations. We employ an isolation-with-migration (IM) model, which assumes that populations split and subsequently exchange migrants, to independently estimate effective population sizes and migration rates. While the maximum effective size of modern humans is estimated at ~10,000, individual populations vary substantially in size, with African populations tending to be larger (2,300-9,000) than non-African populations (300-3,300). We estimate mean rates of bidirectional gene flow at 4.8 x 10-4/generation. Bidirectional migration rates are ~5-fold higher among non-African populations (1.5 x 10-3) than among African populations (2.7 x 10-4). Interestingly, because effective sizes and migration rates are inversely related in African and non-African populations, population migration rates are similar within Africa and Eurasia (e.g., global mean Nm = 2.4).

Conclusion

We conclude that gene flow has played an important role in structuring global human populations and that migration rates should be incorporated as critical parameters in models of human demography.

Link

Polygyny in human evolution

This paper suggests that polygyny has been a feature of our species for most of its history. They arrive at this conclusion by comparing genetic variation in autosomal DNA and X chromosomes.

Autosomal DNA spends an equal amount of time in male and female bodies, while X chromosomes spend twice as long in female than in male bodies. In a polygynous society, many males don't have offspring while most women do. Hence, genetic variation in X chromosomes has a higher chance to arise (more bodies=>more mutations) and to be maintained (more bodies=>less drift).

This ties in quite nicely with my recent suggestion on reproductive inequality for human Y-chromosomes.

Related story in the New Scientist.

Hammer's team discovered more genetic differences in the X chromosome than would be expected if equal numbers of males and females tended to mate, over human history. The only explanation for this pattern is widespread, long-lasting polygyny, he says.

His team's analysis reflects all of human history, and modern monogamy has not even left a blip in our genomes. "I don't know how long monogamy has been with us," Hammer says. "It seems it hasn't been around long, evolutionarily."

PLoS Genetics doi:10.1371/journal.pgen.1000202

Sex-Biased Evolutionary Forces Shape Genomic Patterns of Human Diversity

Sex-Biased Evolutionary Forces Shape Genomic Patterns of Human Diversity et al.

Abstract

Comparisons of levels of variability on the autosomes and X chromosome can be used to test hypotheses about factors influencing patterns of genomic variation. While a tremendous amount of nucleotide sequence data from across the genome is now available for multiple human populations, there has been no systematic effort to examine relative levels of neutral polymorphism on the X chromosome versus autosomes. We analyzed ~210 kb of DNA sequencing data representing 40 independent noncoding regions on the autosomes and X chromosome from each of 90 humans from six geographically diverse populations. We correct for differences in mutation rates between males and females by considering the ratio of within-human diversity to human-orangutan divergence. We find that relative levels of genetic variation are higher than expected on the X chromosome in all six human populations. We test a number of alternative hypotheses to explain the excess polymorphism on the X chromosome, including models of background selection, changes in population size, and sex-specific migration in a structured population. While each of these processes may have a small effect on the relative ratio of X-linked to autosomal diversity, our results point to a systematic difference between the sexes in the variance in reproductive success; namely, the widespread effects of polygyny in human populations. We conclude that factors leading to a lower male versus female effective population size must be considered as important demographic variables in efforts to construct models of human demographic history and for understanding the forces shaping patterns of human genomic variability.

Link

ESHG 2008 abstracts

The European Society of Human Genetics conference is coming up, and there are some very interesting abstracts.

Note: The ESHG site has updated with a notice that the abstracts are embargoed until their presentation time. Therefore, I have decided to remove the body of this post until then, although I think it is a bit weird to embargo something that one places on the public web. In any case, you can find the abstracts easily by going to the site above. (June 1): post restored.

The peopling of North Asia: Y and X perspectives

V. A. Stepanov, V. Kharkov, I. Khitrinskaya, O. Medvedeva, M. Spiridonova, A. Marusin, V. Puzyrev; Institute for Medical Genetics, Tomsk, Russian Federation.

Presentation Number: P07.056

To reconstruct the origin and evolution of human populations in North Asia we investigated the genetic diversity in 50 population samples (about 2000 individuals totally) using Y and X chromosome lineages. Y-chromosomal haplotypes were constructed with unique event polymorphisms (UEP) and STR markers according to Y Chromosome consortium (YCC) classification. SNP markers in a single 60 kb linkage disequilibrium region of ZFX gene was used to trace the X chromosomal population history. The genetic diversity of Y haplogroups was quite high (0.70 - 0.95) in most populations except few very isolated groups. The proportion of inter-population differences in the total genetic variability measured by Fst statistics is 17% for binary haplogroups and 19% for YSTR. Multidimensional scaling and principal component analysis revealed four major components in North Asian Y gene pool, reflecting the presence of Paleoasiatic (Q), Proto-Uralic (N3, N2), Eastern Asian (O, C), and Western Eurasian (R1, I, J) lineages. X-chromosomal haplotypes in North Asia are less divers (gene diversity within populations 0.65 - 0.80) and less differentiated (Fst = 4%) compared to Y lineages. The population clustering by X and Y gives, to a first approximation, a similar picture, and matrixes of genetic distances between populations for X and Y haplotypes significantly correlates. The age of genetic diversity generation and time of population differentiation demonstrates the Upper Paleolithic origin of major Y and X lineages and post-glacial population expansions. This work is supported by RFBR grants ##06-04-48274 and 07-04-01629.

The following seems to be a very important study; in particular the notion that particular Y chromosome/mtDNA haplogroups may be associated with higher or lower fertility may have implications about their distribution.

UPDATE (May 21): I did a quick and dirty analysis of the Y-haplogroup and mtDNA-haplogroup data from Bosch et al. (2006) (Ann Hum Genet. 2006 Jul;70(Pt 4):459-87.), and there is a -0.43 correlation between Y-haplogroup I and mtDNA-haplogroup H and a +0.46 correlation between Y-haplogroup R1 and mtDNA-haplogroup H. While not significant (with only 10 populations), this is definitely in the right direction for a selection effect for/against specific Y-DNA/mtDNA combinations.

... on the other hand, another quick and dirty analysis of 23 populations from Rootsi's survey on Y-haplogroup I and mtDNA frequencies from AJHG Volume 80, Issue 4, April 2007, Pages 759-768 didn't turn up any correlation. Perhaps, someone can look at possible correlations between Y-chromosome and mtDNA haplogroups in Europe to see if anything interesting turns up.

Male infertility induced by mtDNA/Y unfavorable combination? An association study on human mitochondrial DNA

S. C. Gomes1, S. Fernandes2, R. Gonçalves1, A. T. Fernandes1, A. Barros3, H. Geada4, A. Brehm1; 1Human Genetics Laboratory, University of Madeira, Funchal, Portugal, 2Genetics Department, Faculty of Medicine, University of Porto, Porto, Portugal, 3Centre of Reproductive Genetics A Barros, Porto, Portugal, 4Faculty of Medicine, University of Lisbon, Lisboa, Portugal.

Presentation Number: P07.084

There is growing evidence that certain mtDNA haplogroups determine a genetic susceptibility to various disorders bringing out the interest in the possible role of mtDNA background on the phenotype expression of mitochondrial genetic disorders. An association between haplogroup T and asthenospermia has been reported and several sublineages of haplogroup U were associated with differences in sperm motility and vitality. The deletion of some DAZ copies gene in 10-15% of azoospermic and oligospermic patients has been reported but also present in fertile men belonging to certain Y-haplogroups. The findings of one study have rarely been replicated by studies in other populations and conflicting associations have been reported. Our focus in this case-control study is to investigate the existence of other influences, besides a weak mtDNA background, promoting male infertility. The occurrence of a specific mtDNA variant associated to a certain Y-chromosome haplogroup could represent a vital link that will compromise the sperm function and be responsible for male infertility. A group of 99 infertile men and other one composed by 90 subjects with proven fertility were selected and analysed. The frequency of the combination mtDNA-haplogroup H (especially with the CRS sequence) and Y-haplogroup R was higher in fertile than in infertile men seemingly to be favorable to fertility. On the other hand, a considerable number of infertile men belonging to mtDNA-haplogroup H (CRS) and to Y-haplogroup I, associated to a specific DAZ gene deletion pattern- 2+4d, suggests a non favorable combination to male fertility.

The Bayash Roma: phylogenetic dissection of Eurasian paternal genetic elements

I. Martinovic Klaric, M. Pericic Salihovic, L. Barac Lauc, B. Janicijevic; Institute for Anthropological Research, Zagreb, Croatia.

Presentation Number: P07.110

The Bayash consist of numerous and small Romani groups speaking different dialects of the Romanian language and living dispersedly in Croatia, Hungary, Bosnia and Herzegovina, Serbia, Romania, Bulgaria, and to the lesser extent in Macedonia, Greece, Ukraine, Slovakia and Slovenia. Larger Bayash groups migrated to Croatia most likely during the 19th century, after abolition of slavery in Romania. Molecular architecture and the origin of the Croatian Bayash paternal gene pool was addressed by analysing 151 Bayash Y chromosomes from two Croatian regions, 332 Y chromosomes from Romani populations across Europe, 814 Y-chromosomes from non-Romani host populations living in Southeastern, Southern and Eastern Europe as well as with 1680 Y-chromosomes from South Asian populations. The Bayash in Croatia represent one population of largely shared paternal genetic history characterized by substantial percentage (44%) of common H1-M82 and E3b1-M78 lineages. Relatively ancient expansion signals and limited diversity of Indian specific H1-M82 lineages imply descent from closely related paternal ancestors who could have been settled in the Indian subcontinent between 7th and 9th centuries AD. Minimal time divergence of the Bayash subpopulations is consistent with their putative migratory split within Romania towards Wallachia and Transilvania. Substantial percentage of E3b1 lineages and high associated microsatellite variance in the Bayash men is a reflection of significant admixture with majority populations from the Vardar-Morava-Danube catchment basin - possibly a common paternal signature of Romani populations in Southeastern Europe. Additional traces of admixture are evident in the modest presence of typical European haplogroups.

Are the Moravian Valachs of Czech Republic the Aromuns of Central Europe? Model population for isolation and admixture

E. Ehler1,2, V. Vančata2; 1Department of Anthropology and Human Genetics, Charles University in Prague, Faculty of Science, Prague, Czech Republic, 2Department of Biology and Ecological Education, Charles University in Prague, Faculty of Education, Prague, Czech Republic.

Presentation Number: P07.129

Moravian Valachs of Czech Republic are one of the most distinct ethnic groups from Central Europe. Related to similar populations in Poland and Slovakia, they emerge at the end of 15th century, as the north-westernmost prominence of migration that started 250 years earlier in northern Romania. Being predominately highland sheep herders and of putative Romanian origin, they represent a Central European analogue of Balkan Aromanian populations. We have gathered Y-chromosomal, linguistic, ethnographic and historical data for this population and compared them with surrounding as well as with east European populations. Linguistic data show specific parts of shared vocabulary of Romanian origin between several pastoral groups in Central and Eastern Europe. Comparing genetic and linguistic pairwise distance matrices (Mantel test) in these populations did not revealed any significant correlation. Thus we confirmed that plain geographical distance still plays the major role in genetic distances between populations in Europe. From our further analysis it is clear, that the Moravian Valachs, after at least five centuries of admixture, are not overly genetically different from surrounding populations. On the other hand, from the point of view of intra-population diversity, they are much more similar to isolated Balkan populations (e.g. Aromuns) than to Central European populations.

Phylogeography of the human Y chromosome haplogroup E3a

F. Cruciani1, B. Trombetta1, D. Sellitto2, C. Nodale1, R. Scozzari1; 1Sapienza Università di Roma, Rome, Italy, 2Consiglio Nazionale delle Ricerche, Rome, Italy.

Presentation Number: P07.134

The Y chromosome specific biallelic marker DYS271 defines the most common haplogroup (E3a) currently found in sub-Saharan Africa. A sister clade, E3b (E-M215), is rare in sub-Saharan Africa, but very common in northern and eastern Africa. On the whole, these two clades represent more than 70% of the Y chromosomes of the African continent. A third clade belonging to E3 (E3c or E-M329) has been recently reported to be present only in eastern Africa, at low frequencies. In this study we analyzed more than 1,600 Y chromosomes from 55 African populations, using both new and previously described biallelic markers, in order to refine the phylogeny and the geographic distribution of the E3a haplogroup. The most common E-DYS271 sub-clades (E-DYS271*, E-M191, E-U209) showed a non uniform distribution across sub-Saharan Africa. Most of the E-DYS271 chromosomes found in northern and western Africa belong to the paragroup E-DYS271*, which is rare in central and southern Africa. In these latter regions, haplogroups E-M191 and E-U209 show similar frequency distributions and coalescence ages (13 and 11 kyr, respectively), suggesting their involvement in the same migratory event/s. By the use of two new phylogenetically equivalent markers (V38 and V89), the earlier tripartite structure of E3 haplogroup was resolved in favor of a common ancestor for haplogroups E-DYS271 (formerly E3a) and E-M329 (formerly E3c). The new topology of the E3 haplogroup is suggestive of a relatively recent eastern African origin for the majority of the chromosomes presently found in sub-Saharan Africa.

Y-chromosome lineages in Xhosa and Zulu Bantu speaking populations

R. P. A. Gonçalves, H. Spínola, A. Brehm; Human Genetics Laboratory, Funchal, Portugal.

Presentation Number: P07.137

Y-chromosome Single Nucleotide Polymorphisms have been analysed in Zulu and Xhosa, two southern Africa Bantu speaking populations. These two ethnic groups have their origin on the farmer’s Bantu expansion from Niger-Congo border towards sub-Sahel regions on the southern tip of the continent, during the past 3000 years. Seven different Y-chromosome haplogroups were found in Zulu contrasting with only two in Xhosa. E3a, a common haplogroup among West sub-Saharans associated to Bantu migration was the most prevalent in both populations (56.9% in Zulu and 90% in Xhosa). The second most common haplogroup was E2 (29.3% in Zulu and 10% in Xhosa), present both in West and East African populations. The present-day Zulu and Xhosa paternal legacy is essentially of West sub-Saharan origin. Zulu population shows a most diverse genetic influence comparing to Xhosa, revealing some pre-Bantu expansion markers and East African influences. Zulu presents 8.6% Y-chromosome haplogroups (A, B, J1) of non-Bantu influence that could indicate gene flow from other populations, particularly Khoisan.

Human genetic population structure: Patterns and underlying processes

Presentation Time: Tuesday, 9:15 a.m. - 9:45 a.m.

G. Barbujani; University of Ferrara, Department of Biology and Evolution, Ferrara, Italy.

Presentation Number: S15.2

Classical studies of genetic diversity in humans consistently showed that the largest proportion of human diversity occurs among members of the same population. On average, differences among different populations in the same continent represent 5% of the global human variance, and differences among continents another 10%. Genetic variation is largely discordant across the genome, meaning that different loci show different spatial patterns, and implying that a good description of population structure can only be based on the analysis of multiple loci. Studies of single loci are also unlikely to reasonably identify an individual’s place of origin. A general decline of genetic of genetic diversity with distance from Africa, and a parallel increase in linkage disequilibrium, can be accounted for by the effects of a series of founder effects accompanying the spread of anatomically-modern humans from Africa. Recent DNA analyses at the global level show that most allelic variants are cosmopolitan and only a small percentage are continent-specific, whereas a clearer continental structure emerges when considering composite haplotypes. This suggests that, at the global level, gene flow has had a strong impact on genetic diversity, through both directional dispersal and successive short-range migratory exchanges. At the local level, several factors have contributed to genetic differentiation, and, in particular, language barriers have been shown to be associated with small but non-negligible increases of the genetic differences between neighboring populations.

Hierarchical analysis of 28 Y-chromosome SNP’s in the population of the Republic of Macedonia

P. Noveski, S. Trivodalieva, G. D. Efremov, D. Plaseska-Karanfilska;
Macedonian Academy of Sciences and Arts, Research Centre for Genetic Engineering and Biotechnology, Skopje, Macedonia, The Former Yugoslav Republic of.

Presentation Number: P05.211

Analysis of Y-chromosome haplogroups, defined by single nucleotide polymorphisms (SNP’s), has become a standard approach for studying the origin of human populations and measuring the variability among them. Furthermore, Y-SNP’s represent a new forensic tool, because their population specificity may allow to determine the origin of any male sample of interest for forensic purposes. The aim of this study was to develop a strategy for rapid, simple and inexpensive Y-chromosome SNP’s typing in the population of R. Macedonia. We have studied a total of 343 DNA male samples; 211 Macedonians, 111 Albanians and 21 of other ethnic origin (Roma, Serbs and Turks). Methodology included multiplex PCR and single nucleotide extension reaction by SNaPshot multiplex kit. The set of 28 markers has been grouped in 5 multiplexes in order to determine the most frequent haplogroups using only 1 or 2 multiplexes. Twenty different Y haplogroups were determined among 343 male DNA samples. The finding that five haplogroups (E3b1, I1b1, J2b1a, R1a and R1b) comprise more than 70% of the Y chromosomes is consistent with the typical European Y chromosome gene pool. The distribution of the Y-haplogroups differs between Macedonians and Albanians. The most common Y haplogroup among Macedonians is I1b1 (27.5%), followed by three haplogroups present with similar frequencies E3b1 (15.6%), R1a (14.2%) and R1b (11.4%). Among Albanians the most frequent Y haplogroup is E3b1 (28.8%), followed by R1b (18.0%), J2b1a (13.5%) and R1a (12.6%).

The following paper (probably) refers to a recent study, according to which:

One of the most elevated values of 35delG prevalence corresponds to Greece (1/28); the pattern of various 35delG prevalences is interpretated in the present meta-analysis as the result of Ancient Greek colonizations of the "Magna Grecia" in historical times.

Strong linkage disequilibrium for the frequent GJB2 35delG mutation in the Greek population
H. Kokotas¹, L. Van Laer², M. Grigoriadou¹, V. Iliadou³, J. Economides⁴, S. Pomoni¹, A. Pampanos¹, N. Eleftheriades⁵, E. Ferekidou⁶, S. Korres⁶, A. Giannoulia-Karantana⁷, G. Van Camp², M. B. Petersen¹;
¹Institute of Child Health, Athens, Greece, ²University of Antwerp, Antwerp, Belgium, ³AHEPA Hospital, Thessaloniki, Greece, ⁴‘Aghia Sophia’ Children’s Hospital, Athens, Greece, ⁵St. Loukas Hospital, Thessaloniki, Greece, ⁶Athens University, Athens, Greece, ⁷Athens University Medical School, Athens, Greece.

Presentation Number: P06.080

Approximately one in 1,000 children is affected by severe or profound hearing loss at birth or during early childhood (prelingual deafness). Up to forty percent of autosomal recessive, congenital, severe to profound hearing impairment cases result from mutations in a single gene, GJB2. The 35delG mutation accounts for the majority of GJB2 mutations detected in Caucasian populations and represents one of the most frequent disease mutations identified so far. Some previous studies have assumed that the high frequency of the 35delG mutation reflects the presence of a mutational hot spot, whilst other studies support the theory of a common founder. Greece is amongst the countries presenting high frequency of the 35delG mutation (3.5%), and a recent study raised the hypothesis of the origin of this mutation in ancient Greece. We genotyped 60 Greek deafness patients homozygous for the 35delG mutation for six single nucleotide polymorphisms (SNPs) and two microsatellite markers, mapping within or flanking the GJB2 gene, as compared to 60 Greek hearing controls. A strong linkage disequilibrium was found between the 35delG mutation and markers inside or flanking the GJB2 gene, at distances of 34 kb on the centromeric and 90 kb on the telomeric side of the gene, respectively. Our study supports the hypothesis of a founder effect and we further propose that ethnic groups of Greek ancestry could have propagated the 35delG mutation, as evidenced by historical data beginning from the 15^th century BC.

Human population sizes, divergence times and rates of gene flow

Genetics. 2007 Dec;177(4):2195-207.

Inferring human population sizes, divergence times and rates of gene flow from mitochondrial, x and y chromosome resequencing data.

Garrigan D, Kingan SB, Pilkington MM, Wilder JA, Cox MP, Soodyall H, Strassmann B, Destro-Bisol G, de Knijff P, Novelletto A, Friedlaender J, Hammer MF.

We estimate parameters of a general isolation-with-migration model using resequence data from mitochondrial DNA (mtDNA), the Y chromosome, and two loci on the X chromosome in samples of 25-50 individuals from each of 10 human populations. Application of a coalescent-based Markov chain Monte Carlo technique allows simultaneous inference of divergence times, rates of gene flow, as well as changes in effective population size. Results from comparisons between sub-Saharan African and Eurasian populations estimate that 1500 individuals founded the ancestral Eurasian population approximately 40 thousand years ago (KYA). Furthermore, these small Eurasian founding populations appear to have grown much more dramatically than either African or Oceanian populations. Analyses of sub-Saharan African populations provide little evidence for a history of population bottlenecks and suggest that they began diverging from one another upward of 50 KYA. We surmise that ancestral African populations had already been geographically structured prior to the founding of ancestral Eurasian populations. African populations are shown to experience low levels of mitochondrial DNA gene flow, but high levels of Y chromosome gene flow. In particular, Y chromosome gene flow appears to be asymmetric, i.e., from the Bantu-speaking population into other African populations. Conversely, mitochondrial gene flow is more extensive between non-African populations, but appears to be absent between European and Asian populations.

Link

Divergent X chromosome haplotype in Eurasians and East Africans

Yet another piece of evidence in favor of my idea that ancestral Africans were subdivided and did not form a single population. A widely divergent haplotype of the X chromosome was found in Eurasians and East Africans but not at all in the Sub-Saharan Africans of the CEPH Panel. If there was no population structure in Africa, then we would expect to see this hX haplotype in different African locations.

From the paper:

Designated hX, this haplotype was found once in Melanesia (Oceania) and 8 times in widespread locations in Eurasia, including the Orkney Islands, Pakistan, Algeria, Israel, and France. Contrary to the typical pattern found in many genes, in which the variation in non-African populations is a subset of the variation in sub-Saharan Africa, hX was not observed among the HGDP-CEPH males from sub-Saharan Africa (98 individuals).

...

One possible historical model that could generate this pattern supposes that differences between hX and other haplotypes arose in the presence of population structure that allowed for the divergence among Xp11.22 haplotypes. Even if we discount the possibility of a non-African archaic human population as the source of hX, the age and low frequency of the haplotype does suggest a history in which hX persisted and diverged in a separate refugium population (either a separate modern human population or possibly an archaic human population). Models of this type, which suppose the presence of old population strutcture among African populations, have been suggested based on evidence from other regions of the genome (Tishkoff et al. 1996Go; Harding et al. 1997Go; Labuda et al. 2000Go; Tishkoff et al. 2000Go; Zietkiewicz et al. 2003Go; Garrigan, Mobesher, Kingan, et al. 2005Go).

Molecular Biology and Evolution

Divergent Haplotypes and Human History as Revealed in a Worldwide Survey of X-Linked DNA Sequence Variation

Makoto K. Shimada et al.

The population genetic history of a 10.1-kbp noncoding region of the human X chromosome was studied using the males of the HGDP-CEPH Human Genome Diversity Panel (672 individuals from 52 populations). The geographic distribution of patterns of variation was roughly consistent with previous studies, with the major exception that 1 highly divergent haplotype (haplotype X, hX) was observed at low frequency in widely scattered non-African populations and not at all observed in sub-Saharan African populations. Microsatellite (short tandem repeat) variation within the sequenced region was low among copies of hX, even though the estimated time of ancestry of hX and other sequences was 1.44 Myr. The estimated age of the common ancestor of all hX copies was 5,230 years (95% consistency index: 2,000–75,480 years). To further address the presence of hX in Africa, additional samples from Chad and Tanzania were screened. Five additional copies of hX were observed, consistent with a history in which hX was present in Africa prior to the migration of modern humans out of Africa and with eastern Africa being the source of non-African modern human populations. Taken together, these features of hX—that it is much older than other haplotypes and uncommon and patchily distributed throughout Africa, Europe, and Asia—present a cautionary tale for interpretations of human history.

Link

Male and female genomic contributions to African Americans

Hum Genet. 2006 Sep 28; [Epub ahead of print]

Elevated male European and female African contributions to the genomes of African American individuals.

Lind JM, Hutcheson-Dilks HB, Williams SM, Moore JH, Essex M, Ruiz-Pesini E, Wallace DC, Tishkoff SA, O'brien SJ, Smith MW.

The differential relative contribution of males and females from Africa and Europe to individual African American genomes is relevant to mapping genes utilizing admixture analysis. The assessment of ancestral population contributions to the four types of genomic DNA (autosomes, X and Y chromosomes, and mitochondrial) with their differing modes of inheritance is most easily addressed in males. A thorough evaluation of 93 African American males for 2,018 autosomal single nucleotide polymorphic (SNP) markers, 121 X chromosome SNPs, 10 Y chromosome haplogroups specified by SNPs, and six haplogroup defining mtDNA SNPs is presented. A distinct lack of correlation observed between the X chromosome and the autosomal admixture fractions supports separate treatment of these chromosomes in admixture-based gene mapping applications. The European genetic contributions were highest (and African lowest) for the Y chromosome (28.46%), followed by the autosomes (19.99%), then the X chromosome (12.11%), and the mtDNA (8.51%). The relative order of admixture fractions in the genomic compartments validates previous studies that suggested sex-biased gene flow with elevated European male and African female contributions. There is a threefold higher European male contribution compared with European females (Y chromosome vs. mtDNA) to the genomes of African American individuals meaning that admixture-based gene discovery will have the most power for the autosomes and will be more limited for X chromosome analysis.

Link

Sexual dimorphism in gene expression in human brain

From the paper:

Most notably, in man the brain is sexually dimorphic with respect to asymmetry (the cerebral torque) from right frontal to left occipital across the anteroposterior axis (Barrick et al. 2004). Females are more strongly right-handed than males, acquire words more rapidly (Crow et al. 1998) and have faster brain growth (Kretschmann et al. 1979). By contrast, adult brain size is greater in males than females, cerebral asymmetry is more marked, particularly in the posterior part of the brain (Barrick et al. 2004) and there is a modest male superiority for spatial ability. Although most sexual dimorphisms are caused by male and female gonadal secretions, there is evidence for a direct role of sex chromosomes genes in brain sexual differentiation (Carruth et al. 2002; reviewed in Arnold 2004). In this context, an imbalance of PCDH11X/Y products between sexes might be relevant considering that these genes are expressed from early in development (Blanco et al. 2000).

It's nice to see that some women scientists demonstrate their excellence by writing excellent papers about male-female biological differences rather than engage in knee-jerk reactions to legitimate scientific speculation.

Molecular Biology and Evolution (online first)

Inactivation status of PCDH11X: sexual dimorphisms in gene expression levels in brain

Alexandra M. Lopes et al.

Abstract Genes escaping X-inactivation are predicted to contribute to differences in gene dosage between the sexes and are the prime candidates for being involved in the phenotype observed in individuals with X chromosome aneuploidies. Of particular interest is ProtocadherinX (PCDH11X or PCDHX), a recently described gene expressed in brain. In humans, PCDH11X has a homologue on the Y chromosome and is predicted to escape from X-inactivation. Employing bisulphite sequencing analysis we found absence of CpG island methylation on both the active and the inactive X chromosomes, providing a strong indication that PCDH11X escapes inactivation in humans. Furthermore, a sexual dimorphism in levels of expression in brain tissue was observed by quantitative real-time PCR, with females presenting an up to 2-fold excess in the abundance of PCDH11X transcripts. We relate these findings to sexually dimorphic traits in the human brain. Interestingly, PCDH11X/Y gene pair is unique to Homo sapiens, since the X-linked gene was transposed to the Y chromosome after the human–chimpanzee lineages split. Although no differences in promoter methylation were found between humans and chimpanzees, evidence of an upregulation of PCDH11X in humans deserves further investigation.

Link

Out of Africa vs. Multiregionalism, the debate that will not end

I was recently glancing through the excellent Human Evolutionary Genetics, and one of the opinion boxes in the book was titled "Modern Human origins - why it's time to move on". In it, Robert Foley and Marta Mirazon Lahr pronounce the victory of the out of Africa model and the death of multiregionalism:

The 'out of Africa' model of human evolution has basically proved to be empirically sound, and the field is now (at last!) moving on.

On the other hand, Erik Trinkaus, on a recent article on modern human emergence seems to reject the pure Out of Africa model as well as the regional continuity model:

Versions of the assimilation model have remained contenders for the interpretation of modern human phylogenetic emergence, if frequently overshadowed by the more polarized regional continuity (with gene flow) and (out of Africa with) replacement scenarios. The last two interpretations are finally intellectually dead. Both are contradicted by available evidence, and it is time for the discussion to move on. Yet, despite the general acceptance of some form of the assimilation model, issues remain.

So, perhaps we should move on, but where? Most anthropologists and geneticists today may reject the multiregional model, and accept that most recent human ancestry is derived from Africa, yet the existence and extent of non-African ancestry in modern humans is a matter of great controversy.

For example Michael Hammer and colleagues have recently published a paper which explicitly rejects the African-ness of a particular haplotype on the X chromosome. A paper on the non-admixture between moderns and Neanderthals, but also a paper on a 3-million year old polymorphism in Europeans which may have been introduced into the European gene pool by Neanderthals. Not to mention of lice speaking of modern human-erectus hybridization in Asia, a 2 million year old non-African polymorphism in Asians, 1.1 million year polymorphism in North Africa and the Middle East, and research which suggests that the fact that Africans have more ancestral alleles than non-Africans should not be interpreted as evidence of an African origin of humanity (all of them here).

Henry Harpending and Vinayak Eswaran have written a letter in the latest issue of Science, in which he takes issue with another article on ancient Out-of-Africa migrations and their Orang Asli descendants:

For example, nuclear loci rarely, if ever, show the low coalescence times (~200,000 years) seen in mtDNA, nor do they show strictly African roots. Indeed, there is now growing evidence of strictly non-African polymorphisms that date to before the birth of modern humans (1-5).

Vincent Macaulay and the other authors of the paper reply:

In cases where autosomal loci do have the necessary resolution, they suggest the replacement model (6-8). The discordant population-size estimates referred to by Harpending and Eswaran are likely more apparent than real, since these long-term values are usually obtained with the multiregional stipulation of random mating and constant population size. The analysis of overly simplistic models with methods that throw away what little information there is in most of these loci throws up straw men, such as the apparent lack of "strong signals of expansion" in some autosomal loci (9).

It is becoming awfully hard to keep up with the debate, especially since the experts themselves interpret the evidence in completely different ways. Should we despair of the ability of genetics to throw any light on our species' origin, and go back on discovering and measuring skulls? The African mitochondrial Eve discovery seemed to tilt the balance towards the Out of Africa hypothesis (first proposed forcefully by W.W. Howells), but our optimism that genetics would succeed where palaeoanthropology had failed may have been premature. Almost twenty years later, the discussion seems to have barely just begun!

What do you think?

Which model of human origins do you accept?
	Out-of-Africa
	Out-of-Africa with Assimilation
	Multiregional evolution
Free polls from Pollhost.com

Read also, the Multiregional Stipulation Society by John Hawks.

ESHG abstracts

I had previously posted some titles from this year's European Society of Human Genetics conference. There is now a pdf volume on the ESHG which contains all the abstracts of the conference. Some of them have already been published, and doubtlessly more of them will be published next year. I will discuss below some of the more intriguing entries:

F. Cruciani et al., Molecular dissection of the Y chromosome haplogroups A, E and R1b

The male-specific region of the human Y chromosome (MSY) is characterized by a low amount of sequence diversity compared to the mtDNA, the autosomes and the X chromosome. Recently, the use of DHPLC and direct sequencing of DNA has permitted to identify more than 300 new single nucleotide polymorphisms (SNPs) on the MSY. The analysis of the geographic distribution of the haplogroups identified by these markers has provided new insights in the history of human populations, at the same time, it came out that undetected Y chromosome SNPs still contain useful information. In this study we have analyzed the sequence variation of 60 kb of the TBL1Y gene. While previous studies have analyzed the sequence variation of the Y chromosome in a random sample of individuals, we here focus on 22 chromosomes belonging to three specific haplogroups (A, R1b and E), whose geographic distribution is relevant for the human evolutionary history of Africa and/or western Eurasia. We discovered 32 new SNPs, and placed them in the known Y chromosome phylogenetic tree: about half of the new mutations identify new branches of the tree. The geographic distribution of five new E-M78 sub-haplogroups, analyzed in more than 6,000 subjects from Eurasia and Africa, has led to the identification of interesting evolutionary patterns.

The discovery of new subclades, especially for E-M78 and R1b will be especially welcome for those interested in finer distinctions in these widely prevalent haplogroups. R1b for example occurs throughout the Caucasoid world, and so far very few meaningful sub-haplogroups of it were known. E-M78 is the main sublineage of haplogroup E3b and until now there was evidence fo haplotype clusters that differentiated E-M78 chromosomes; the discovery of new sub-haplogroups will probably reflect to some degree these previously known haplotype clusters.

People interested in their own personal anthropology may be advised to wait until the publication of the R1b and E-M78 sub-haplogroups and their incorporation into commercial "fine-resolution" SNP tests, if they are considering undertaking such a test.

I. Kutuev et al., Phylogeographic analysis of mtDNA and Y chromosome lineages in Caucasus populations

The Greater Caucasus marks a traditional boundary between Europe and Asia. Linguistically, it is one of the most diverse areas of the continental Eurasia, while genetics of the people living there is poorly understood. Mitochondrial DNA and NRY variability was studied in 23 Caucasus populations speaking Caucasus, Turkic, andIndo-European languages. Total sample comprised more than 1700 individuals on Y chromosome and more than 2100 individuals on mtDNA. Genetic outliers among the studied populations are relatively recently arrived Turkic speaking Nogays. The indigenous Caucasus populations possess generally less than 5% of eastern Eurasian mtDNA and Y-chromosomal haplotypes - in a profound contrast to the Turkic-speaking people at the other side of the Caspian, but not so dissimilar compared to the Volga-Turkic Tatars and Chuvashis or to the Anatolian Turks. Haplogroup frequency variation within the Caucasus populations, in some instances significant, appears to be caused primarily by specific aspects of the demographic history of populations. Phylogeographically, a particularly intriguing finding is the presence, though at low frequencies, of a predominantly northeastern African haplogroup M1 in many North Caucasus populations, though they lack sub-Saharan L lineages, relatively frequent in the Arab-speaking Levant. Results obtained help to place the Caucasus populations into the scenario of the peopling of Eurasia with anatomically modern humans. Possible migration routs, peopling of steppe and mountain parts of the Caucasus and causes of high linguistic diversity presence in this region is analyzed in this study.

The finding of M1 lineages in the Caucasus not associated with Sub-Saharan L lineages is important, because it can be explained in only one of two ways:

1. M1 originated in Asia, so its presence in east Africa can be explained by back-migration from Asia. We know that macrohaplogroup M originated in Asia, but it is not clear whether M1 itself originated in Asia or Africa; the "trail" of M lineages between South Asia and Eastern Africa is still flimsy, so we cannot draw any conclusions on this matter yet.
   
2. M1 originated in eastern Africa, but during a time when there was a much small level of penetration of sub-Saharan L lineages into the region.

V. Stepanov et al., Genetic diversity and differentiation of Y-chromosomal lineages in North Eurasia

Composition and frequency of Y-chromosomal haplogroups, defined by the genotyping of 36 biallelic loci in non-recombining part of Ychromosome, was revealed for native population of Siberia, Central Asia and Eastern Europe. Slavonic ethnic groups, which geographically represent Eastern Europe, are characterized by the high frequency of R1a1, I*, I1b, and N3a clades and by the presence of R1b3, J2, E, and G. Most frequent haplorgoup is R1a1, which comprises 44-51% of Y-chromosomes. The distinguishing peculiarity of Central Asian Caucasoids is the high frequency of Caucasoid clades R1a1, J*, J2, and the presence of R1b3 and G. Twenty-five haplogroups were found in gene pool of native Siberian populations. Only 7 of them have the frequency higher than 3%. In sum these 7 clades comprise 86% of Siberian samples. In populations of Southern Siberia the most frequent haplogroup is R1a1. The high frequency of N3a is characteristic for Eastern Siberians, and in Yakuts its frequency is almost 90%. Koryaks, Buryats and Nivkhs have the highest frequency of C3* lineage among investigated populations. Haplogroup O* revealed with variable frequency in most of Siberian. Highest frequency of Q* was found in Ketsand Northern Altayans (85% and 32%, respectively).The high level of genetic differentiation of North Eurasian population on Y-chromosomal lineages was revealed. The proportion of inter-population differences in the total genetic variability of region’s population according to the analysis of molecular variance is 19.04%. Genetic differences between territorial groups took 6.9% of total genetic variability, whereas 12.8% is the inter-population differences within groups.

This study seems to confirm what we already knew about the distribution of haplogroups in northern Eurasia, but it seems like a comprehensive survey of the area, which will be very useful when it appears in print.

S. Sengupta et al., Genescape of India, as Reconstructed from Polymorphic DNA Variation in the Y chromosome

The contemporary male gene pool of ethnic India largely comprises haplogroups that originated indigenously, in southeast Asia, and in west and central Asia. The indigenous haplogroup is predominant among the tribal group . The southeast Asian influence is largely on the male gene pools of Tibeto-Burman speaking tribals and Austro-Asiatic and Dravidian. The west and central Asian influence is primarily on caste groups - both Indo-European and Dravidian. The haplogroup diversity within the various tribal groups is lower than that within the caste groups. Analyses of molecular variance showed higher genetic variability among populations within linguistic clusters of tribals compared to castes. Moreover, the between group variability in the Indo-European caste cluster is higher than that in the Dravidian
caste cluster. This may be a reflection of diverse ancestries, antiquities and isolation of the tribals, coupled with subsequent cultural (linguistic) homogenization. Lesser between group genetic variability in caste groups may be a reflection of their recent founding history. The complete congruence of the patterns of Y-chromosomal and mitochondrial DNA differentiation may be indicative of inflow of both male and female genes from similar source populations. The rank order of FST values showed that tribes and castes are most differentiated, followed by upper and middle caste, upper and lower caste and middle and lower caste.

Again, this study seems to confirm the indigenous component in Indians, and the higher prevalence of western and central Asian Caucasoid haplogroups in castes compared to tribals. Also of interest is the finding that the main difference in the Indian population is between castes and tribals: within the castes, differentiation decreases towards the lower castes, the most differentiated ones being the upper castes.

E. Bogácsi-Szabó et al., Maternal and paternal lineages in ancient and modern Hungarians

Hungarian language represents the westernmost group of the Finno-Ugric language phylum, surrounded entirely by Indo-European speaking populations. Their linguistic isolation in the Carpathian basin suggests the possibility that they might also show a significant genetic isolation. According to historical data at the end of the 9th century Hungarian conquerors from the west side of the Ural Mountains settled down into the Carpathian Basin and took the hegemony. To determine the genetic background of Hungarians we examined mitochondrial and Y chromosomal DNA from ancient `conquerors` from Hungary, originated from the 10th century and from modern Hungarian-speaking adults from today's Hungary and Transylvanian Seklers (Romania). DNA was extracted from 35 excavated ancient bones and hair samples of 125 and 80 modern Hungarians and Seklers, respectively. Mitochondrial haplogroups were determined with HVS I sequencing and RFLP typing. The mtDNA HVS I sequences were compared with 2615 samples from 34 Eurasian populations retrieved from published data. ARLEQUIN 2.001 Software was used to estimate genetic distances between populations. The resulting matrix was summarized in two dimensions by use of Multidimensional Scaling. The M46 biallelic Y chromosomal marker (TAT, often called Uralic migration marker) was also investigated from 2 ancient, 34 modern Hungarian and 60 Sekler samples. Our results suggest that the modern Hungarian gene pool is very similar to other central European ones concerning the mitochondrial and Y chromosomal markers, while the ancient population contains more Asian type elements.

This is a very exciting study comparing ancient Magyar mtDNA and Y chromosomes (at least the Tat-C marker) with those of modern Hungarian speakers. Physical anthropologists have long identified a Mongoloid and mixed Mongoloid component in the Magyars, and this is now confirmed with the finding of Tat-C and Mongoloid mtDNA in the ancient Magyars at a higher frequency than in the modern population. Today, Hungarians are predominantly Caucasoid, and this is supported by the molecular data and reflects the assimilation of the indigenous Caucasoid population by the more "Asian" original Magyar population.

F. di Giacomo et al., Y chromosomal variation in the Czech Republic

In order to analyse the contribution of the Czech Republic to the genetic landscape of Europe, we typed 257 male subjects from 5 locations for 17 Unique Event Polymorphisms of the Y chromosome. Sixteen haplogroups or sub-haplogroups were identified, with only 5 chromosomes uncharacterized. Overall, the degree of population structuring was low. The three commonest haplogroups were R1a
(0.344), P*(xR1a) (0.281) and I (0.184). M157, M56 and M87 showed no variation within haplogroup R1a. Haplogroup I was mostly represented as I1b* and I1b2 was also detected in this population. Thus, the majority of the Czech male gene pool is accounted for by the three main haplogroups found in western and central Europe, the Balkans and the Carpathians. Haplogroup J was found at low frequency, in agreement with a low gene flow with the Mediterranean. In order to draw inferences on the dynamics of the Czech population, we typed 141 carriers of the 3 most common haplogroups for 10 microsatellites, and applied coalescent analyses. While the age of the I clade agreed with that reported in the vast study of Rootsi et al (2004), the ages of its sub-haplogroups differed considerably, showing that the I chromosomes sampled in the Czech Republic are a subset of those found throughout Europe. Haplogroup R1a turned out to be the youngest with an estimated age well after the Last Glacial Maximum. For all three major haplogroups the results indicate a fast population growth, beginning at approximately 60-80 generations ago.

The young age of R1a1 in Czechs, combined with its high frequency make it a likely candidate as reflecting historical or recent prehistorical events, and less likely to reflect the post-LGM recolonization of Europe.