Relationships Between Wright's F ST and F IS Statistics in a Context of Wahlund Effect.

Waples (2015) has suggested a formula for the Wahlund effect in a case of unequal contribution of samples from genetically different populations that relates Wright's inbreeding coefficient, F IS , and normalized variance in allele frequencies between populations, F ST . I generalize this relationship to a case of multiple alleles and multiple populations not assuming Hardy-Weinberg ratios prior to mixing. This can help to evaluate the impact of a Wahlund effect on heterozygote deficiency relative to other factors such as null alleles, nonrandom mating, or selection. It is suggested that Wahlund effect cannot be an important factor of deviations from Hardy-Weinberg proportions in natural populations in the majority of instances, but it can have a substantial contribution to heterozygote deficiency in a population that has low genetic diversity compared to that among immigrants or in mixed samples that contain comparable fractions of individuals from genetically different populations.

Extended Y chromosome haplotypes resolve multiple and unique lineages of the Jewish priesthood.

It has been known for over a decade that a majority of men who self report as members of the Jewish priesthood (Cohanim) carry a characteristic Y chromosome haplotype termed the Cohen Modal Haplotype (CMH). The CMH has since been used to trace putative Jewish ancestral origins of various populations. However, the limited number of binary and STR Y chromosome markers used previously did not provide the phylogenetic resolution needed to infer the number of independent paternal lineages that are encompassed within the Cohanim or their coalescence times. Accordingly, we have genotyped 75 binary markers and 12 Y-STRs in a sample of 215 Cohanim from diverse Jewish communities, 1,575 Jewish men from across the range of the Jewish Diaspora, and 2,099 non-Jewish men from the Near East, Europe, Central Asia, and India. While Cohanim from diverse backgrounds carry a total of 21 Y chromosome haplogroups, 5 haplogroups account for 79.5% of Cohanim Y chromosomes. The most frequent Cohanim lineage (46.1%) is marked by the recently reported P58 T->C mutation, which is prevalent in the Near East. Based on genotypes at 12 Y-STRs, we identify an extended CMH on the J-P58* background that predominates in both Ashkenazi and non-Ashkenazi Cohanim and is remarkably absent in non-Jews. The estimated divergence time of this lineage based on 17 STRs is 3,190 +/- 1,090 years. Notably, the second most frequent Cohanim lineage (J-M410*, 14.4%) contains an extended modal haplotype that is also limited to Ashkenazi and non-Ashkenazi Cohanim and is estimated to be 4.2 +/- 1.3 ky old. These results support the hypothesis of a common origin of the CMH in the Near East well before the dispersion of the Jewish people into separate communities, and indicate that the majority of contemporary Jewish priests descend from a limited number of paternal lineages.

Dissecting the molecular architecture and origin of Bayash Romani patrilineages: genetic influences from South-Asia and the Balkans.

The Bayash are a branch of Romanian speaking Roma living dispersedly in Central, Eastern, and Southeastern Europe. To better understand the molecular architecture and origin of the Croatian Bayash paternal gene pool, 151 Bayash Y chromosomes were analyzed for 16 SNPs and 17 STRs and compared with European Romani and non-Romani majority populations from Europe, Turkey, and South Asia. Two main layers of Bayash paternal gene pool were identified: ancestral (Indian) and recent (European). The reduced diversity and expansion signals of H1a patrilineages imply descent from closely related paternal ancestors who could have settled in the Indian subcontinent, possibly as early as between the eighth and tenth centuries AD. The recent layer of the Bayash paternal pool is dominated by a specific subset of E1b1b1a lineages that are not found in the Balkan majority populations. At least two private mutational events occurred in the Bayash during their migrations from the southern Balkans toward Romania. Additional admixture, evident in the low frequencies of typical European haplogroups, J2, R1a, I1, R1b1b2, G, and I2a, took place primarily during the early Bayash settlement in the Balkans and the Romani bondage in Romania. Our results indicate two phenomena in the Bayash and analyzed Roma: a significant preservation of ancestral H1a haplotypes as a result of considerable, but variable level of endogamy and isolation and differential distribution of less frequent, but typical European lineages due to different patterns of the early demographic history in Europe marked by differential admixture and genetic drift.

Y-chromosome diversity characterizes the Gulf of Oman.

Arabia has served as a strategic crossroads for human disseminations, providing a natural connection between the distant populations of China and India in the east to the western civilizations along the Mediterranean. To explore this region's critical role in the migratory episodes leaving Africa to Eurasia and back, high-resolution Y-chromosome analysis of males from the United Arab Emirates (164), Qatar (72) and Yemen (62) was performed. The role of the Levant in the Neolithic dispersal of the E3b1-M35 sublineages is supported by the data, and the distribution and STR-based analyses of J1-M267 representatives points to their spread from the north, most likely during the Neolithic. With the exception of Yemen, southern Arabia, South Iran and South Pakistan display high diversity in their Y-haplogroup substructure possibly a result of gene flow along the coastal crescent-shaped corridor of the Gulf of Oman facilitating human dispersals. Elevated rates of consanguinity may have had an impact in Yemen and Qatar, which experience significant heterozygote deficiencies at various hypervariable autosomal STR loci.

Paleolithic Y-haplogroup heritage predominates in a Cretan highland plateau.

The island of Crete, credited by some historical scholars as a central crucible of western civilization, has been under continuous archeological investigation since the second half of the nineteenth century. In the present work, the geographic stratification of the contemporary Cretan Y-chromosome gene pool was assessed by high-resolution haplotyping to investigate the potential imprints of past colonization episodes and the population substructure. In addition to analyzing the possible geographic origins of Y-chromosome lineages in relatively accessible areas of the island, this study includes samples from the isolated interior of the Lasithi Plateau--a mountain plain located in eastern Crete. The potential significance of the results from the latter region is underscored by the possibility that this region was used as a Minoan refugium. Comparisons of Y-haplogroup frequencies among three Cretan populations as well as with published data from additional Mediterranean locations revealed significant differences in the frequency distributions of Y-chromosome haplogroups within the island. The most outstanding differences were observed in haplogroups J2 and R1, with the predominance of haplogroup R lineages in the Lasithi Plateau and of haplogroup J lineages in the more accessible regions of the island. Y-STR-based analyses demonstrated the close affinity that R1a1 chromosomes from the Lasithi Plateau shared with those from the Balkans, but not with those from lowland eastern Crete. In contrast, Cretan R1b microsatellite-defined haplotypes displayed more resemblance to those from Northeast Italy than to those from Turkey and the Balkans.

A counter-clockwise northern route of the Y-chromosome haplogroup N from Southeast Asia towards Europe.

A large part of Y chromosome lineages in East European and East Asian human populations belong to haplogroup (hg) NO, which is composed of two sister clades N-M231 and O-M175. The O-clade is relatively old (around 30 thousand years (ky)) and encompasses the vast majority of east and Southeast Asian male lineages, as well as significant proportion of those in Oceanian males. On the other hand, our detailed analysis of hg N suggests that its high frequency in east Europe is due to its more recent expansion westward on a counter-clock northern route from inner Asia/southern Siberia, approximately 12-14 ky ago. The widespread presence of hg N in Siberia, together with its absence in Native Americans, implies its spread happened after the founder event for the Americas. The most frequent subclade N3, arose probably in the region of present day China, and subsequently experienced serial bottlenecks in Siberia and secondary expansions in eastern Europe. Another branch, N2, forms two distinctive subclusters of STR haplotypes, Asian (N2-A) and European (N2-E), the latter now mostly distributed in Finno-Ugric and related populations. These phylogeographic patterns provide evidence consistent with male-mediated counter-clockwise late Pleistocene-Holocene migratory trajectories toward Northwestern Europe from an ancestral East Asian source of Paleolithic heritage.

African Y chromosome and mtDNA divergence provides insight into the history of click languages.

BACKGROUND: About 30 languages of southern Africa, spoken by Khwe and San, are characterized by a repertoire of click consonants and phonetic accompaniments. The Jumid R:'hoansi (!Kung) San carry multiple deeply coalescing gene lineages. The deep genetic diversity of the San parallels the diversity among the languages they speak. Intriguingly, the language of the Hadzabe of eastern Africa, although not closely related to any other language, shares click consonants and accompaniments with languages of Khwe and San. RESULTS: We present original Y chromosome and mtDNA variation of Hadzabe and other ethnic groups of Tanzania and Y chromosome variation of San and peoples of the central African forests: Biaka, Mbuti, and Lisongo. In the context of comparable published data for other African populations, analyses of each of these independently inherited DNA segments indicate that click-speaking Hadzabe and Jumid R:'hoansi are separated by genetic distance as great or greater than that between any other pair of African populations. Phylogenetic tree topology indicates a basal separation of the ancient ancestors of these click-speaking peoples. That genetic divergence does not appear to be the result of recent gene flow from neighboring groups. CONCLUSIONS: The deep genetic divergence among click-speaking peoples of Africa and mounting linguistic evidence suggest that click consonants date to early in the history of modern humans. At least two explanations remain viable. Clicks may have persisted for tens of thousands of years, independently in multiple populations, as a neutral trait. Alternatively, clicks may have been retained, because they confer an advantage during hunting in certain environments.

Ranks of genuine associations in whole-genome scans.

With the recent advances in high-throughput genotyping techniques, it is now possible to perform whole-genome association studies to fine map causal polymorphisms underlying important traits that influence susceptibility to human diseases and efficacy of drugs. Once a genome scan is completed the results can be sorted by the association statistic value. What is the probability that true positives will be encountered among the first most associated markers? When a particular polymorphism is found associated with the trait, there is a chance that it represents either a "true" or a "false" association (TA vs. FA). Setting appropriate significance thresholds has been considered to provide assurance of sufficient odds that the associations found to be significant are genuine. However, the problem with genome scans involving thousands of markers is that the statistic values of FAs can reach quite extreme magnitudes. In such situations, the distributions corresponding to TAs and the most extreme FAs become comparable and significance thresholds tend to penalize TAs and FAs in a similar fashion. When sorting between true and false associations, the "typical" place (i.e., rank) of TAs among the most significant outcomes becomes important, ordered by the association statistic value. The distribution of ranks that we study here allows calculation of several useful quantities. In particular, it gives the number of most significant markers needed for a follow-up study to guarantee that a true association is included with certain probability. This can be calculated conditionally on having applied a multiple-testing correction. Effects of multilocus (e.g., haplotype association) tests and impact of linkage disequilibrium on the distribution of ranks associated with TAs are evaluated and can be taken into account.

Separating the post-Glacial coancestry of European and Asian Y chromosomes within haplogroup R1a.

Human Y-chromosome haplogroup structure is largely circumscribed by continental boundaries. One notable exception to this general pattern is the young haplogroup R1a that exhibits post-Glacial coalescent times and relates the paternal ancestry of more than 10% of men in a wide geographic area extending from South Asia to Central East Europe and South Siberia. Its origin and dispersal patterns are poorly understood as no marker has yet been described that would distinguish European R1a chromosomes from Asian. Here we present frequency and haplotype diversity estimates for more than 2000 R1a chromosomes assessed for several newly discovered SNP markers that introduce the onset of informative R1a subdivisions by geography. Marker M434 has a low frequency and a late origin in West Asia bearing witness to recent gene flow over the Arabian Sea. Conversely, marker M458 has a significant frequency in Europe, exceeding 30% in its core area in Eastern Europe and comprising up to 70% of all M17 chromosomes present there. The diversity and frequency profiles of M458 suggest its origin during the early Holocene and a subsequent expansion likely related to a number of prehistoric cultural developments in the region. Its primary frequency and diversity distribution correlates well with some of the major Central and East European river basins where settled farming was established before its spread further eastward. Importantly, the virtual absence of M458 chromosomes outside Europe speaks against substantial patrilineal gene flow from East Europe to Asia, including to India, at least since the mid-Holocene.

Developing STR databases on structured populations: the native South Siberian population versus the Russian population.

Developing a forensic DNA database on a population that consists of local ethnic groups separated by physical and cultural barriers is questionable as it can be genetically subdivided. On the other side, small sizes of ethnic groups, especially in alpine regions where they are sub-structured further into small villages, prevent collecting a large sample from each ethnic group. For such situations, we suggest to obtain both a total population database on allele frequencies across ethnic groups and a list of theta-values between the groups and the total data. We have genotyped 558 individuals from the native population of South Siberia, consisting of nine ethnic groups, at 17 autosomal STR loci of the kit packages AmpFlSTR SGM Plus i, Cyrillic AmpFlSTR Profiler Plus. The groups differentiate from each other with average theta-values of around 1.1%, and some reach up to three to four percent at certain loci. There exists between-village differentiation as well. Therefore, a database for the population of South Siberia is composed of data on allele frequencies in the pool of ethnic groups and data on theta-values that indicate variation in allele frequencies across the groups. Comparison to additional data on northeastern Asia (the Chukchi and Koryak) shows that differentiation in allele frequencies among small groups that are separated by large geographic distance can be even greater. In contrast, populations of Russians that live in large cities of the European part of Russia are homogeneous in allele frequencies, despite large geographic distance between them, and thus can be described by a database on allele frequencies alone, without any specific information on theta-values.

An STR database on the Volga-Ural population.

This work develops a reference STR database on the Volga-Ural population, Russia, comprised of 640 individuals that were sampled from eight ethnic groups (Finno-Ugric Mari, Mordva-Moksha, Mordva-Erzja, Komi-Permjak, and Udmurt, and Turkic-speaking Bashkir, Tatar-Mishary, and Chuvash) and typed with 10 autosomal STR markers: TH01, CSF1P0, FGA, vWA, D3S1358, TPOX, D16S539, D8S1179, D13S317, FES. The groups differentiate in allele frequencies, and therefore we computed theta-values between allele frequencies in each ethnic groups and those in the database as a measure of their differentiation. Nevertheless, the Volga-Ural ethnic groups form a relatively compact cluster that greatly deviate from the Romanic Moldovans and the Turkic Yakuts, taken for comparison, and are closer to the Slavic Russians, Belarusians, and Ukrainians, although significantly differ from those as well.

A reference data base on STR allele frequencies in the Belarus population developed from paternity cases.

The study considers data on 15 STR-loci from paternity cases across Belarus districts from 2004 to the beginning of 2006 (set #1, 580 individuals) and since that to the beginning of 2007 (set #2, 530 individuals); the data majorly consist of ethnic Belarusians. No significant difference was found between the sets, as well as between the country districts in which the cases occurred. The allele frequencies obtained are very similar to those based on population survey at common loci. Therefore, a data base can be constructed of data from wide survey on paternity cases. Pooling the sets together provides a reference data base on the Belarus population. Additionally, we compared the allele profiles to those in other Slavic groups from the former USSR: Russians from Moscow and eastern Ukrainians from Kharkov city.

Decreased rate of evolution in Y chromosome STR loci of increased size of the repeat unit.

BACKGROUND: Polymorphic Y chromosome short tandem repeats (STRs) have been widely used in population genetic and evolutionary studies. Compared to di-, tri-, and tetranucleotide repeats, STRs with longer repeat units occur more rarely and are far less commonly used. PRINCIPAL FINDINGS: In order to study the evolutionary dynamics of STRs according to repeat unit size, we analysed variation at 24 Y chromosome repeat loci: 1 tri-, 14 tetra-, 7 penta-, and 2 hexanucleotide loci. According to our results, penta- and hexanucleotide repeats have approximately two times lower repeat variance and diversity than tri- and tetranucleotide repeats, indicating that their mutation rate is about half of that of tri- and tetranucleotide repeats. Thus, STR markers with longer repeat units are more robust in distinguishing Y chromosome haplogroups and, in some cases, phylogenetic splits within established haplogroups. CONCLUSIONS: Our findings suggest that Y chromosome STRs of increased repeat unit size have a lower rate of evolution, which has significant relevance in population genetic and evolutionary studies.

Combining p-values in large-scale genomics experiments.

In large-scale genomics experiments involving thousands of statistical tests, such as association scans and microarray expression experiments, a key question is: Which of the L tests represent true associations (TAs)? The traditional way to control false findings is via individual adjustments. In the presence of multiple TAs, p-value combination methods offer certain advantages. Both Fisher's and Lancaster's combination methods use an inverse gamma transformation. We identify the relation of the shape parameter of that distribution to the implicit threshold value; p-values below that threshold are favored by the inverse gamma method (GM). We explore this feature to improve power over Fisher's method when L is large and the number of TAs is moderate. However, the improvement in power provided by combination methods is at the expense of a weaker claim made upon rejection of the null hypothesis - that there are some TAs among the L tests. Thus, GM remains a global test. To allow a stronger claim about a subset of p-values that is smaller than L, we investigate two methods with an explicit truncation: the rank truncated product method (RTP) that combines the first K-ordered p-values, and the truncated product method (TPM) that combines p-values that are smaller than a specified threshold. We conclude that TPM allows claims to be made about subsets of p-values, while the claim of the RTP is, like GM, more appropriately about all L tests. GM gives somewhat higher power than TPM, RTP, Fisher, and Simes methods across a range of simulations.

A comprehensive population survey on the distribution of STR frequencies in Belarus.

This work develops a detailed STR database from 11 population samples and samples from paternity analyses from different districts of Belarus. The combined data on 2020 individuals form a total database for the country, with the exclusion power of 99.987% based on 11 STR loci. Possible differentiation in allele frequencies between population samples, small in terms of F-statistics and undetectable by standard statistical tests, is discussed.

The Himalayas as a directional barrier to gene flow.

High-resolution Y-chromosome haplogroup analyses coupled with Y-short tandem repeat (STR) haplotypes were used to (1) investigate the genetic affinities of three populations from Nepal--including Newar, Tamang, and people from cosmopolitan Kathmandu (referred to as "Kathmandu" subsequently)--as well as a collection from Tibet and (2) evaluate whether the Himalayan mountain range represents a geographic barrier for gene flow between the Tibetan plateau and the South Asian subcontinent. The results suggest that the Tibetans and Nepalese are in part descendants of Tibeto-Burman-speaking groups originating from Northeast Asia. All four populations are represented predominantly by haplogroup O3a5-M134-derived chromosomes, whose Y-STR-based age (+/-SE) was estimated at 8.1+/-2.9 thousand years ago (KYA), more recent than its Southeast Asian counterpart. The most pronounced difference between the two regions is reflected in the opposing high-frequency distributions of haplogroups D in Tibet and R in Nepal. With the exception of Tamang, both Newar and Kathmandu exhibit considerable similarities to the Indian Y-haplogroup distribution, particularly in their haplogroup R and H composition. These results indicate gene flow from the Indian subcontinent and, in the case of haplogroup R, from Eurasia as well, a conclusion that is also supported by the admixture analysis. In contrast, whereas haplogroup D is completely absent in Nepal, it accounts for 50.6% of the Tibetan Y-chromosome gene pool. Coalescent analyses suggest that the expansion of haplogroup D derivatives--namely, D1-M15 and D3-P47 in Tibet--involved two different demographic events (5.1+/-1.8 and 11.3+/-3.7 KYA, respectively) that are more recent than those of D2-M55 representatives common in Japan. Low frequencies, relative to Nepal, of haplogroup J and R lineages in Tibet are also consistent with restricted gene flow from the subcontinent. Yet the presence of haplogroup O3a5-M134 representatives in Nepal indicates that the Himalayas have been permeable to dispersals from the east. These genetic patterns suggest that this cordillera has been a biased bidirectional barrier.

Difference between evolutionarily effective and germ line mutation rate due to stochastically varying haplogroup size.

Within a Y-chromosome haplogroup defined by unique event mutations, variation in microsatellites can accumulate due to their rapid mutation. Estimates based on pedigrees for the Y-chromosome microsatellite mutation rate are 3 or more times greater than the same estimates from evolutionary considerations. We show by simulation that the haplogroups that survive the stochastic processes of drift and extinction accumulate microsatellite variation at a lower rate than predicted from corresponding pedigree estimates; in particular, under constant total population size, the accumulated variance is on average 3-4 times smaller.

Melanesian and Asian origins of Polynesians: mtDNA and Y chromosome gradients across the Pacific.

The human settlement of the Pacific Islands represents one of the most recent major migration events of mankind. Polynesians originated in Asia according to linguistic evidence or in Melanesia according to archaeological evidence. To shed light on the genetic origins of Polynesians, we investigated over 400 Polynesians from 8 island groups, in comparison with over 900 individuals from potential parental populations of Melanesia, Southeast and East Asia, and Australia, by means of Y chromosome (NRY) and mitochondrial DNA (mtDNA) markers. Overall, we classified 94.1% of Polynesian Y chromosomes and 99.8% of Polynesian mtDNAs as of either Melanesian (NRY-DNA: 65.8%, mtDNA: 6%) or Asian (NRY-DNA: 28.3%, mtDNA: 93.8%) origin, suggesting a dual genetic origin of Polynesians in agreement with the "Slow Boat" hypothesis. Our data suggest a pronounced admixture bias in Polynesians toward more Melanesian men than women, perhaps as a result of matrilocal residence in the ancestral Polynesian society. Although dating methods are consistent with somewhat similar entries of NRY/mtDNA haplogroups into Polynesia, haplotype sharing suggests an earlier appearance of Melanesian haplogroups than those from Asia. Surprisingly, we identified gradients in the frequency distribution of some NRY/mtDNA haplogroups across Polynesia and a gradual west-to-east decrease of overall NRY/mtDNA diversity, not only providing evidence for a west-to-east direction of Polynesian settlements but also suggesting that Pacific voyaging was regular rather than haphazard. We also demonstrate that Fiji played a pivotal role in the history of Polynesia: humans probably first migrated to Fiji, and subsequent settlement of Polynesia probably came from Fiji.

Polarity and temporality of high-resolution y-chromosome distributions in India identify both indigenous and exogenous expansions and reveal minor genetic influence of Central Asian pastoralists.

Although considerable cultural impact on social hierarchy and language in South Asia is attributable to the arrival of nomadic Central Asian pastoralists, genetic data (mitochondrial and Y chromosomal) have yielded dramatically conflicting inferences on the genetic origins of tribes and castes of South Asia. We sought to resolve this conflict, using high-resolution data on 69 informative Y-chromosome binary markers and 10 microsatellite markers from a large set of geographically, socially, and linguistically representative ethnic groups of South Asia. We found that the influence of Central Asia on the pre-existing gene pool was minor. The ages of accumulated microsatellite variation in the majority of Indian haplogroups exceed 10,000-15,000 years, which attests to the antiquity of regional differentiation. Therefore, our data do not support models that invoke a pronounced recent genetic input from Central Asia to explain the observed genetic variation in South Asia. R1a1 and R2 haplogroups indicate demographic complexity that is inconsistent with a recent single history. Associated microsatellite analyses of the high-frequency R1a1 haplogroup chromosomes indicate independent recent histories of the Indus Valley and the peninsular Indian region. Our data are also more consistent with a peninsular origin of Dravidian speakers than a source with proximity to the Indus and with significant genetic input resulting from demic diffusion associated with agriculture. Our results underscore the importance of marker ascertainment for distinguishing phylogenetic terminal branches from basal nodes when attributing ancestral composition and temporality to either indigenous or exogenous sources. Our reappraisal indicates that pre-Holocene and Holocene-era--not Indo-European--expansions have shaped the distinctive South Asian Y-chromosome landscape.