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1.  Deep Roots for Aboriginal Australian Y Chromosomes 
Current Biology  2016;26(6):809-813.
Australia was one of the earliest regions outside Africa to be colonized by fully modern humans, with archaeological evidence for human presence by 47,000 years ago (47 kya) widely accepted [1, 2]. However, the extent of subsequent human entry before the European colonial age is less clear. The dingo reached Australia about 4 kya, indirectly implying human contact, which some have linked to changes in language and stone tool technology to suggest substantial cultural changes at the same time [3]. Genetic data of two kinds have been proposed to support gene flow from the Indian subcontinent to Australia at this time, as well: first, signs of South Asian admixture in Aboriginal Australian genomes have been reported on the basis of genome-wide SNP data [4]; and second, a Y chromosome lineage designated haplogroup C∗, present in both India and Australia, was estimated to have a most recent common ancestor around 5 kya and to have entered Australia from India [5]. Here, we sequence 13 Aboriginal Australian Y chromosomes to re-investigate their divergence times from Y chromosomes in other continents, including a comparison of Aboriginal Australian and South Asian haplogroup C chromosomes. We find divergence times dating back to ∼50 kya, thus excluding the Y chromosome as providing evidence for recent gene flow from India into Australia.
Graphical Abstract
•We have sequenced 13 Aboriginal Australian Y chromosomes•These diverged from Y chromosomes in other continents around 50,000 years ago•They diverged from Papua New Guinean Y chromosomes soon after this•We find no evidence for Holocene male gene flow to Australia from South Asia
Bergström et al. show that Aboriginal Australian Y chromosomes diverged from Eurasian, including South Asian, Y chromosomes ∼50,000 years ago. This is around the time that Australia was first populated and thus disproves the previous hypothesis of prehistoric Y chromosome gene flow from India ∼5,000 years ago.
PMCID: PMC4819516  PMID: 26923783
2.  Wide distribution and altitude correlation of an archaic high-altitude-adaptive EPAS1 haplotype in the Himalayas 
Human Genetics  2016;135:393-402.
High-altitude adaptation in Tibetans is influenced by introgression of a 32.7-kb haplotype from the Denisovans, an extinct branch of archaic humans, lying within the endothelial PAS domain protein 1 (EPAS1), and has also been reported in Sherpa. We genotyped 19 variants in this genomic region in 1507 Eurasian individuals, including 1188 from Bhutan and Nepal residing at altitudes between 86 and 4550 m above sea level. Derived alleles for five SNPs characterizing the core Denisovan haplotype (AGGAA) were present at high frequency not only in Tibetans and Sherpa, but also among many populations from the Himalayas, showing a significant correlation with altitude (Spearman’s correlation coefficient = 0.75, p value 3.9 × 10−11). Seven East- and South-Asian 1000 Genomes Project individuals shared the Denisovan haplotype extending beyond the 32-kb region, enabling us to refine the haplotype structure and identify a candidate regulatory variant (rs370299814) that might be interacting in an additive manner with the derived G allele of rs150877473, the variant previously associated with high-altitude adaptation in Tibetans. Denisovan-derived alleles were also observed at frequencies of 3–14 % in the 1000 Genomes Project African samples. The closest African haplotype is, however, separated from the Asian high-altitude haplotype by 22 mutations whereas only three mutations, including rs150877473, separate the Asians from the Denisovan, consistent with distant shared ancestry for African and Asian haplotypes and Denisovan adaptive introgression.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-016-1641-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4796332  PMID: 26883865
3.  Genomic evidence for the Pleistocene and recent population history of Native Americans 
Raghavan, Maanasa | Steinrücken, Matthias | Harris, Kelley | Schiffels, Stephan | Rasmussen, Simon | DeGiorgio, Michael | Albrechtsen, Anders | Valdiosera, Cristina | Ávila-Arcos, María C. | Malaspinas, Anna-Sapfo | Eriksson, Anders | Moltke, Ida | Metspalu, Mait | Homburger, Julian R. | Wall, Jeff | Cornejo, Omar E. | Moreno-Mayar, J. Víctor | Korneliussen, Thorfinn S. | Pierre, Tracey | Rasmussen, Morten | Campos, Paula F. | de Barros Damgaard, Peter | Allentoft, Morten E. | Lindo, John | Metspalu, Ene | Rodríguez-Varela, Ricardo | Mansilla, Josefina | Henrickson, Celeste | Seguin-Orlando, Andaine | Malmström, Helena | Stafford, Thomas | Shringarpure, Suyash S. | Moreno-Estrada, Andrés | Karmin, Monika | Tambets, Kristiina | Bergström, Anders | Xue, Yali | Warmuth, Vera | Friend, Andrew D. | Singarayer, Joy | Valdes, Paul | Balloux, Francois | Leboreiro, Ilán | Vera, Jose Luis | Rangel-Villalobos, Hector | Pettener, Davide | Luiselli, Donata | Davis, Loren G. | Heyer, Evelyne | Zollikofer, Christoph P. E. | Ponce de León, Marcia S. | Smith, Colin I. | Grimes, Vaughan | Pike, Kelly-Anne | Deal, Michael | Fuller, Benjamin T. | Arriaza, Bernardo | Standen, Vivien | Luz, Maria F. | Ricaut, Francois | Guidon, Niede | Osipova, Ludmila | Voevoda, Mikhail I. | Posukh, Olga L. | Balanovsky, Oleg | Lavryashina, Maria | Bogunov, Yuri | Khusnutdinova, Elza | Gubina, Marina | Balanovska, Elena | Fedorova, Sardana | Litvinov, Sergey | Malyarchuk, Boris | Derenko, Miroslava | Mosher, M. J. | Archer, David | Cybulski, Jerome | Petzelt, Barbara | Mitchell, Joycelynn | Worl, Rosita | Norman, Paul J. | Parham, Peter | Kemp, Brian M. | Kivisild, Toomas | Tyler-Smith, Chris | Sandhu, Manjinder S. | Crawford, Michael | Villems, Richard | Smith, David Glenn | Waters, Michael R. | Goebel, Ted | Johnson, John R. | Malhi, Ripan S. | Jakobsson, Mattias | Meltzer, David J. | Manica, Andrea | Durbin, Richard | Bustamante, Carlos D. | Song, Yun S. | Nielsen, Rasmus | Willerslev, Eske
Science (New York, N.Y.)  2015;349(6250):aab3884.
How and when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we find that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (KYA), and after no more than 8,000-year isolation period in Beringia. Following their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 KYA, one that is now dispersed across North and South America and the other is restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative ‘Paleoamerican’ relict populations, including the historical Mexican Pericúes and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.
PMCID: PMC4733658  PMID: 26198033
4.  Iron Age and Anglo-Saxon genomes from East England reveal British migration history 
Nature Communications  2016;7:10408.
British population history has been shaped by a series of immigrations, including the early Anglo-Saxon migrations after 400 CE. It remains an open question how these events affected the genetic composition of the current British population. Here, we present whole-genome sequences from 10 individuals excavated close to Cambridge in the East of England, ranging from the late Iron Age to the middle Anglo-Saxon period. By analysing shared rare variants with hundreds of modern samples from Britain and Europe, we estimate that on average the contemporary East English population derives 38% of its ancestry from Anglo-Saxon migrations. We gain further insight with a new method, rarecoal, which infers population history and identifies fine-scale genetic ancestry from rare variants. Using rarecoal we find that the Anglo-Saxon samples are closely related to modern Dutch and Danish populations, while the Iron Age samples share ancestors with multiple Northern European populations including Britain.
This study examines ancient genomes of individuals from the late Iron Age to the middle Anglo-Saxon period in the East of England. Using a newly devised analytic algorithm, the author also estimate the relative ancestry of East English genome derived from Anglo-Saxon migrations and to the rest of Europe.
PMCID: PMC4735688  PMID: 26783965
5.  Ancient DNA and the rewriting of human history: be sparing with Occam’s razor 
Genome Biology  2016;17:1.
Ancient DNA research is revealing a human history far more complex than that inferred from parsimonious models based on modern DNA. Here, we review some of the key events in the peopling of the world in the light of the findings of work on ancient DNA.
PMCID: PMC4707776  PMID: 26753840
6.  Genes Regulated by Vitamin D in Bone Cells Are Positively Selected in East Asians 
PLoS ONE  2015;10(12):e0146072.
Vitamin D and folate are activated and degraded by sunlight, respectively, and the physiological processes they control are likely to have been targets of selection as humans expanded from Africa into Eurasia. We investigated signals of positive selection in gene sets involved in the metabolism, regulation and action of these two vitamins in worldwide populations sequenced by Phase I of the 1000 Genomes Project. Comparing allele frequency-spectrum-based summary statistics between these gene sets and matched control genes, we observed a selection signal specific to East Asians for a gene set associated with vitamin D action in bones. The selection signal was mainly driven by three genes CXXC finger protein 1 (CXXC1), low density lipoprotein receptor-related protein 5 (LRP5) and runt-related transcription factor 2 (RUNX2). Examination of population differentiation and haplotypes allowed us to identify several candidate causal regulatory variants in each gene. Four of these candidate variants (one each in CXXC1 and RUNX2 and two in LRP5) had a >70% derived allele frequency in East Asians, but were present at lower (20–60%) frequency in Europeans as well, suggesting that the adaptation might have been part of a common response to climatic and dietary changes as humans expanded out of Africa, with implications for their role in vitamin D-dependent bone mineralization and osteoporosis insurgence. We also observed haplotype sharing between East Asians, Finns and an extinct archaic human (Denisovan) sample at the CXXC1 locus, which is best explained by incomplete lineage sorting.
PMCID: PMC4697808  PMID: 26719974
7.  An extended Tajima’s D neutrality test incorporating SNP calling and imputation uncertainties 
Statistics and its interface  2015;8(4):447-456.
To identify evolutionary events from the footprints left in the patterns of genetic variation in a population, people use many statistical frameworks, including neutrality tests. In datasets from current high throughput sequencing and genotyping platforms, it is common to have missing data and low-confidence SNP calls at many segregating sites. However, the traditional statistical framework for neutrality tests does not allow for these possibilities; therefore the usual way of treating missing data is to ignore segregating sites with missing/low confidence calls, regardless of the good SNP calls at these sites in other individuals. In this work, we propose a modified neutrality test, Extended Tajima’s D, which incorporates missing data and SNP-calling uncertainties. Because we do not specify any particular error-generating mechanism, this approach is robust and widely applicable. Simulations show that in most cases the power of the new test is better than the original Tajima’s D, given the same type I error. Applications to real data show that it detects fewer outliers associated with low quality data.
PMCID: PMC4678577  PMID: 26681995
Neutrality test; Tajima’s D; Missing genotype; Next generation sequencing
8.  Mountain gorilla genomes reveal the impact of long-term population decline and inbreeding 
Science (New York, N.Y.)  2015;348(6231):242-245.
Mountain gorillas are an endangered great ape subspecies and a prominent focus for conservation, yet we know little about their genomic diversity and evolutionary past. We sequenced whole genomes from multiple wild individuals and compared the genomes of all four Gorilla subspecies. We found that the two eastern subspecies have experienced a prolonged population decline over the past 100,000 years, resulting in very low genetic diversity and an increased overall burden of deleterious variation. A further recent decline in the mountain gorilla population has led to extensive inbreeding, such that individuals are typically homozygous at 34% of their sequence, leading to the purging of severely deleterious recessive mutations from the population. We discuss the causes of their decline and the consequences for their future survival.
PMCID: PMC4668944  PMID: 25859046
10.  Global diversity, population stratification, and selection of human copy number variation 
Science (New York, N.Y.)  2015;349(6253):aab3761.
In order to explore the diversity and selective signatures of duplication and deletion human copy number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single nucleotide variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load.
PMCID: PMC4568308  PMID: 26249230
11.  Genetic Heritage of the Balto-Slavic Speaking Populations: A Synthesis of Autosomal, Mitochondrial and Y-Chromosomal Data 
PLoS ONE  2015;10(9):e0135820.
The Slavic branch of the Balto-Slavic sub-family of Indo-European languages underwent rapid divergence as a result of the spatial expansion of its speakers from Central-East Europe, in early medieval times. This expansion–mainly to East Europe and the northern Balkans–resulted in the incorporation of genetic components from numerous autochthonous populations into the Slavic gene pools. Here, we characterize genetic variation in all extant ethnic groups speaking Balto-Slavic languages by analyzing mitochondrial DNA (n = 6,876), Y-chromosomes (n = 6,079) and genome-wide SNP profiles (n = 296), within the context of other European populations. We also reassess the phylogeny of Slavic languages within the Balto-Slavic branch of Indo-European. We find that genetic distances among Balto-Slavic populations, based on autosomal and Y-chromosomal loci, show a high correlation (0.9) both with each other and with geography, but a slightly lower correlation (0.7) with mitochondrial DNA and linguistic affiliation. The data suggest that genetic diversity of the present-day Slavs was predominantly shaped in situ, and we detect two different substrata: ‘central-east European’ for West and East Slavs, and ‘south-east European’ for South Slavs. A pattern of distribution of segments identical by descent between groups of East-West and South Slavs suggests shared ancestry or a modest gene flow between those two groups, which might derive from the historic spread of Slavic people.
PMCID: PMC4558026  PMID: 26332464
12.  The African Genome Variation Project shapes medical genetics in Africa 
Nature  2014;517(7534):327-332.
Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterisation of African genetic diversity is needed. The African Genome Variation Project (AGVP) provides a resource to help design, implement and interpret genomic studies in sub-Saharan Africa (SSA) and worldwide. The AGVP represents dense genotypes from 1,481 and whole genome sequences (WGS) from 320 individuals across SSA. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across SSA. We identify new loci under selection, including for malaria and hypertension. We show that modern imputation panels can identify association signals at highly differentiated loci across populations in SSA. Using WGS, we show further improvement in imputation accuracy supporting efforts for large-scale sequencing of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa, showing for the first time that such designs are feasible.
PMCID: PMC4297536  PMID: 25470054
13.  Expansion of the HSFY gene family in pig lineages 
BMC Genomics  2015;16(1):442.
Amplified gene families on sex chromosomes can harbour genes with important biological functions, especially relating to fertility. The Y-linked heat shock transcription factor (HSFY) family has become amplified on the Y chromosome of the domestic pig (Sus scrofa), in an apparently independent event to an HSFY expansion on the Y chromosome of cattle (Bos taurus). Although the biological functions of HSFY genes are poorly understood, they appear to be involved in gametogenesis in a number of mammalian species, and, in cattle, HSFY gene copy number may correlate with levels of fertility.
We have investigated the HSFY family in domestic pig, and other suid species including warthog, bushpig, babirusa and peccaries. The domestic pig contains at least two amplified variants of HSFY, distinguished predominantly by presence or absence of a SINE within the intron. Both these variants are expressed in testis, and both are present in approximately 50 copies each in a single cluster on the short arm of the Y. The longer form has multiple nonsense mutations rendering it likely non-functional, but many of the shorter forms still have coding potential. Other suid species also have these two variants of HSFY, and estimates of copy number suggest the HSFY family may have amplified independently twice during suid evolution.
The HSFY genes have become amplified in multiple species lineages independently. HSFY is predominantly expressed in testis in domestic pig, a pattern conserved with cattle, in which HSFY may play a role in fertility. Further investigation of the potential associations of HSFY with fertility and testis development may be of agricultural interest.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1650-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4460688  PMID: 26055083
Evolution; Sex chromosomes; Gene sequencing
14.  Structural variation on the human Y chromosome from population-scale resequencing 
Croatian Medical Journal  2015;56(3):194-207.
To investigate the information about Y-structural variants (SVs) in the general population that could be obtained by low-coverage whole-genome sequencing.
We investigated SVs on the male-specific portion of the Y chromosome in the 70 individuals from Africa, Europe, or East Asia sequenced as part of the 1000 Genomes Pilot project, using data from this project and from additional studies on the same samples. We applied a combination of read-depth and read-pair methods to discover candidate Y-SVs, followed by validation using information from the literature, independent sequence and single nucleotide polymorphism-chip data sets, and polymerase chain reaction experiments.
We validated 19 Y-SVs, 2 of which were novel. Non-reference allele counts ranged from 1 to 64. The regions richest in variation were the heterochromatic segments near the centromere or the DYZ19 locus, followed by the ampliconic regions, but some Y-SVs were also present in the X-transposed and X-degenerate regions. In all, 5 of the 27 protein-coding gene families on the Y chromosome varied in copy number.
We confirmed that Y-SVs were readily detected from low-coverage sequence data and were abundant on the chromosome. We also reported both common and rare Y-SVs that are novel.
PMCID: PMC4500966  PMID: 26088844
15.  Copy number variation in the human Y chromosome in the UK population 
Human Genetics  2015;134(7):789-800.
We have assessed copy number variation (CNV) in the male-specific part of the human Y chromosome discovered by array comparative genomic hybridization (array-CGH) in 411 apparently healthy UK males, and validated the findings using SNP genotype intensity data available for 149 of them. After manual curation taking account of the complex duplicated structure of Y-chromosomal sequences, we discovered 22 curated CNV events considered validated or likely, mean 0.93 (range 0–4) per individual. 16 of these were novel. Curated CNV events ranged in size from <1 kb to >3 Mb, and in frequency from 1/411 to 107/411. Of the 24 protein-coding genes or gene families tested, nine showed CNV. These included a large duplication encompassing the AMELY and TBL1Y genes that probably has no phenotypic effect, partial deletions of the TSPY cluster and AZFc region that may influence spermatogenesis, and other variants with unknown functional implications, including abundant variation in the number of RBMY genes and/or pseudogenes, and a novel complex duplication of two segments overlapping the AZFa region and including the 3′ end of the UTY gene.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-015-1562-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4460274  PMID: 25957587
16.  Deep Phylogenetic Analysis of Haplogroup G1 Provides Estimates of SNP and STR Mutation Rates on the Human Y-Chromosome and Reveals Migrations of Iranic Speakers 
PLoS ONE  2015;10(4):e0122968.
Y-chromosomal haplogroup G1 is a minor component of the overall gene pool of South-West and Central Asia but reaches up to 80% frequency in some populations scattered within this area. We have genotyped the G1-defining marker M285 in 27 Eurasian populations (n= 5,346), analyzed 367 M285-positive samples using 17 Y-STRs, and sequenced ~11 Mb of the Y-chromosome in 20 of these samples to an average coverage of 67X. This allowed detailed phylogenetic reconstruction. We identified five branches, all with high geographical specificity: G1-L1323 in Kazakhs, the closely related G1-GG1 in Mongols, G1-GG265 in Armenians and its distant brother clade G1-GG162 in Bashkirs, and G1-GG362 in West Indians. The haplotype diversity, which decreased from West Iran to Central Asia, allows us to hypothesize that this rare haplogroup could have been carried by the expansion of Iranic speakers northwards to the Eurasian steppe and via founder effects became a predominant genetic component of some populations, including the Argyn tribe of the Kazakhs. The remarkable agreement between genetic and genealogical trees of Argyns allowed us to calibrate the molecular clock using a historical date (1405 AD) of the most recent common genealogical ancestor. The mutation rate for Y-chromosomal sequence data obtained was 0.78×10-9 per bp per year, falling within the range of published rates. The mutation rate for Y-chromosomal STRs was 0.0022 per locus per generation, very close to the so-called genealogical rate. The “clan-based” approach to estimating the mutation rate provides a third, middle way between direct farther-to-son comparisons and using archeologically known migrations, whose dates are subject to revision and of uncertain relationship to genetic events.
PMCID: PMC4388827  PMID: 25849548
17.  Insights into the origin of rare haplogroup C3* Y chromosomes in South America from high-density autosomal SNP genotyping 
•Revisited the previous discovery of a rare Y haplogroup in two Ecuador populations.•Hypotheses for the origin of the haplogroup tested with autosomal SNP genotype data.•We favoured one of the three hypotheses, ‘founder plus drift’.
The colonization of Americas is thought to have occurred 15–20 thousand years ago (Kya), with little or no subsequent migration into South America until the European expansions beginning 0.5 Kya. Recently, however, haplogroup C3* Y chromosomes were discovered in two nearby Native American populations from Ecuador. Since this haplogroup is otherwise nearly absent from the Americas but is common in East Asia, and an archaeological link between Ecuador and Japan is known from 6 Kya, an additional migration 6 Kya was suggested. Here, we have generated high-density autosomal SNP genotypes from the Ecuadorian populations and compared them with genotypes from East Asia and elsewhere to evaluate three hypotheses: a recent migration from Japan, a single pulse of migration from Japan 6 Kya, and no migration after the First Americans. First, using forward-time simulations and an appropriate demographic model, we investigated our power to detect both ancient and recent gene flow at different levels. Second, we analyzed 207,321 single nucleotide polymorphisms from 16 Ecuadorian individuals, comparing them with populations from the HGDP panel using descriptive and formal tests for admixture. Our simulations revealed good power to detect recent admixture, and that ≥5% admixture 6 Kya ago could be detected. However, in the experimental data we saw no evidence of gene flow from Japan to Ecuador. In summary, we can exclude recent migration and probably admixture 6 Kya as the source of the C3* Y chromosomes in Ecuador, and thus suggest that they represent a rare founding lineage lost by drift elsewhere.
PMCID: PMC4312352  PMID: 25435155
Past human migrations; Ecuador; Admixture; Simulations
18.  Genetic characterisation of Greek population isolates reveals strong genetic drift at missense and trait-associated variants 
Nature communications  2014;5:5345.
Isolated populations are emerging as a powerful study design in the search for low frequency and rare variant associations with complex phenotypes. Here we genotype 2,296 samples from two isolated Greek populations, the Pomak villages (HELIC-Pomak) in the North of Greece; and the Mylopotamos villages (HELIC-MANOLIS) on Crete. We compare their genomic characteristics to the general Greek population and establish them as genetic isolates. In the MANOLIS cohort we observe an enrichment of missense variants amongst the variants that have drifted up in frequency by >5 fold. In the Pomak cohort we find novel associations at variants on chr11p15.4 showing large allele frequency increases (from 0.2% in the general Greek population to 4.6% in the isolate) with haematological traits, for example with mean corpuscular volume (rs7116019, p=2.3×10−26). We replicate this association in a second set of Pomak samples (combined p=2.0×10−36). We demonstrate significant power gains in detecting medical trait associations.
PMCID: PMC4242463  PMID: 25373335
19.  The Y-Chromosome Tree Bursts into Leaf: 13,000 High-Confidence SNPs Covering the Majority of Known Clades 
Molecular Biology and Evolution  2014;32(3):661-673.
Many studies of human populations have used the male-specific region of the Y chromosome (MSY) as a marker, but MSY sequence variants have traditionally been subject to ascertainment bias. Also, dating of haplogroups has relied on Y-specific short tandem repeats (STRs), involving problems of mutation rate choice, and possible long-term mutation saturation. Next-generation sequencing can ascertain single nucleotide polymorphisms (SNPs) in an unbiased way, leading to phylogenies in which branch-lengths are proportional to time, and allowing the times-to-most-recent-common-ancestor (TMRCAs) of nodes to be estimated directly. Here we describe the sequencing of 3.7 Mb of MSY in each of 448 human males at a mean coverage of 51×, yielding 13,261 high-confidence SNPs, 65.9% of which are previously unreported. The resulting phylogeny covers the majority of the known clades, provides date estimates of nodes, and constitutes a robust evolutionary framework for analyzing the history of other classes of mutation. Different clades within the tree show subtle but significant differences in branch lengths to the root. We also apply a set of 23 Y-STRs to the same samples, allowing SNP- and STR-based diversity and TMRCA estimates to be systematically compared. Ongoing purifying selection is suggested by our analysis of the phylogenetic distribution of nonsynonymous variants in 15 MSY single-copy genes.
PMCID: PMC4327154  PMID: 25468874
Y-chromosome phylogeny; single nucleotide polymorphisms; targeted resequencing; Y-STRs; purifying selection
20.  Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants 
Nature Communications  2014;5:5345.
Isolated populations are emerging as a powerful study design in the search for low-frequency and rare variant associations with complex phenotypes. Here we genotype 2,296 samples from two isolated Greek populations, the Pomak villages (HELIC-Pomak) in the North of Greece and the Mylopotamos villages (HELIC-MANOLIS) in Crete. We compare their genomic characteristics to the general Greek population and establish them as genetic isolates. In the MANOLIS cohort, we observe an enrichment of missense variants among the variants that have drifted up in frequency by more than fivefold. In the Pomak cohort, we find novel associations at variants on chr11p15.4 showing large allele frequency increases (from 0.2% in the general Greek population to 4.6% in the isolate) with haematological traits, for example, with mean corpuscular volume (rs7116019, P=2.3 × 10−26). We replicate this association in a second set of Pomak samples (combined P=2.0 × 10−36). We demonstrate significant power gains in detecting medical trait associations.
Isolated populations can increase power to detect low frequency and rare risk variants associated with complex phenotypes. Here, the authors identify variants associated with haematological traits in two isolated Greek populations that would be difficult to detect in the general population, due to their low frequency.
PMCID: PMC4242463  PMID: 25373335
21.  Gene Conversion Violates the Stepwise Mutation Model for Microsatellites in Y-Chromosomal Palindromic Repeats 
Human Mutation  2014;35(5):609-617.
The male-specific region of the human Y chromosome (MSY) contains eight large inverted repeats (palindromes), in which high-sequence similarity between repeat arms is maintained by gene conversion. These palindromes also harbor microsatellites, considered to evolve via a stepwise mutation model (SMM). Here, we ask whether gene conversion between palindrome microsatellites contributes to their mutational dynamics. First, we study the duplicated tetranucleotide microsatellite DYS385a,b lying in palindrome P4. We show, by comparing observed data with simulated data under a SMM within haplogroups, that observed heteroallelic combinations in which the modal repeat number difference between copies was large, can give rise to homoallelic combinations with zero-repeats difference, equivalent to many single-step mutations. These are unlikely to be generated under a strict SMM, suggesting the action of gene conversion. Second, we show that the intercopy repeat number difference for a large set of duplicated microsatellites in all palindromes in the MSY reference sequence is significantly reduced compared with that for nonpalindrome-duplicated microsatellites, suggesting that the former are characterized by unusual evolutionary dynamics. These observations indicate that gene conversion violates the SMM for microsatellites in palindromes, homogenizing copies within individual Y chromosomes, but increasing overall haplotype diversity among chromosomes within related groups.
PMCID: PMC4233959  PMID: 24610746
Y chromosome; gene conversion; palindrome; microsatellite; stepwise mutation model; DYS385
22.  Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer 
Nature genetics  2014;46(5):487-491.
The somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the life of the cancer patient1-3. Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures1,4 and a signature of localized hypermutation called kataegis1,4. A germline copy number polymorphism involving APOBEC3A and APOBEC3B, which effectively deletes APOBEC3B5, has been associated with a modest increased risk of breast cancer6-8. Here, we show that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers. The results suggest that the APOBEC3A/3B germline deletion allele confers cancer susceptibility through increased activity of APOBEC-dependent mutational processes, although the mechanism by which this occurs remains unknown.
PMCID: PMC4137149  PMID: 24728294
23.  Using ancestry-informative markers to identify fine structure across 15 populations of European origin 
European Journal of Human Genetics  2014;22(10):1190-1200.
The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify population structure in such studies using only common variants with minor allele frequency (MAF) >5% we find that this may result in highly informative SNPs being discarded, and suggest that instead all SNPs with MAF >1% may be used. We established informative axes of variation identified via principal component analysis and highlight important features of the genetic structure of diverse European-descent populations, some studied for the first time at this scale. Finally, we investigated the substructure within each of these 15 populations and identified SNPs that help capture hidden stratification. This work can provide information regarding the designing and interpretation of association results in the International Consortia.
PMCID: PMC4169539  PMID: 24549058
population stratification; AIMs; principal component analysis
24.  A global analysis of Y-chromosomal haplotype diversity for 23 STR loci 
Purps, Josephine | Siegert, Sabine | Willuweit, Sascha | Nagy, Marion | Alves, Cíntia | Salazar, Renato | Angustia, Sheila M.T. | Santos, Lorna H. | Anslinger, Katja | Bayer, Birgit | Ayub, Qasim | Wei, Wei | Xue, Yali | Tyler-Smith, Chris | Bafalluy, Miriam Baeta | Martínez-Jarreta, Begoña | Egyed, Balazs | Balitzki, Beate | Tschumi, Sibylle | Ballard, David | Court, Denise Syndercombe | Barrantes, Xinia | Bäßler, Gerhard | Wiest, Tina | Berger, Burkhard | Niederstätter, Harald | Parson, Walther | Davis, Carey | Budowle, Bruce | Burri, Helen | Borer, Urs | Koller, Christoph | Carvalho, Elizeu F. | Domingues, Patricia M. | Chamoun, Wafaa Takash | Coble, Michael D. | Hill, Carolyn R. | Corach, Daniel | Caputo, Mariela | D’Amato, Maria E. | Davison, Sean | Decorte, Ronny | Larmuseau, Maarten H.D. | Ottoni, Claudio | Rickards, Olga | Lu, Di | Jiang, Chengtao | Dobosz, Tadeusz | Jonkisz, Anna | Frank, William E. | Furac, Ivana | Gehrig, Christian | Castella, Vincent | Grskovic, Branka | Haas, Cordula | Wobst, Jana | Hadzic, Gavrilo | Drobnic, Katja | Honda, Katsuya | Hou, Yiping | Zhou, Di | Li, Yan | Hu, Shengping | Chen, Shenglan | Immel, Uta-Dorothee | Lessig, Rüdiger | Jakovski, Zlatko | Ilievska, Tanja | Klann, Anja E. | García, Cristina Cano | de Knijff, Peter | Kraaijenbrink, Thirsa | Kondili, Aikaterini | Miniati, Penelope | Vouropoulou, Maria | Kovacevic, Lejla | Marjanovic, Damir | Lindner, Iris | Mansour, Issam | Al-Azem, Mouayyad | Andari, Ansar El | Marino, Miguel | Furfuro, Sandra | Locarno, Laura | Martín, Pablo | Luque, Gracia M. | Alonso, Antonio | Miranda, Luís Souto | Moreira, Helena | Mizuno, Natsuko | Iwashima, Yasuki | Neto, Rodrigo S. Moura | Nogueira, Tatiana L.S. | Silva, Rosane | Nastainczyk-Wulf, Marina | Edelmann, Jeanett | Kohl, Michael | Nie, Shengjie | Wang, Xianping | Cheng, Baowen | Núñez, Carolina | Pancorbo, Marian Martínez de | Olofsson, Jill K. | Morling, Niels | Onofri, Valerio | Tagliabracci, Adriano | Pamjav, Horolma | Volgyi, Antonia | Barany, Gusztav | Pawlowski, Ryszard | Maciejewska, Agnieszka | Pelotti, Susi | Pepinski, Witold | Abreu-Glowacka, Monica | Phillips, Christopher | Cárdenas, Jorge | Rey-Gonzalez, Danel | Salas, Antonio | Brisighelli, Francesca | Capelli, Cristian | Toscanini, Ulises | Piccinini, Andrea | Piglionica, Marilidia | Baldassarra, Stefania L. | Ploski, Rafal | Konarzewska, Magdalena | Jastrzebska, Emila | Robino, Carlo | Sajantila, Antti | Palo, Jukka U. | Guevara, Evelyn | Salvador, Jazelyn | Ungria, Maria Corazon De | Rodriguez, Jae Joseph Russell | Schmidt, Ulrike | Schlauderer, Nicola | Saukko, Pekka | Schneider, Peter M. | Sirker, Miriam | Shin, Kyoung-Jin | Oh, Yu Na | Skitsa, Iulia | Ampati, Alexandra | Smith, Tobi-Gail | Calvit, Lina Solis de | Stenzl, Vlastimil | Capal, Thomas | Tillmar, Andreas | Nilsson, Helena | Turrina, Stefania | De Leo, Domenico | Verzeletti, Andrea | Cortellini, Venusia | Wetton, Jon H. | Gwynne, Gareth M. | Jobling, Mark A. | Whittle, Martin R. | Sumita, Denilce R. | Wolańska-Nowak, Paulina | Yong, Rita Y.Y. | Krawczak, Michael | Nothnagel, Michael | Roewer, Lutz
In a worldwide collaborative effort, 19,630 Y-chromosomes were sampled from 129 different populations in 51 countries. These chromosomes were typed for 23 short-tandem repeat (STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, GATAH4, DYS481, DYS533, DYS549, DYS570, DYS576, and DYS643) and using the PowerPlex Y23 System (PPY23, Promega Corporation, Madison, WI). Locus-specific allelic spectra of these markers were determined and a consistently high level of allelic diversity was observed. A considerable number of null, duplicate and off-ladder alleles were revealed. Standard single-locus and haplotype-based parameters were calculated and compared between subsets of Y-STR markers established for forensic casework. The PPY23 marker set provides substantially stronger discriminatory power than other available kits but at the same time reveals the same general patterns of population structure as other marker sets. A strong correlation was observed between the number of Y-STRs included in a marker set and some of the forensic parameters under study. Interestingly a weak but consistent trend toward smaller genetic distances resulting from larger numbers of markers became apparent.
PMCID: PMC4127773  PMID: 24854874
Gene diversity; Discriminatory power; AMOVA; Population structure; Database
25.  Human genomic regions with exceptionally high levels of population differentiation identified from 911 whole-genome sequences 
Genome Biology  2014;15(6):R88.
Population differentiation has proved to be effective for identifying loci under geographically localized positive selection, and has the potential to identify loci subject to balancing selection. We have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes.
We demonstrate that while sites with low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively.
We identify known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research.
PMCID: PMC4197830  PMID: 24980144

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