Low levels of genetic divergence across geographically and linguistically diverse populations from India

Ongoing modernization in India has elevated the prevalence of many complex genetic diseases associated with a western lifestyle and diet to near-epidemic proportions. However, although India comprises more than one sixth of the world's human population, it has largely been omitted from genomic surveys that provide the backdrop for association studies of genetic disease. Here, by genotyping India-born individuals sampled in the United States, we carry out an extensive study of Indian genetic variation. We analyze 1,200 genome-wide polymorphisms in 432 individuals from 15 Indian populations. We find that populations from India, and populations from South Asia more generally, constitute one of the major human subgroups with increased similarity of genetic ancestry. However, only a relatively small amount of genetic differentiation exists among the Indian populations. Although caution is warranted due to the fact that United States–sampled Indian populations do not represent a random sample from India, these results suggest that the frequencies of many genetic variants are distinctive in India compared to other parts of the world and that the effects of population heterogeneity on the production of false positives in association studies may be smaller in Indians (and particularly in Indian-Americans) than might be expected for such a geographically and linguistically diverse subset of the human population.     

Integrating Linguistics,Social Structure,and Geography to Model Genetic Diversity within India

India represents an intricate tapestry of population substructure shaped by geography, language, culture, and social stratification. Although geography closely correlates with genetic structure in other parts of the world, the strict endogamy imposed by the Indian caste system and the large number of spoken languages add further levels of complexity to understand Indian population structure. To date, no study has attempted to model and evaluate how these factors have interacted to shape the patterns of genetic diversity within India. We merged all publicly available data from the Indian subcontinent into a data set of 891 individuals from 90 well-defined groups. Bringing together geography, genetics, and demographic factors, we developed Correlation Optimization of Genetics and Geodemographics to build a model that explains the observed population genetic substructure. We show that shared language along with social structure have been the most powerful forces in creating paths of gene flow in the subcontinent. Furthermore, we discover the ethnic groups that best capture the diverse genetic substructure using a ridge leverage score statistic. Integrating data from India with a data set of additional 1,323 individuals from 50 Eurasian populations, we find that Indo-European and Dravidian speakers of India show shared genetic drift with Europeans, whereas the Tibeto-Burman speaking tribal groups have maximum shared genetic drift with East Asians.     

Multiple origins of the mtDNA 9-bp deletion in populations of South India

The origins and genetic affinities of the more than 500 tribal populations living in South Asia are widely disputed. This may reflect differential contributions that continental populations have made to tribal groups in South Asia. We assayed for the presence of the intergenic COII/tRNALys 9-bp deletion in human mtDNA in 646 individuals from 12 caste and 14 tribal populations of South India and compared them to individuals from Africa, Europe, and Asia. The 9-bp deletion is observed in four South Indian tribal populations, the Irula, Yanadi, Siddi, and Maria Gond, and in the Nicobarese. Length polymorphisms of the 9-bp motif are present in the Santal, Khonda Dora, and Jalari, all of whom live in a circumscribed region on the eastern Indian coast. Phylogenetic analyses of mtDNA control region sequence from individuals with the 9-bp deletion indicate that it has arisen independently in some Indian tribal populations. Other 9-bp deletion haplotypes are likely to be of Asian and African origin, implying multiple origins of the 9-bp deletion in South India. These results demonstrate varying genetic affinities of different South Indian tribes to continental populations and underscore the complex histories of the tribal populations living in South Asia. Am J Phys Anthropol 109:147–158, 1999. © 1999 Wiley-Liss, Inc.     

The 9-bp deletion between the mitochondrial lysine tRNA and COII genes in tribal populations of India

A 9-base-pair (bp) deletion located between the lysine tRNA (MTTK) and COII (MTCOX*2) genes in the human mitochondrial genome is a valuable marker for tracing population relationships. Previous research has shown that the 9-bp deletion is associated with two major clusters of control region sequences; one occurs in sub-Saharan Africa, while the other is associated with Asian populations and populations of Asian origin. We surveyed 898 individuals from 16 tribal populations in India and found 6 individuals with the 9-bp deletion. Sequences of the first hypervariable segment (HV1) of the mtDNA control region from these 9-bp deletion-bearing mtDNAs were compared to those previously reported from Asian and African populations. Phylogenetic analysis indicates three distinct clusters of tribal Indian 9-bp deletion mtDNA types. One cluster, found in northeast India, includes southeast Asian and Indonesian mtDNA types. The remaining two clusters appear to have unique origins in southern India. These data provide further evidence of past migrations from Asia into the northeast corner of the Indian subcontinent.     

Genetic diversity and admixture patterns in Indian populations

India is a diverse land whose population holds the history of waves of human dispersal. Recent studies suggest two major ancestral contributions to most of the Indian sub-populations. However, present day Indians are thought to contain huge genetic diversity derived consequent to multiple cultural, linguistic and geographical variations. Genome-wide survey of individuals from current North (N-In) and South (S-In) India along with populations from HapMap Phase III and Indian sub-populations from HUGO Pan-Asian SNP Consortium is performed. Multivariate analysis (MDS and PCA) was carried out after merging data from the current study and other consortia. Indian sub-populations clustered separately from populations of major global geographical regions in MDS and PCA in a loose agglomeration except for two Indian subpopulations clustering near far eastern populations. F_st values indicated diversity among Indian sub-populations which was substantiated by STRUCTURE analysis suggesting the possibility of additional admixture events.     

The origin of Indian Star tortoises (Geochelone elegans) based on nuclear and mitochondrial DNA analysis: A story of rescue and repatriation

The Indian Star tortoise (Geochelone elegans) belongs to the family Testunidae and is distributed in southwest India and Sri Lanka. In addition to facing loss of its natural habitat, the species is also illegally traded as food and as an exotic pet internationally. Here we report DNA-based analyses for identification and repatriation of these tortoises into their natural habitat. We have attempted to establish the geographical origin of these tortoises rescued from smugglers, by comparing the microsatellite and mitochondrial markers of rescued animals with animals of known provenance. Star tortoises exhibited strong genetic structure in India. The populations from western India were genetically distinct at microsatellite and mitochondrial loci from southern populations. The rescued individuals had similar multilocus genotypes and mitochondrial DNA haplotypes as the reference individuals from south India. However, the precise geographic origin of many of the rescued samples remains unresolved, because we could not assign them to southern populations and the Neighbor-Joining cluster analysis indicated that some of rescued tortoises formed distinct clusters. These data strongly suggest that the rescued group of tortoises is composed of a mix of individuals from differentiated source populations that are probably located in southern India and possibly Sri Lanka. Our study provides valuable information based on molecular markers for the assessment of genetic diversity in Indian Star tortoises.     

Indian genetic heritage in Southeast Asian populations

The great ethnolinguistic diversity found today in mainland Southeast Asia (MSEA) reflects multiple migration waves of people in the past. Maritime trading between MSEA and India was established at the latest 300 BCE, and the formation of early states in Southeast Asia during the first millennium CE was strongly influenced by Indian culture, a cultural influence that is still prominent today. Several ancient Indian-influenced states were located in present-day Thailand, and various populations in the country are likely to be descendants of people from those states. To systematically explore Indian genetic heritage in MSEA populations, we generated genome-wide SNP data (using the Affymetrix Human Origins array) for 119 present-day individuals belonging to 10 ethnic groups from Thailand and co-analyzed them with published data using PCA, ADMIXTURE, and methods relying on f-statistics and on autosomal haplotypes. We found low levels of South Asian admixture in various MSEA populations for whom there is evidence of historical connections with the ancient Indian-influenced states but failed to find this genetic component in present-day hunter-gatherer groups and relatively isolated groups from the highlands of Northern Thailand. The results suggest that migration of Indian populations to MSEA may have been responsible for the spread of Indian culture in the region. Our results also support close genetic affinity between Kra-Dai-speaking (also known as Tai-Kadai) and Austronesian-speaking populations, which fits a linguistic hypothesis suggesting cladality of the two language families.     

Spectrum of large copy number variations in 26 diverse Indian populations: potential involvement in phenotypic diversity

Copy number variations (CNVs) have provided a dynamic aspect to the apparently static human genome. We have analyzed CNVs larger than 100 kb in 477 healthy individuals from 26 diverse Indian populations of different linguistic, ethnic and geographic backgrounds. These CNVRs were identified using the Affymetrix 50K Xba 240 Array. We observed 1,425 and 1,337 CNVRs in the deletion and amplification sets, respectively, after pooling data from all the populations. More than 50% of the genes encompassed entirely in CNVs had both deletions and amplifications. There was wide variability across populations not only with respect to CNV extent (ranging from 0.04–1.14% of genome under deletion and 0.11–0.86% under amplification) but also in terms of functional enrichments of processes like keratinization, serine proteases and their inhibitors, cadherins, homeobox, olfactory receptors etc. These did not correlate with linguistic, ethnic, geographic backgrounds and size of populations. Certain processes were near exclusive to deletion (serine proteases, keratinization, olfactory receptors, GPCRs) or duplication (homeobox, serine protease inhibitors, embryonic limb morphogenesis) datasets. Populations having same enriched processes were observed to contain genes from different genomic loci. Comparison of polymorphic CNVRs (5% or more) with those cataloged in Database of Genomic Variants revealed that 78% (2473) of the genes in CNVRs in Indian populations are novel. Validation of CNVs using Sequenom MassARRAY revealed extensive heterogeneity in CNV boundaries. Exploration of CNV profiles in such diverse populations would provide a widely valuable resource for understanding diversity in phenotypes and disease.     

A microsatellite study to disentangle the ambiguity of linguistic,geographic, ethnic and genetic influences on tribes of India to get a better clarity of the antiquity and peopling of South Asia

An understanding of the genetic affinity and the past history of the tribal populations of India requires the untangling of the confounding influences of language, ethnicity, and geography on the extant diverse tribes. The present study examines the genetic relationship of linguistically (Dravidian, Austro‐Asiatic, and Tibeto‐Burman) and ethnically (Australian and East Asian) diverse tribal populations (46) inhabiting different regions of the Indian subcontinent. For the purpose, we have utilized the published data on allele frequency of 15 autosomal STR loci of our study on six Adi sub‐tribes of Arunachal Pradesh and compared the same with the reported allele frequency data, for nine common autosomal STR loci, of 40 other tribes. Phylogenetic and principal component analyses exhibit geography based clustering of Tibeto‐Burman speakers and separation of the Mundari and Mon‐Khmer speaking Austro‐Asiatic populations. The combined analyses of all 46 populations show clustering of the groups belonging to same ethnicity and inhabiting contiguous geographic regions, irrespective of their different languages. These results help us to reconstruct and understand three plausible scenarios of the antiquity of Indian tribal populations: the Dravidian and Austro‐Asiatic (Mundari) tribes were possibly derived from common early settlers; the Tibeto‐Burman tribes possibly belonged to a different ancestry and the Mon‐Khmer speaking Austro‐Asiatic populations share a common ancestry with some of the Tibeto‐Burman speakers. Am J Phys Anthropol, 2009. © 2009 Wiley‐Liss, Inc.     

High-resolution analysis of Y-chromosomal polymorphisms reveals signatures of population movements from central Asia and West Asia into India

Linguistic evidence suggests that West Asia and Central Asia have been the two major geographical sources of genes in the contemporary Indian gene pool. To test the nature and extent of similarities in the gene pools of these regions we have collected DNA samples from four ethnic populations of northern India, and have screened these samples for a set of 18 Y-chromosome polymorphic markers (12 unique event polymorphisms and six short tandem repeats). These data from Indian populations have been analysed in conjunction with published data from several West Asian and Central Asian populations. Our analyses have revealed traces of population movement from Central Asia and West Asia into India. Two haplogroups, HG-3 and HG-9, which are known to have arisen in the Central Asian region, are found in reasonably high frequencies (41.7% and 14.3% respectively) in the study populations. The ages estimated for these two haplogroups are less in the Indian populations than those estimated from data on Middle Eastern populations. A neighbour-joining tree based on Y-haplogroup frequencies shows that the North Indians are genetically placed between the West Asian and Central Asian populations. This is consistent with gene flow from West Asia and Central Asia into India.     

Shared and unique components of human population structure and genome-wide signals of positive selection in South Asia

South Asia harbors one of the highest levels genetic diversity in Eurasia, which could be interpreted as a result of its long-term large effective population size and of admixture during its complex demographic history. In contrast to Pakistani populations, populations of Indian origin have been underrepresented in previous genomic scans of positive selection and population structure. Here we report data for more than 600,000 SNP markers genotyped in 142 samples from 30 ethnic groups in India. Combining our results with other available genome-wide data, we show that Indian populations are characterized by two major ancestry components, one of which is spread at comparable frequency and haplotype diversity in populations of South and West Asia and the Caucasus. The second component is more restricted to South Asia and accounts for more than 50% of the ancestry in Indian populations. Haplotype diversity associated with these South Asian ancestry components is significantly higher than that of the components dominating the West Eurasian ancestry palette. Modeling of the observed haplotype diversities suggests that both Indian ancestry components are older than the purported Indo-Aryan invasion 3,500 YBP. Consistent with the results of pairwise genetic distances among world regions, Indians share more ancestry signals with West than with East Eurasians. However, compared to Pakistani populations, a higher proportion of their genes show regionally specific signals of high haplotype homozygosity. Among such candidates of positive selection in India are MSTN and DOK5, both of which have potential implications in lipid metabolism and the etiology of type 2 diabetes.     

Multiple population structure of the giant mottled eel, Anguilla marmorata

The population structure of the giant mottled eel, Anguilla marmorata, was investigated with mitochondrial and microsatellite DNA analyses using 449 specimens from 13 localities throughout the species range. Control region F-statistics indicated the North Pacific (Japan, Taiwan, Philippines, Sulawesi), South Pacific (Tahiti, Fiji, New Caledonia, Papua New Guinea), eastern Indian Ocean (Sumatra), western Indian Ocean (Réunion, Madagascar), Ambon, and Guam regions were significantly different (Phi(ST) = 0.131-0.698, P < 0.05) while only a few differences were observed between localities within the South Pacific. These regions were roughly clustered in the neighbour-joining tree, although Ambon individuals were mainly divided into North and South Pacific groups. Analysis with eight microsatellite loci showed almost identical results to those of the control region, except no genetic difference was observed between the western and eastern Indian Ocean (F(ST) = 0.009, P > 0.05). The Bayesian cluster analysis of the microsatellite data detected two genetic groups. One included four North Pacific localities, and the other included eight localities in the South Pacific, Indian Ocean, and Guam, but Ambon individuals were evenly assigned to these two groups. These results showed that A. marmorata has four genetically different populations (North Pacific, South Pacific, Indian Ocean, Guam region). The North Pacific population is fully panmictic whereas the South Pacific and Indian Ocean populations have a metapopulation structure. Interestingly, Guam was suggested to be inhabited by a reproductive population restricted to that region, and the individuals from the North and South Pacific populations co-exist in Ambon.     

Genetic variation in South Indian castes: evidence from Y-chromosome, mitochondrial, and autosomal polymorphisms

Background

Major population movements, social structure, and caste endogamy have influenced the genetic structure of Indian populations. An understanding of these influences is increasingly important as gene mapping and case-control studies are initiated in South Indian populations.

Results

We report new data on 155 individuals from four Tamil caste populations of South India and perform comparative analyses with caste populations from the neighboring state of Andhra Pradesh. Genetic differentiation among Tamil castes is low (R_ST = 0.96% for 45 autosomal short tandem repeat (STR) markers), reflecting a largely common origin. Nonetheless, caste- and continent-specific patterns are evident. For 32 lineage-defining Y-chromosome SNPs, Tamil castes show higher affinity to Europeans than to eastern Asians, and genetic distance estimates to the Europeans are ordered by caste rank. For 32 lineage-defining mitochondrial SNPs and hypervariable sequence (HVS) 1, Tamil castes have higher affinity to eastern Asians than to Europeans. For 45 autosomal STRs, upper and middle rank castes show higher affinity to Europeans than do lower rank castes from either Tamil Nadu or Andhra Pradesh. Local between-caste variation (Tamil Nadu R_ST = 0.96%, Andhra Pradesh R_ST = 0.77%) exceeds the estimate of variation between these geographically separated groups (R_ST = 0.12%). Low, but statistically significant, correlations between caste rank distance and genetic distance are demonstrated for Tamil castes using Y-chromosome, mtDNA, and autosomal data.

Conclusion

Genetic data from Y-chromosome, mtDNA, and autosomal STRs are in accord with historical accounts of northwest to southeast population movements in India. The influence of ancient and historical population movements and caste social structure can be detected and replicated in South Indian caste populations from two different geographic regions.     

Analysis of Indian population based on Y-STRs reveals existence of male gene flow across different language groups

A study of three different Y-specific microsatellites (Y-STRs) in the populations from Uttar Pradesh (UP), Bihar (BI), Punjab (PUNJ), and Bengal (WB), speaking modern indic dialects with its roots in Indo-Aryan language, and from South of India (SI), speaking the South Indian languages with their root in Dravidian language, has shown that the predominant alleles observed represent the whole range of allelic variation reported in different population groups globally. These results indicate that the Indian population is most diverse. The similarity between the allelic variants between the populations studied by others in Africa and Asia and in this study between WB, PUNJ, UP, BI, and SI are of interest. It demonstrates that these population groups, housed in eight states of the country in different geographic locations, broadly correspond with Indo-Aryan and Dravidian language families. Further, our analyses based on haplotype frequency of different marker loci and gene diversity reveals that none of the population groups have remained isolated from others. High levels of haplotype diversity exist in all the clusters of population. Nonsignificant results based on Markov chain steps and Slatkin's linearized genetic distances indicate that there has been migration to and from in these population groups. However, some of the marginally significant interpopulation differences could be attributed to one or more of the castes with high diversity embedded within the population groups studied. Haplotype sharing between populations, F(ST) statistics, and phylogenetic analysis identifies genetic relatedness to be more between individuals belonging to two different states of India, WB and PUNJ, followed by UP and BI, whereas SI branched out separately.     

Identification of Medically Actionable Secondary Findings in the 1000 Genomes

The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.     

The Genetics of Bene Israel from India Reveals Both Substantial Jewish and Indian Ancestry

The Bene Israel Jewish community from West India is a unique population whose history before the 18^th century remains largely unknown. Bene Israel members consider themselves as descendants of Jews, yet the identity of Jewish ancestors and their arrival time to India are unknown, with speculations on arrival time varying between the 8th century BCE and the 6th century CE. Here, we characterize the genetic history of Bene Israel by collecting and genotyping 18 Bene Israel individuals. Combining with 486 individuals from 41 other Jewish, Indian and Pakistani populations, and additional individuals from worldwide populations, we conducted comprehensive genome-wide analyses based on F_ST, principal component analysis, ADMIXTURE, identity-by-descent sharing, admixture linkage disequilibrium decay, haplotype sharing and allele sharing autocorrelation decay, as well as contrasted patterns between the X chromosome and the autosomes. The genetics of Bene Israel individuals resemble local Indian populations, while at the same time constituting a clearly separated and unique population in India. They are unique among Indian and Pakistani populations we analyzed in sharing considerable genetic ancestry with other Jewish populations. Putting together the results from all analyses point to Bene Israel being an admixed population with both Jewish and Indian ancestry, with the genetic contribution of each of these ancestral populations being substantial. The admixture took place in the last millennium, about 19–33 generations ago. It involved Middle-Eastern Jews and was sex-biased, with more male Jewish and local female contribution. It was followed by a population bottleneck and high endogamy, which can lead to increased prevalence of recessive diseases in this population. This study provides an example of how genetic analysis advances our knowledge of human history in cases where other disciplines lack the relevant data to do so.     

Immunoglobulin (GM and KM) allotypes in the Sikh population of India

The populations of India are genetically diverse, both within and between geographic regions; immunoglobulin (GM) allotypes provide important information on genetic differences between populations, since the frequencies of combinations of allotypes (termed "haplotypes") vary dramatically among ethnic groups. As part of a project to assess genetic diversity among defined Indian populations, we have examined eight GM allotypes in a sample of 101 unrelated Sikhs who have migrated to Toronto, Canada: Glm(1, 2, 3, 17) and G3m (5, 15, 16, 21). Sikhs are a religious group that arose in the Punjab about 1500 A.D.; most of the original converts are believed to have been middle to upper-middle caste Hindus. Gm allotyping showed that six Gm haplotypes occurred at polymorphic frequencies (greater than 0.01) in Sikhs: Gm3;5, Gm1,17;21, Gm1,2,17;21, Gm1,17;5, Gm1,17;15,16, and Gm1,3;5. These haplotypes have all been previously reported in Indian populations. The frequencies of the first four haplotypes resembled the published frequencies for lower-caste Hindus of NW India more than upper-caste Hindus. However, the last two haplotypes have been found only in upper-caste Hindus. The frequency of one of these, Gm1,17;15,16 was higher in Sikhs (0.09) than has been reported in any Indian population with the exception of Parsis (who are descended from Iranians). We speculate that the high frequency of this haplotype may have been characteristic of some of the Hindu castes in the Punjab from which Sikhs are descended.     

MAJOR GENETIC DIFFERENCES BETWEEN CROWN-OF-THORNS STARFISH (ACANTHASTER PLANCI) POPULATIONS IN THE INDIAN AND PACIFIC OCEANS

Spatial variation in allelic frequencies at nine allozyme loci were assayed in 20 populations of the crown-of-thorns starfish, Acanthaster planci, collected throughout the Pacific and Indian Oceans. These data were analyzed together with published data, for the same loci, from an additional 19 populations, giving a total sample size of approximately 1800 individuals. There was a marked discontinuity between the Indian and Pacific Ocean populations, but those off Western Australia and from the Southeast Asian region had a strong Pacific affinity. The genetic groups were congruent with the distributions of two color morph groups: gray-green to red-brown forms in the Pacific and a blue to pale red form in the Indian Ocean. These patterns of genetic structure are similar to those described for the starfish Linckia laevigata, which has similar life-history characteristics. Vicariant events may have influenced some populations within the Pacific, but the allozyme data cannot resolve the effects of these events clearly. Patterns of variation within regions were consistent with isolation by distance, but, at larger scales, were obscured by regional vicariance and some outliers, particularly by apparently high levels of gene flow between Japan and the Great Barrier Reef, Australia. Apparent gene flow between population pairs was not closely related to present-day ocean currents. The results demonstrate a strong influence of allopatric separation on genetic divergence at large geographic scales, but also show evidence of slow rates of change in gene frequencies consistent with the large population sizes of this species. Low levels of divergence between groups demonstrate the genetic structure is recent (Pleistocene) and are likely responses to changes in climate and sea level.