Congruence of genomic and ethnolinguistic affinities among five tribal populations of Madhya Pradesh (India)

The central Indian state of Madhya Pradesh is home to a large number of tribal populations of diverse linguistic and ethnic backgrounds. With a view to examining how well genomic affinities among tribal populations of this state correspond with their ethnic and linguistic affinities, we analysed DNA samples of individuals drawn from five tribes with diverse, but reasonably well-documented, ethnohistorical and linguistic backgrounds. Each DNA sample was scored at 16 biallelic DNA marker loci. On the basis of these data, genomic affinities among these populations were estimated. We have found an extremely good correspondence between the genomic and ethnolinguistic affinities

Fundamental genomic unity of ethnic India is revealed by analysis of mitochondrial DNA

Mitochondrial DNA (mtDNA) profiles of 23 ethnic populations of India drawn from diverse cultural, linguistic and geographical backgrounds are presented. There is extensive sharing of a small number of mtDNA haplotypes, reconstructed on the basis of restriction fragment length polymorphisms, among the populations. This indicates that Indian populations were founded by a small number of females, possibly arriving on one of the early waves of out-of-Africa migration of modern humans; ethnic differentiation occurred subsequently through demographic expansions and geographic dispersal. The Asian-specific haplogroup M is in high frequency in most populations, especially tribal populations and Dravidian populations of southern India. Populations in which the frequencies of haplogroup M are relatively lower show higher frequencies of haplogroup U; such populations are primarily caste populations of northern India. This finding is indicative of a higher Caucasoid admixture in northern Indian populations. By examining the sharing of haplotypes between Indian and south-east Asian populations, we have provided evidence that south-east Asia was peopled by two waves of migration, one originating in India and the other originating in southern China. These findings have been examined and interpreted in the light of inferences derived from previous genomic and historical studies

DNA sequence variation and haplotype structure of the ICAM1 and TNF genes in 12 ethnic groups of India reveal patterns of importance in designing association studies

We have examined the patterns of DNA sequence variation in and around the genes coding for ICAM1 and TNF, which play functional and correlated roles in inflammatory processes and immune cell responses, in 12 diverse ethnic groups of India. We aimed to (a) quantify the nature and extent of the variation, and (b) analyse the observed patterns of variation in relation to population history and ethnic background. At the ICAM1 and TNF loci, respectively, the total numbers of SNPs that were detected were 28 and 12. Many of these SNPs are not shared across ethnic groups and are unreported in the dbSNP or TSC databases, including two fairly common non-synonymous SNPs at positions 13487 and 13542 in the ICAM1 gene. Conversely, the TNF-376A SNP that is reported to be associated with susceptibility to malaria was not found in our study populations, even though some of the populations inhabit malaria endemic areas. Wide between-population variation in the frequencies of shared SNPs and coefficients of linkage disequilibrium have been observed. These findings have profound implications in case-control association studies

Deciphering genetic regulation of CD14 by SP1 through characterization of peripheral blood mononuclear transcriptome of P. faiciparum and P. vivax infected malaria patientsResearch in context section

Background: Plasmodium falciparum and Plasmodium vivax are two major parasites responsible for malaria which remains a threat to almost 50% of world's population despite decade-long eradication program. One possible reason behind this conundrum is that the bases of clinical variability in malaria caused by either species are complex and poorly understood. Methods: Whole-genome transcriptome was analyzed to identify the active and predominant pathways in the PBMC of P. falciparum and P. vivax infected malaria patients. Deregulated genes were identified and annotated using R Bioconductor and DAVID/KEGG respectively. Genetic and functional regulation of CD14, a prioritized candidate, were established by quantitative RT-PCR, genotyping using RFLP and resequencing, mapping of transcription factor binding using CONSITE and TFBIND, dual luciferase assay, western blot analysis, RNAi- mediated gene knockdown and chromatin-immunoprecipation. Findings: The study highlighted that deregulation of host immune and inflammatory genes particularly CD14 as a key event in P. falciparum malaria. An abundance of allele-C of rs5744454, located in CD14 promoter, in severe malaria motivated us to establish an allele-specific regulation of CD14 by SP1. An enhancement of SP1 and CD14 expression was observed in artemisinin treated human monocyte cell line. Interpretation: Our data not only reinstates that CD14 of TLR pathway plays a predominant role in P. falciparum malaria, it establishes a functional basis for genetic association of rs5744454 with P. falciparum severe malaria by demonstrating a cis-regulatory role of this promoter polymorphism. Moreover, the study points towards a novel pharmacogenetic aspect of artemisinin-based anti-malarial therapy. Fund: DST-SERB, Govt. of India, SR/SO/HS-0056/2013. Keywords: Malaria, Plasmodium falciparum, Transcriptome, CD14, SP1, Host Polymorphis

Diversity analysis of MSP1 identifies conserved epitope organization in block 2 amidst high sequence variability in Indian Plasmodium falciparum isolates

Abstract Background Despite its immunogenicity, the polymorphic nature of merozoite surface protein 1, an important vaccine candidate for Plasmodium falciparum malaria, remains a concern. This study analyses the impact of genetic variability and parasite population structure on epitope organization of different MSP1 segments. Methods Altogether 98 blood samples collected from P. falciparum infected mild and severe malaria patients of Chhattisgarh and West Bengal were used to sequence regions encoding block 2 and MSP1-19 of msp1. Sequences were analysed using MEGA7, DnaSPv5, Arlequin3.5 and BepiPred. Results All three major MSP1 block 2 allele families namely K1, MAD20 and RO33 were detected in the samples and they together resulted in 41 indel variants. Chhattisgarh samples displayed an average MOI of 2.07 ± 1.59 which was higher in mild malaria and in age group < 18 years. Ultra-structure of block 2 alleles revealed that mutation and repeat expansion were two major mechanisms responsible for allelic variability of K1 and MAD20. Regions flanking block 2 were highly variable in Chhattisgarh with average mismatch differences (k) ranging from 1.198 to 5.156 for three families. In contrast, region encompassing MSP1-19 exhibited limited heterogeneity (kChhattisgarh = 1.45, kWest Bengal = 1.363). Of the 50 possible B cell linear epitopes predicted from block 2 variants, 94.9% (131 of 138) of the parasites could be represented by three conserved antigens. Conclusions Present data indicates that natural selection and transmission intensity jointly play a role in controlling allelic diversity of MSP1 in Indian parasite isolates. Despite remarkable genetic variability, a limited number of predominant and conserved epitopes are present in Indian parasite isolates reinstating the importance of MSP1 as a promising malaria vaccine candidate

Genomic structures and population histories of linguistically distinct tribal groups of India

There are various conflicting hypotheses regarding the origins of the tribal groups of India, who belong to three major language groups – Austro-Asiatic, Dravidian and Tibeto-Burman. To test some of the major hypotheses we designed a genetic study in which we sampled tribal populations belonging to all the three language groups. We used a set of autosomal DNA markers, mtDNA restriction-site polymorphisms (RSPs) and mtDNA hypervariable segment-1 (HVS-1) sequence polymorphisms in this study. Using the unlinked autosomal markers we found that there is a fair correspondence between linguistic and genomic affinities among the Indian tribal groups. We reconstructed mtDNA RSP haplotypes and found that there is extensive haplotype sharing among all tribal populations. However, there is very little sharing of mtDNA HVS-1 sequences across populations, and none across language groups. Haplogroup M is ubiquitous, and the subcluster U2i of haplogroup U occurs in a high frequency. Our analyses of haplogroup and HVS-1 sequence data provides evidence in support of the hypothesis that the Austro-Asiatic speakers are the most ancient inhabitants of India. Our data also support the earlier finding that some of the western Eurasian haplogroups found in India may have been present in India prior to the entry of Aryan speakers. However, we do not find compelling evidence to support the theory that haplogroup M was brought into India on an “out of Africa” wave of migration through a southern exit route from Ethiopia. On the contrary, our data raise the possibility that this haplogroup arose in India and was later carried to East Africa from India

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