Adaptatiivsete tunnuste gen eetika ja soo-spetsiifilised demograafilised protsessid Lõuna-Aasia populatsioonides

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Oma kuulsas, enam kui 140 aasta eest avaldatud raamatus “Inimese põlvnemine”, pööras suur Briti loodusteadlane Charles Darwin olulist tähelepanu inimpopulatsioonide varieerumisele. Ta põhjendas veenvalt, et vaatamata märkimisväärsele fenotüüpsele ja kultuurilisele mitmekesisusele on inimkonda õige ette kujutada ühtse rassina, kes jagab kusagil sügavas minevikus ühist päritolu suurte inimahvidega. Lisaks juhtis ta tähelepanu asjaolule, et oluline osa sellest mitmekesisusest on seletatav loodusliku valikuga ning rõhutas populatsioonide segunemise võimalikku tähtsust. Darwini mõtted omasid ulatuslikku mõju nii teaduses kui laiemalt, kuid alles viimase paarikümne aasta jooksul, seoses uute uurimismeetodite kasutuselevõtmisega, oleme me hakanud mõistma fenotüüpse varieeruvuse geneetilist tausta. Populatsioonigeneetika on tänu andmekogumise ja analüüsi meetodite täiustumisele muutunud kiiresti arenevaks uurimissuunaks. Samas on see alles arengu algfaasis, sest põhjuslikud seletused nõuavad geneetika ja genoomika sünteesi ja evolutsioonilist argumentatsiooni koos süvateadmistega inimese füsioloogiast, biokeemiast ja arengubioloogiast, mis on sageli põimunud meie kui liigi sotsiaalse ja kultuurilise arenguga laiemas tähenduses. Lõuna-Aasia keeleline, sotsiaalne ja fenotüübiline vahelduvus pakub võimaluse uurida erinevaid evolutsioonilisi hüpoteese detailiderikkas mudelsüsteemis eesmärgiga rekonstrueerida sündmusi, mis on kujundanud meid selliseks, nagu me oleme tänapäeval. Käesolevas doktoritöös on Lõuna-Aasia populatsioonid mudeliks kahe laiema eesmärgi täitmisel. Esmalt, leida geneetilised tegurid kahele inimesele kui liigile olulisele kohastumusele - nahavärvile ja laktaasi aktiivsuse elukestvale püsimisele (LAEP), võimele seedida piimasuhkrut ka täiskasvanuna. Teiseks, rekonstrueerida Lõuna- ja Kagu-Aasias elavate austroaasia keeli rääkivate rahvaste demograafiline ajalugu. Ekspeditsioonil Indiasse mõõtsime kohalike elanike nahapigmentatsiooni. Leidsime, et India elanike nahavärv varieerub suures ulatuses ning selle eest vastutab olulisel määral SLC24A5 geen. Uurisime selle lookuse erinevate alleelide tänast esinemissagedust mõjutanud loodusliku valiku mustreid, fülogeneetilisi suhted ja varieeruvust inimpopulatsioonides üle maailma. Leidsime, et Lääne-Euraasia ja Lõuna-Aasia elanikel on ühine heleda nahavärviga seotud SLC24A5 geeni variant, mis on ühtlasi evolutsiooniliselt samatekkeline. Laktaasi geeni LCT võimendusjärjestuse piirkonna uuring andis põhjaliku ülevaate LAEP`i põhjustest Lõuna-Aasias. Naha värvi ja LAEP’i põhjustavate kandidaat-SNPde (rs1426654 ja -13910T) fülogeograafiline uuring näitas, et nende tunnuste evolutsioonis on olulised loodusliku valiku ja demograafia ühismõjud. Töö teise eesmärgi saavutamiseks kasutasime erinevaid andmestikke - üle kogu genoomi jaotunud autosoomseid SNPsid, ema- ja isaliine. Just autosoomsete SNPde analüüs tõi esmakordselt tõendeid kahesuunalisest geenivoolust Bengali lahe kallastel. Väidame, et tänapäeva India austroaasia keeli, vähemalt munda keeli, kõnelevad rahvad pärinevad Kagu-Aasia väljarännetest ja hilisemast segunemisest India elanikega. Töö tulemused toovad esile tänapäeva Lõuna-Aasia populatsioonide geneetilist struktuuri mõjutanud demograafilised protsessid ja on oluliselt parandanud uuritud kohastumuste üldist mõistmist.In “The Descent of Man”, his famous book published more than 140 years ago, the great British naturalist Charles Darwin, devoted much attention to the variation within and across human populations. He convincingly argued that humanity, irrespective of considerable phenotypic and cultural differences, is a single race that shares a common root with greater apes in some distant past. Furthermore, he also pointed out that much of the observed variation can be explained by natural selection and stressed on the potential role of admixture between human communities. Darwin’s ideas had a considerable influence both for science and much wider. But only over the last decades, with better approaches available, we are beginning to understand the genetic basis of the phenotypic variation and various human adaptations. The field of population genetics, with its advancements in data acquisition and analysis, is by now a fast-growing active field of scientific enquiry, yet very much still in its initial stages, because causative explanations require synthesis of genetics and genomics, evolutionary reasoning, with in-depth knowledge of human physiology, biochemistry and developmental biology, often linked to social and cultural advancements of our species in a broader sense. South Asia, bearing in mind geographic, linguistic, socio-cultural and phenotypic diversity of the region, offers a rich in detailed model system to test various evolutionary hypotheses and to reconstruct the events that helped us to shape what we are today. Hence, in the current dissertation, we have broadly covered two general aims related to human diversity. Firstly, to decipher the genetic attributes of two important adaptive traits in humans - skin color and lactase persistence (the unique ability to digest lactose in adulthood) and secondly, to reconstruct the population history of Austroasiatic-speaking populations presently settled in South and Southeast Asia. Our expedition, involving skin color measurements, reflected high pigmentation diversity among local inhabitants. Our further analyses revealed SLC24A5 as one of the main determinants of skin pigmentation variation among South Asians. Additionally, an evolutionary approach was used to study the gene and important insights on the selection patterns, phylogenetic relationships and diversity patterns among global populations were obtained. We found that light skin associated variant of SLC24A5, shared by West Eurasians and South Asians, occur on the same haplotype background and we suggest its identity by descent. Our study of enhancer region of LCT among Indian populations provided a comprehensive view on the genetic basis of lactase persistence in the subcontinent. Phylogeography of the important candidate SNPs for the studied traits further revealed that combination of processes involving selection and demography have been crucial in the evolution of these traits. An integrated genetic approach of mitochondrial DNA, Y chromosome and autosomes to delineate the ancestry palette of Austroasiatic-speaking populations refined our understanding of their origin and dispersal routes. Autosomal analyses, in particular, provided the first evidence of bidirectional gene flow(s) alongside of the Bay-of-Bengal. We propose that the present-day Austroasiatics, at least in case of Munda, are derived from dispersal from Southeast Asia, followed by admixture with local Indian populations. The conclusions obtained in the dissertation thus bear significance in improving our general understanding of the evolutionary architecture of the studied adaptive traits and unique demographic processes that govern the genetic structuring of the present-day South Asians

The light skin allele of SLC24A5 in South Asians and Europeans shares identity by descent

Skin pigmentation is one of the most variable phenotypic traits in humans. A non-synonymous substitution (rs1426654) in the third exon of SLC24A5 accounts for lighter skin in Europeans but not in East Asians. A previous genome-wide association study carried out in a heterogeneous sample of UK immigrants of South Asian descent suggested that this gene also contributes significantly to skin pigmentation variation among South Asians. In the present study, we have quantitatively assessed skin pigmentation for a largely homogeneous cohort of 1228 individuals from the Southern region of the Indian subcontinent. Our data confirm significant association of rs1426654 SNP with skin pigmentation, explaining about 27% of total phenotypic variation in the cohort studied. Our extensive survey of the polymorphism in 1573 individuals from 54 ethnic populations across the Indian subcontinent reveals wide presence of the derived-A allele, although the frequencies vary substantially among populations. We also show that the geospatial pattern of this allele is complex, but most importantly, reflects strong influence of language, geography and demographic history of the populations. Sequencing 11.74 kb of SLC24A5 in 95 individuals worldwide reveals that the rs1426654-A alleles in South Asian and West Eurasian populations are monophyletic and occur on the background of a common haplotype that is characterized by low genetic diversity. We date the coalescence of the light skin associated allele at 22–28 KYA. Both our sequence and genome-wide genotype data confirm that this gene has been a target for positive selection among Europeans. However, the latter also shows additional evidence of selection in populations of the Middle East, Central Asia, Pakistan and North India but not in South India

The genetic structure of south Asian populations as revealed by 650 000 SNPs

The analyses of dense marker sets covering the whole genome has revolutionised the field of (human) population genetics. Driven largely by the needs of biomedical research, these new data are helping to unveil our demographic past, exemplified by the study of mtDNA and Y-chromosome variation during the past ∼20 years. We have analysed (Illumina 650K SNPs) over 320 new samples from South and Central Asia and the Caucasus, together with the publicly available databases (HGDP panel and our published data set of ∼600 Eurasian samples) and illustrated the power of full genome analyses by addressing two specific questions. (i) What is the nature of genetic continuity and discontinuity between South Asia, Middle East and Central Asia? (ii) What are the genetic origins of the Munda speakers of India? We use principal component and structure-like analyses to reveal the structure in the genome wide SNP data. The most striking feature of the genetic structure of South Asian populations is the clear separation of the Indus valley and southern India populations. The genetic component prevalent in the latter region is marginal in the former and absent outside South Asia. By contrast, the component ubiquitous to Indus valley is also present (∼30-40 %) among Indo-European speakers from Ganges valley and Dravidic speakers in southern India. Furthermore, this component can also be found in Central Asia and the Caucasus as well as in Middle East. We explored possibilities to identify the source region for this genetic component. Alternative models put the origins of Munda languages speakers either in South Asia (the Munda speakers sport exclusively autochthonous South Asian mtDNA variants) or in Southeast Asia, where the other Austro Asiatic languages have spread. Y-chromosome variation supports the latter model through sharing of hg O2a in both regions. We show that in addition to the dominant ancestry component being shared between the Indian Dravidic and Munda speakers, up to 30% of Munda speakers retain an ancestry component otherwise prevalent in East Asia. There is no widespread sign of South Asian ancestry component in Southeast Asia. This provides genomic support to the model by which Indian Austro-Asiatic populations derive from dispersal from Southeast/East Asia, followed by an extensive admixture with local Indian populations

The light skin allele of SLC24A5 in South Asians and Europeans shares identity by descent.

Skin pigmentation is one of the most variable phenotypic traits in humans. A non-synonymous substitution (rs1426654) in the third exon of SLC24A5 accounts for lighter skin in Europeans but not in East Asians. A previous genome-wide association study carried out in a heterogeneous sample of UK immigrants of South Asian descent suggested that this gene also contributes significantly to skin pigmentation variation among South Asians. In the present study, we have quantitatively assessed skin pigmentation for a largely homogeneous cohort of 1228 individuals from the Southern region of the Indian subcontinent. Our data confirm significant association of rs1426654 SNP with skin pigmentation, explaining about 27% of total phenotypic variation in the cohort studied. Our extensive survey of the polymorphism in 1573 individuals from 54 ethnic populations across the Indian subcontinent reveals wide presence of the derived-A allele, although the frequencies vary substantially among populations. We also show that the geospatial pattern of this allele is complex, but most importantly, reflects strong influence of language, geography and demographic history of the populations. Sequencing 11.74 kb of SLC24A5 in 95 individuals worldwide reveals that the rs1426654-A alleles in South Asian and West Eurasian populations are monophyletic and occur on the background of a common haplotype that is characterized by low genetic diversity. We date the coalescence of the light skin associated allele at 22-28 KYA. Both our sequence and genome-wide genotype data confirm that this gene has been a target for positive selection among Europeans. However, the latter also shows additional evidence of selection in populations of the Middle East, Central Asia, Pakistan and North India but not in South India

Phylogeography of mtDNA haplogroup R7 in the Indian peninsula.

BACKGROUND: Human genetic diversity observed in Indian subcontinent is second only to that of Africa. This implies an early settlement and demographic growth soon after the first 'Out-of-Africa' dispersal of anatomically modern humans in Late Pleistocene. In contrast to this perspective, linguistic diversity in India has been thought to derive from more recent population movements and episodes of contact. With the exception of Dravidian, which origin and relatedness to other language phyla is obscure, all the language families in India can be linked to language families spoken in different regions of Eurasia. Mitochondrial DNA and Y chromosome evidence has supported largely local evolution of the genetic lineages of the majority of Dravidian and Indo-European speaking populations, but there is no consensus yet on the question of whether the Munda (Austro-Asiatic) speaking populations originated in India or derive from a relatively recent migration from further East. RESULTS: Here, we report the analysis of 35 novel complete mtDNA sequences from India which refine the structure of Indian-specific varieties of haplogroup R. Detailed analysis of haplogroup R7, coupled with a survey of approximately 12,000 mtDNAs from caste and tribal groups over the entire Indian subcontinent, reveals that one of its more recently derived branches (R7a1), is particularly frequent among Munda-speaking tribal groups. This branch is nested within diverse R7 lineages found among Dravidian and Indo-European speakers of India. We have inferred from this that a subset of Munda-speaking groups have acquired R7 relatively recently. Furthermore, we find that the distribution of R7a1 within the Munda-speakers is largely restricted to one of the sub-branches (Kherwari) of northern Munda languages. This evidence does not support the hypothesis that the Austro-Asiatic speakers are the primary source of the R7 variation. Statistical analyses suggest a significant correlation between genetic variation and geography, rather than between genes and languages. CONCLUSION: Our high-resolution phylogeographic study, involving diverse linguistic groups in India, suggests that the high frequency of mtDNA haplogroup R7 among Munda speaking populations of India can be explained best by gene flow from linguistically different populations of Indian subcontinent. The conclusion is based on the observation that among Indo-Europeans, and particularly in Dravidians, the haplogroup is, despite its lower frequency, phylogenetically more divergent, while among the Munda speakers only one sub-clade of R7, i.e. R7a1, can be observed. It is noteworthy that though R7 is autochthonous to India, and arises from the root of hg R, its distribution and phylogeography in India is not uniform. This suggests the more ancient establishment of an autochthonous matrilineal genetic structure, and that isolation in the Pleistocene, lineage loss through drift, and endogamy of prehistoric and historic groups have greatly inhibited genetic homogenization and geographical uniformity.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Genotype-Phenotype Study of the Middle Gangetic Plain in India Shows Association of rs2470102 with Skin Pigmentation

Our understanding of the genetics of skin pigmentation has been largely skewed towards populations of European ancestry, imparting less attention to South Asian populations, who behold huge pigmentation diversity. Here, we investigate skin pigmentation variation in a cohort of 1,167 individuals in the Middle Gangetic Plain of the Indian subcontinent. Our data confirm the association of rs1426654 with skin pigmentation among South Asians, consistent with previous studies, and also show association for rs2470102 single nucleotide polymorphism. Our haplotype analyses further help us delineate the haplotype distribution across social categories and skin color. Taken together, our findings suggest that the social structure defined by the caste system in India has a profound influence on the skin pigmentation patterns of the subcontinent. In particular, social category and associated single nucleotide polymorphisms explain about 32% and 6.4%, respectively, of the total phenotypic variance. Phylogeography of the associated single nucleotide polymorphisms studied across 52 diverse populations of the Indian subcontinent shows wide presence of the derived alleles, although their frequencies vary across populations. Our results show that both polymorphisms (rs1426654 and rs2470102) play an important role in the skin pigmentation diversity of South Asians

Reconstructing the demographic history of the Himalayan and adjoining populations

The rugged topography of the Himalayan region has hindered large-scale human migrations, population admixture and assimilation. Such complexity in geographical structure might have facilitated the existence of several small isolated communities in this region. We have genotyped about 850,000 autosomal markers among 35 individuals belonging to the four major populations inhabiting the Himalaya and adjoining regions. In addition, we have genotyped 794 individuals belonging to 16 ethnic groups from the same region, for uniparental (mitochondrial and Y chromosomal DNA) markers. Our results in the light of various statistical analyses suggest a closer link of the Himalayan and adjoining populations to East Asia than their immediate geographical neighbours in South Asia. Allele frequency-based analyses likely support the existence of a specific ancestry component in the Himalayan and adjoining populations. The admixture time estimate suggests a recent westward migration of populations living to the East of the Himalaya. Furthermore, the uniparental marker analysis among the Himalayan and adjoining populations reveal the presence of East, Southeast and South Asian genetic signatures. Interestingly, we observed an antagonistic association of Y chromosomal haplogroups O3 and D clines with the longitudinal distance. Thus, we summarise that studying the Himalayan and adjoining populations is essential for a comprehensive reconstruction of the human evolutionary and ethnolinguistic history of eastern Eurasia

Limb development genes underlie variation in human fingerprint patterns

Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized “pattern-block” correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning

Genetic variation among species, races, forms and inbred lines of lac insects belonging to the genus Kerria (Homoptera, Tachardiidae)

The lac insects (Homoptera: Tachardiidae), belonging to the genus Kerria, are commercially exploited for the production of lac. Kerria lacca is the most commonly used species in India. RAPD markers were used for assessing genetic variation in forty-eight lines of Kerria, especially among geographic races, infrasubspecific forms, cultivated lines, inbred lines, etc., of K. lacca. In the 48 lines studied, the 26 RAPD primers generated 173 loci, showing 97.7% polymorphism. By using neighbor-joining, the dendrogram generated from the similarity matrix resolved the lines into basically two clusters and outgroups. The major cluster, comprising 32 lines, included mainly cultivated lines of the rangeeni form, geographic races and inbred lines of K. lacca. The second cluster consisted of eight lines of K. lacca, seven of the kusmi form and one of the rangeeni from the southern state of Karnataka. The remaining eight lines formed a series of outgroups, this including a group of three yellow mutant lines of K. lacca and other species of the Kerria studied, among others. Color mutants always showed distinctive banding patterns compared to their wild-type counterparts from the same population. This study also adds support to the current status of kusmi and rangeeni, as infraspecific forms of K. lacca

Genomic analyses inform on migration events during the peopling of Eurasia.

High-coverage whole-genome sequence studies have so far focused on a limited number of geographically restricted populations, or been targeted at specific diseases, such as cancer. Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history and refuelled the debate on the mutation rate in humans. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record, and admixture between AMHs and Neanderthals predating the main Eurasian expansion, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago.Support was provided by: Estonian Research Infrastructure Roadmap grant no 3.2.0304.11-0312; Australian Research Council Discovery grants (DP110102635 and DP140101405) (D.M.L., M.W. and E.W.); Danish National Research Foundation; the Lundbeck Foundation and KU2016 (E.W.); ERC Starting Investigator grant (FP7 - 261213) (T.K.); Estonian Research Council grant PUT766 (G.C. and M.K.); EU European Regional Development Fund through the Centre of Excellence in Genomics to Estonian Biocentre (R.V.; M.Me. and A.Me.), and Centre of Excellence for Genomics and Translational Medicine Project No. 2014-2020.4.01.15-0012 to EGC of UT (A.Me.) and EBC (M.Me.); Estonian Institutional Research grant IUT24-1 (L.S., M.J., A.K., B.Y., K.T., C.B.M., Le.S., H.Sa., S.L., D.M.B., E.M., R.V., G.H., M.K., G.C., T.K. and M.Me.) and IUT20-60 (A.Me.); French Ministry of Foreign and European Affairs and French ANR grant number ANR-14-CE31-0013-01 (F.-X.R.); Gates Cambridge Trust Funding (E.J.); ICG SB RAS (No. VI.58.1.1) (D.V.L.); Leverhulme Programme grant no. RP2011-R-045 (A.B.M., P.G. and M.G.T.); Ministry of Education and Science of Russia; Project 6.656.2014/K (S.A.F.); NEFREX grant funded by the European Union (People Marie Curie Actions; International Research Staff Exchange Scheme; call FP7-PEOPLE-2012-IRSES-number 318979) (M.Me., G.H. and M.K.); NIH grants 5DP1ES022577 05, 1R01DK104339-01, and 1R01GM113657-01 (S.Tis.); Russian Foundation for Basic Research (grant N 14-06-00180a) (M.G.); Russian Foundation for Basic Research; grant 16-04-00890 (O.B. and E.B); Russian Science Foundation grant 14-14-00827 (O.B.); The Russian Foundation for Basic Research (14-04-00725-a), The Russian Humanitarian Scientific Foundation (13-11-02014) and the Program of the Basic Research of the RAS Presidium “Biological diversity” (E.K.K.); Wellcome Trust and Royal Society grant WT104125AIA & the Bristol Advanced Computing Research Centre (http://www.bris.ac.uk/acrc/) (D.J.L.); Wellcome Trust grant 098051 (Q.A.; C.T.-S. and Y.X.); Wellcome Trust Senior Research Fellowship grant 100719/Z/12/Z (M.G.T.); Young Explorers Grant from the National Geographic Society (8900-11) (C.A.E.); ERC Consolidator Grant 647787 ‘LocalAdaptatio’ (A.Ma.); Program of the RAS Presidium “Basic research for the development of the Russian Arctic” (B.M.); Russian Foundation for Basic Research grant 16-06-00303 (E.B.); a Rutherford Fellowship (RDF-10-MAU-001) from the Royal Society of New Zealand (M.P.C.)