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Rajasthan is a state located in the north-western part of India and it has been cited as a major route of human migration since ancient times. The present study was conducted to find out the genetic affinity of Rajasthani population with the population living in its east and the west. In particular, we compared them with the population of Pakistan which shares the common geographical boundary with the Rajasthan while also having a look at their inter and intra population affinities with the population belonging to other Indian states. We investigated the genetic structure and population parameters of Rajasthani populations obtained for twenty polymorphic autosomal STR loci from 669 unrelated individuals belonging to its three population groups including Mina, Gujjar and the admixed population of Rajasthan. The studied populations showed a wide range of genetic diversity and besides the genetic structure of the studied populations, it was found that the average heterozygosity value was highest among the populations of Rajasthan, possibly, because of gene flow from different directions. Various statistical analyses suggested that the Rajasthani populations had a higher affinity with the North Indian populations rather than with the Pakistani population.

Muthukrishnan Eaaswarkhanth,1,* Motasem Melhem,1,* Prem Sharma,1 Rasheeba Nizam,1 Ashraf Al Madhoun,1 Gyaneshwer Chaubey,2 Osama Alsmadi,3 Ebaa AlOzairi,1 Fahd Al-Mulla11Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman, 15462, Kuwait; 2Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, India; 3Department of Cell Therapy & Applied Genomics, King Hussein Cancer Center, Amman, Jordan*These authors contributed equally to this workBackground: The association of mitochondrial DNA (mtDNA) variations with obesity has been investigated in diverse populations across the world. However, such obesity-associated mtDNA examinations are rarely conducted in Arab populations.Materials and methods: We re-sequencedmtDNA displacement loop (D-loop) region of 395 Arab individuals of Kuwait. We categorized the individuals based on their BMI scores as obese (n=232; BMI ≥30 kg/m2), overweight (n=110; BMI ≥25 kg/m2and G, and m.523delAC were positively correlated with obesity, while m.310T>C, and m.16318A>T were negatively associated. All these variants, except m.16318A>T, remain statistically significant after adjusting for age and gender. We found that the variant m.73A>Gincreases the likelihood of being obese by 6-fold, whereas haplogroup H decreases the probability of being obese in Arab individuals of Kuwait. Haplotype analysis revealed that a haplotype, A263G-C309CT-T310C, defining the H2a clade of H haplogroup, reduces the probability of being obese.Conclusion: Our study reports, for the first time, the obesity-related mtDNA variants in Arabs of Kuwait. Based on the mtDNA D-loop region variations, we detected particular variants and haplogroup that are related with increased and decreased probability of being obese in the Kuwait Arab population. Keywords: obesity, mitochondrial DNA, D-loop, haplogroup, haplotype, SNVs

The Gond comprise the largest tribal group of India with a population exceeding 12 million. Linguistically, the Gond belong to the Gondi–Manda subgroup of the South Central branch of the Dravidian language family. Ethnographers, anthropologists and linguists entertain mutually incompatible hypotheses on their origin. Genetic studies of these people have thus far suffered from the low resolution of the genetic data or the limited number of samples. Therefore, to gain a more comprehensive view on ancient ancestry and genetic affinities of the Gond with the neighbouring populations speaking Indo-European, Dravidian and Austroasiatic languages, we have studied four geographically distinct groups of Gond using high-resolution data. All the Gond groups share a common ancestry with a certain degree of isolation and differentiation. Our allele frequency and haplotype-based analyses reveal that the Gond share substantial genetic ancestry with the Indian Austroasiatic (ie, Munda) groups, rather than with the other Dravidian groups to whom they are most closely related linguistically.

Due to the lack of written records or inscription, the origin and affiliation of Indian Jewish populations with other world populations remain contentious. Previous genetic studies have found evidence for a minor shared ancestry of Indian Jewish with Middle Eastern (Jewish) populations. However, these studies (relied on limited individuals), haven't explored the detailed temporal and spatial admixture process of Indian Jewish populations with the local Indian populations. Here, using large sample size with combination of high resolution biparental (autosomal) and uniparental markers (Y chromosome and mitochondrial DNA), we reconstructed genetic history of Indian Jewish by investigating the patterns of genetic diversity. Consistent with the previous observations, we detected minor Middle Eastern specific ancestry component among Indian Jewish communities, but virtually negligible in their local neighbouring Indian populations. The temporal test of admixture suggested that the first admixture of migrant Jewish populations from Middle East to South India (Cochin) occurred during fifth century. Overall, we concluded that the Jewish migration and admixture in India left a record in their genomes, which can link them to the 'Jewish Diaspora'.

Archaeogenetics was described by Renfrew as ‘the study of the human past using the techniques of molecular genetics’ – involving the collaboration of geneticists with archaeologists, anthropologists, historical linguists, and climatologists. He traced its origins to the pioneering work of Cavalli-Sforza in the 1960s, using classical genetic markers (such as blood groups, etc.). Ammerman and Cavalli-Sforza developed a suite of new approaches, in particular the use of principal component maps, to evaluate the distribution of genetic variation in space. Their results on Europe, in particular, were taken to imply large-scale demic diffusion of farming communities from the Near East with the advent of the Neolithic. The discipline was then renewed in the 1980s by Wilson's work on mitochondrial DNA (mtDNA), as DNA sequencing started to become routine, making it possible for the first time to build genealogical trees of lineages within a species.

South Asian populations harbor a high degree of genetic diversity, due in part to demographic history. Two studies on genome-wide variation in Indian populations have shown that most Indian populations show varying degrees of admixture between ancestral north Indian and ancestral south Indian components. As a result of this structure, genetic variation in India appears to follow a geographic cline. Similarly, Indian populations seem to show detectable differences in diabetes and obesity prevalence between different geographic regions of the country. We tested the hypothesis that genetic variation at diabetes-and obesity-associated loci may be potentially related to different genetic ancestries. We genotyped 2977 individuals from 61 populations across India for 18 SNPs in genes implicated in T2D and obesity. We examined patterns of variation in allele frequency across different geographical gradients and considered state of origin and language affiliation. Our results show that most of the 18 SNPs show no significant correlation with latitude, the geographic cline reported in previous studies, or by language family. Exceptions include KCNQ1 with latitude and THADA and JAK1 with language, which suggests that genetic variation at previously ascertained diabetes-associated loci may only partly mirror geographic patterns of genome-wide diversity in Indian populations.

Väitekirja elektrooniline versioon ei sisalda publikatsioone., Soov mõista Lõuna-Aasia inimasustuse evolutsioonilist ajalugu on olnud juba kaua aega evolutsioonilise, populatsiooni- ja meditsiinigeneetika uurijate huviväljas. Siinses dissertatsioonis läbiviidud uurimistöö keskendus esmajoones makro-haplogrupp M uurimisele, mis moodustab 60% India rahvaste emaliinidest, samuti mõnede, fülogeneetiliselt informatiivsetele makro-haplogrupp R harudele. Meie eesmärgiks oli lokaliseerida haplogruppide ekspansiooni ajas ja ruumis ning testida mudeleid, mis kirjeldavad geenide ja kultuuride vahekorda ning hõimude ja kastide geneetilise varieeruvuse ruumi tervikuna. Analüüs tõi ilmseks mitmeid uusi sügavaid makro-haplogrupp M harusid, mis kinnitab seisukohta nende tekkest Lõuna-Aasias. Indo-euroopa keelt rääkiva Põhja-India mushari populatsiooni uurimine näitas, et nende geneetiline varieeruvus seletub kultuurilise nihkega, millega ei ole kaasnenud olulist geneetilist muutust. Me oletame, et tegemist on laialtlevinenud keelevahetuse fenomeniga. Meie uuringud teiste mtDNA haplogruppide, spetsiifiliselt R7 osas näitasid, et ürgsete emaliinide levikupilt seletub esmajoones subkontinendi geograafilise, mitte aga keelelise maastikuga. Kokkuvõttes me järeldame, et ulatuslik endogaamia, tingituna arvukatest kastide- ja hõimudesisestest ja -vahelistest sotsiaalsetest tõketest, võimendatuna lisaks erinevate evolutsiooniliste mõjurite poolt, nagu juhuslik geneetiline triiv, populatsioonide fragmenteerumine, kuid seda pikaajalise kõrge asustustiheduse foonil, on hoidnud India subkondinendi populatsioonid geneetiliselt mitmekesistena ja erinevatena. Rohkete autohtoonsete geeniliinide olemasolu Lõuna-Aasias näitab omakorda seda, et iseäranis sealsed emaliinide variatsioonid ei ole olulisel määral väljunud regioonist peale selle esmaasustamist ning mtDNA algse varieeruvuse teket. Saadud andmestik võimaldab kavandada mitmeid uusi uurimissuundi selleks, et kaevuda sügavamalt Lõuna-Aasia rahvaste geneetilisse pärandi kihtidesse., An understanding of evolutionary history of peopling of South Asia has long been a subject of interest for the researchers working in evolutionary, population and medical genetics. The work undertaken in this thesis was largely focused on macrohaplogroup M encompassing 60% of Indian maternal genepool, and to some phylogeographically informative branches of macrohaplogroup R. Our aim was to localize likely haplogroup expansions in space and time(s) and to test further the gene-culture and caste-tribe genetic continuum models. Our analysis revealed several novel deep rooting lineages of macrohaplogroup M, reinforcing the concept of in-situ origin of these clades in South Asia. Our genetic analysis on Indo-European speaking Mushar population of North India reflected the cultural process in South Asia, where language shift has taken place by cultural diffusion, without any large genetic exchange. We assume that this is a widespread phenomenon, not restricted to South Asia. Our study on the origins of other mtDNA haplogroups, in particular haplogroup R7, indicates that the spread of South Asian specific ancient matrilineages follow predominantly geographic rather than linguistic landscape of the subcontinent. Overall, we conclude that high level of endogamy created by numerous social boundaries within and between castes and tribes, along with the influence of several evolutionary forces such as genetic drift, fragmentation, but in parallel long time large population size, has kept the Indian subcontinent populations genetically diverse and distant from each other. At the same time, presence of a large variety of autochthonous to South Asia genetic lineages suggests log-time limited gene flow between India and neighbouring it continental populations, in particular outflow of the Indian matrilineal pool after the settlement of the subcontinent and initial diversification of its mtDNA pool. The obtained results allow to formulate a number of new avenues of research to further explore the strata of genetic heritage of South Asia.

To investigate the possible sources of maternal lineages among Roma in Medimurje and elsewhere, we looked for the most prevalent haplogroups that are represented in our sample and also present at relatively high frequencies among other Roma groups. We completely sequenced over 50 mitochondrial DNAs from different populations from South Asia, European Roma and Near East. The most prevalent mtDNA haplogorups among Roma from Medimurje county in Croatia are M5a1b, X2e, d and U3b1. Complete mtDNA anlayses reveals the phylogeographic position of these highly Roma specific lineages among populations from South Asia, Near East and Caucasus.

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.).

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.

Väitekirja elektrooniline versioon ei sisalda publikatsioone, Käesolev on viies Tartu Ülikoolis valminud väitekiri Lõuna-Aasia rahvaste geneetilisest ajaloost. Asustatud kaasaegse inimese poolt märksa enne viimase jääaja maksimumi, elab tänapäeval selles regioonis üle 1.8 miljardi inimese – pea veerand inimkonnast. Seega ei ole võimalik süvitsi mõista kaasaegse inimese geneetise varieeruvuse kujunemist, sh eriti väljapool Sahara-alust Aafrikat, omamata detailsemat teadmist Lõuna-Aasia rahvaste geneetikast Väitekiri põhineb neljal ilmunud artiklil. Neist esimeses uurisime Kirde-Indiat asustavaid rahvaid seoses võimaliku pärinevusega Induse oru kultuurist ja järgnenud vedade ajastust. Teine ja kolmas artikkel on pühendatud migratsioonidele, mis tõid Indiasse religioosses mõttes uusi rahvagruppe: parsid Iraanist alates 7. sajandi lõpupoolelt ja juudid, kelle saabumine Indiasse on toimunud mitme lainena. Neljandas artiklis on vaatluse all Nepaalis, kuid ka India põhjapoolsetes osariikides elutsev rahvarohke tharu hõim. Esimes artikli huvitavamaks leiuks on usutavasti juba vedade ajastust tuntud Rori populatsiooni genoomis väljenduv suurem geneetiline afiinsus põhjapoolse stepivööndi rahvastega, samuti ka lääne-eurooplastega, mis räägib põhja-lõunasuunalistest migratsiooni(de)st eelajaloolisel ajal. Parside saabumist Lõuna-Aasiasse seostatakse Iraani islamiseerumisega 7. sajandil. Võrreldes parside genoome nende ajaloolises kontekstis leidsime ulatusliku segunemise Lõuna-Aasia rahvastega, sealjuures asümeetriliselt isa ja emaliinides. Sama saab väita ka Indias judaistliku traditsiooni elemente säilitanud erinevate kogukondade kohta, kelle genoomis on siiski selgelt säilunud Lähis- ja Kesk-Ida pärandit. Puudutavalt aga geneetiliselt ulatuslikult varieeruvat tharu hõimu, kelle hulgas on selgesti eristatav ka Ida-Aasia komponent, segunenuna Lõuna-Aasia pärandiga, paistab õigustatud olevat neid vaadelda esmajoones mitte sedavõrd deemilise, kuivõrd just kultuurilise konstruktsioonina., Presented hereby is the 5th in a series of PhD theses prepared in Tartu University, addressing genetics of population history of the South Asian peoples. Inhabited considerably before the Last Glacial Maximum, the region harbors by now about 1.8 billion humans – almost a quarter of the global population. Therefore, understanding of present-day variation of the latter, in particular outside sub-Saharan Africa, is not possible without deeper knowledge about genetics of South Asian populations. This thesis is based on four published papers. The first one is focused on selected populations inhabiting northeastern Indus Valley, bearing, in particular, in mind ancient Indus Valley civilization and following it Vedic period. The second and the third paper address historically somewhat better known migrations, bringing to India religiously distinct Parsi and Jewish peoples. The fourth paper analyses the genetic variation of a populous Tharu tribe, living predominantly in Nepal, but also in northern provinces of India. Perhaps the most interesting finding of the first paper is that the presumably identified already in Vedic texts, Ror population exhibits significant genetic affinity with northern Steppe and West European peoples, testifying about prehistoric north to south migration(s). The arrival of Parsis to South Asia in 7th century was a consequence of the Islamization of Iran. Comparing Parsi genomes in their historic contexts, we observed their extensive admixture with South Asians, in particular, asymmetrically in paternal and maternal lineages. Nearly the same can be said about different Indian communities that preserved Judaist traditions: their genomes show affinities to peoples living in the Near and Middle East. As far as the genetically highly diverse Tharu tribe is concerned, a clearly distinct East Asian contribution can be seen, admixed with South Asian genetic heritage. It seems justified to identify the Tharu as cultural, rather than demic phenomenon., https://www.ester.ee/record=b5429496

The ectodysplasin receptor (EDAR) is a tumor necrosis factor receptor (TNF) superfamily member. A substitution in an exon of EDAR at position 370 (EDARV370A) creates a gain of function mutant present at high frequencies in Asian and Indigenous American populations but absent in others. Its frequency is intermediate in populations of Mexican ancestry. EDAR regulates the development of ectodermal tissues, including mammary ducts. Obesity and type 2 diabetes mellitus are prevalent in people with Indigenous and Latino ancestry. Latino patients also have altered prevalence and presentation of breast cancer. It is unknown whether EDARV370A might connect these phenomena. The goals of this study were to determine 1) whether EDARV370A is associated with metabolic phenotypes and 2) if there is altered breast anatomy in women carrying EDARV370A. Participants were from two Latino cohorts, the Arizona Insulin Resistance (AIR) registry and Sangre por Salud (SPS) biobank. The frequency of EDARV370A was 47% in the Latino cohorts. In the AIR registry, carriers of EDARV370A (GG homozygous) had significantly (p < 0.05) higher plasma triglycerides, VLDL, ALT, 2-hour post-challenge glucose, and a higher prevalence of prediabetes/diabetes. In a subset of the AIR registry, serum levels of ectodysplasin A2 (EDA-A2) also were associated with HbA1c and prediabetes (p < 0.05). For the SPS biobank, participants that were carriers of EDARV370A had lower breast density and higher HbA1c (both p < 0.05). The significant associations with measures of glycemia remained when the cohorts were combined. We conclude that EDARV370A is associated with characteristics of the metabolic syndrome and breast density in Latinos.

BackgroundThe Parsis, one of the smallest religious community in the world, reside in South Asia. Previous genetic studies on them, although based on low resolution markers, reported both Iranian and Indian ancestries. To understand the population structure and demographic history of this group in more detail, we analyzed Indian and Pakistani Parsi populations using high-resolution autosomal and uniparental (Y-chromosomal and mitochondrial DNA) markers. Additionally, we also assayed 108 mitochondrial DNA markers among 21 ancient Parsi DNA samples excavated from Sanjan, in present day Gujarat, the place of their original settlement in India.ResultsOur extensive analyses indicated that among present-day populations, the Parsis are genetically closest to Middle Eastern (Iranian and the Caucasus) populations rather than their South Asian neighbors. They also share the highest number of haplotypes with present-day Iranians and we estimate that the admixture of the Parsis with Indian populations occurred ∼1,200 years ago. Enriched homozygosity in the Parsi reflects their recent isolation and inbreeding. We also observed 48% South-Asian-specific mitochondrial lineages among the ancient samples, which might have resulted from the assimilation of local females during the initial settlement.ConclusionsWe show that the Parsis are genetically closest to the Neolithic Iranians, followed by present-day Middle Eastern populations rather than those in South Asia and provide evidence of sex-specific admixture from South Asians to the Parsis. Our results are consistent with the historically-recorded migration of the Parsi populations to South Asia in the 7thcentury and in agreement with their assimilation into the Indian sub-continent’s population and cultural milieu “like sugar in milk”. Moreover, in a wider context our results suggest a major demographic transition in West Asia due to Islamic-conquest.