Browsing by Author "Kumarasamy Thangaraj"

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A rare non-synonymous c.102C>G SNP in the IFNB1 gene might be a risk factor for cerebral malaria in Indian populations
(2013) Aditya Nath Jha; Vipin Kumar Singh; Rajender Singh; Sudhanshu S. Pati; Pradeep K. Patra; Lalji Singh; Kumarasamy Thangaraj
Interferon beta1 (IFNB1) is a type I interferon that is mainly known for its antiviral activity, but it also regulates a number of anti-inflammatory and immunomodulatory functions. Studies on mouse models of cerebral malaria have established that IFNB1 regulates severe malaria pathogenesis and increases overall survival against malaria. It down-regulates pro-inflammatory cytokines: TNF, IFNG and ICAM-1, resulting in decreased adherence of Plasmodium falciparum parasitized RBC to capillary wall, entry into the brain and delayed onset of death. Therefore, we hypothesized that variations in IFNB1 gene could regulate malarial pathogenesis. We re-sequenced the complete IFNB1 gene along with 900bp of 5' up-stream and 500bp of 3'-UTR in 437 individuals from malaria endemic regions of the Orissa and Chhattisgarh states of India. The subjects comprised of 173 cases of severe malaria, 101 of mild malaria, and 156 ethnically matched asymptomatic controls. Data were statistically compared between cases and controls for their possible association with P. falciparum malarial outcome. Two single nucleotide polymorphisms (SNPs): a synonymous c.153C>T (rs1051922) and a non-synonymous substitution c.102C>G (rs139262191, p.Ser34Arg) were identified. The genotype and allele distribution of c.153C>T did not differ significantly between the study groups [mild, χ22=4.10, p-value<0.13 and severe χ22=0.06, p-value<0.97]. Interestingly, the rare non-synonymous SNP (rs139262191) was observed only in malaria patients. The differences between all cases and controls did not reach statistical significance, however, a statistically significant difference was observed between the asymptomatic control group and the cerebral malaria group [OR=20.32, 95% CI=1.08-382.63, p-value=0.044]. Moreover, the genotypes between cerebral malaria positive and negative groups were not significantly different [OR=5.58, 95% CI=0.61-50.97, p-value=0.123]. Our findings suggest that the IFNB1 variant, p.Ser34Arg, might be a risk factor for cerebral malaria in Indian populations. © 2013 Elsevier B.V.
Analysis of genetic variants in the IL4 promoter and VNTR loci in Indian patients with Visceral Leishmaniasis
(Elsevier Inc., 2014) Anshuman Mishra; Aditya Nath Jha; Hoang van Tong; Vipin Kumar Singh; Carlos E.M. Gomes; Lalji Singh; Thirumalaisamy P. Velavan; Kumarasamy Thangaraj
Visceral Leishmaniasis (VL) is the most severest form of Leishmaniasis and resistance to infection is mediated by cellular immune responses. Interleukin 4 (IL-4) orchestrates of Th2 and Th1 immune responses during infections. In this study, we aimed to investigate possible association between three functional IL-4 polymorphisms -590C/T (rs2243250), -34C/T (rs2070874) and 70bp VNTR (rs79071878 in intron3) with VL in an Indian cohort comprising of 197 VL patients and 193 healthy controls. The three investigated IL-4 polymorphisms were in strong linkage disequilibrium. The investigated IL-4 alleles, genotypes and the reconstructed haplotypes were not significantly distributed between the VL patients and healthy controls. Our study signifies no possible association of functional IL-4 polymorphisms with Indian VL and postulate other vital genes involved in the IL-4 pathway may provide genetic clues to elucidate of IL-4 regulation and immune-pathogenesis during VL. © 2014 American Society for Histocompatibility and Immunogenetics.
Ancient human genomes suggest three ancestral populations for present-day Europeans
(Nature Publishing Group, 2014) Iosif Lazaridis; Nick Patterson; Alissa Mittnik; Gabriel Renaud; Swapan Mallick; Karola Kirsanow; Peter H. Sudmant; Joshua G. Schraiber; Sergi Castellano; Mark Lipson; Bonnie Berger; Christos Economou; Ruth Bollongino; Qiaomei Fu; Kirsten I. Bos; Susanne Nordenfelt; Heng Li; Cesare De Filippo; Kay Prüfer; Susanna Sawyer; Cosimo Posth; Wolfgang Haak; Fredrik Hallgren; Elin Fornander; Nadin Rohland; Dominique Delsate; Michael Francken; Jean-Michel Guinet; Joachim Wahl; George Ayodo; Hamza A. Babiker; Graciela Bailliet; Elena Balanovska; Oleg Balanovsky; Ramiro Barrantes; Gabriel Bedoya; Haim Ben-Ami; Judit Bene; Fouad Berrada; Claudio M. Bravi; Francesca Brisighelli; George B.J. Busby; Francesco Cali; Mikhail Churnosov; David E.C. Cole; Daniel Corach; Larissa Damba; George Van Driem; Stanislav Dryomov; Jean-Michel Dugoujon; Sardana A. Fedorova; Irene Gallego Romero; Marina Gubina; Michael Hammer; Brenna M. Henn; Tor Hervig; Ugur Hodoglugil; Aashish R. Jha; Sena Karachanak-Yankova; Rita Khusainova; Elza Khusnutdinova; Rick Kittles; Toomas Kivisild; William Klitz; Vaidutis Kučinskas; Alena Kushniarevich; Leila Laredj; Sergey Litvinov; Theologos Loukidis; Robert W. Mahley; Béla Melegh; Ene Metspalu; Julio Molina; Joanna Mountain; Klemetti Näkkäläjärvi; Desislava Nesheva; Thomas Nyambo; Ludmila Osipova; Jüri Parik; Fedor Platonov; Olga Posukh; Valentino Romano; Francisco Rothhammer; Igor Rudan; Ruslan Ruizbakiev; Hovhannes Sahakyan; Antti Sajantila; Antonio Salas; Elena B. Starikovskaya; Ayele Tarekegn; Draga Toncheva; Shahlo Turdikulova; Ingrida Uktveryte; Olga Utevska; René Vasquez; Mercedes Villena; Mikhail Voevoda; Cheryl A. Winkler; Levon Yepiskoposyan; Pierre Zalloua; Tatijana Zemunik; Alan Cooper; Cristian Capelli; Mark G. Thomas; Andres Ruiz-Linares; Sarah A. Tishkoff; Lalji Singh; Kumarasamy Thangaraj; Richard Villems; David Comas; Rem Sukernik; Mait Metspalu; Matthias Meyer; Evan E. Eichler; Joachim Burger; Montgomery Slatkin; Svante Pääbo; Janet Kelso; David Reich; Johannes Krause
We sequenced the genomes of a ∼7,000-year-old farmer from Germany and eight ∼8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes1-4 with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians3, who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations' deep relationships and show that early European farmers had ∼44% ancestry from a 'basal Eurasian' population that split before the diversification of other non-African lineages. ©2014 Macmillan Publishers Limited. All rights reserved.
Common variant c.-22 + 155C > T of BDNF as a genetic risk factor of opium addiction
(Elsevier B.V., 2022) Anit Kumar; Sheikh Nizamuddin; Niraj Rai; Biswajit Roy; Manju Kashyap; Gaurav Gupta; Vineet Kaswan; Naveen Kumar Kaushik; Jatin Bodwal; Poonam Rana; Anshuman Mishra; Gyaneshwer Chaubey; H.T. Marc Timmers; Kumarasamy Thangaraj; Amit Kaushik
Opioid use disorder is largely genetic in nature. The common genetic variants present in population might be modulating the risk by affecting expression level of genes in the brain. Here, we study common variants in promoter region of brain-derived neurotrophic factor (BDNF) and Dopamine receptor D2 (DRD2) in a highly prevalent opium addiction geographical region. We identify highly expressed isoforms using CAGE datasets and its associated promoter. Common variants were extracted from promoters and genotyped in addicts compared to controls. The associated variants obtained through hitchhiking events were removed and eQTL analysis was performed. We identified two mutations (rs7944119:G > T and rs13306221:C > T) in the promoter of BDNF to be significantly associated with the addiction. In the dominant inheritance model, both rs7944119 and rs13306221 increases the risk of addiction. Of these two, rs7944119 was in linkage disequilibrium with rs13306221 and showed association due to hitchhiking. The rs13306221-T was associated with a lower expression level of the short BDNF isoform in the Cerebellar cortex. This finding suggests that rs13306221 (c.-22 + 155C > T) could increase risk of addiction by decreasing the expression level of the short isoform of BDNF, therefore, changes in the expression of the BDNF might not be the effect, but rather a cause of opium addiction disorder. Or, subjects with less expression of BDNF are more prone to addiction and addiction further decreases expression of BDNF short isoform in the brain. Although, it should be explored further in more detail. © 2022 Elsevier B.V.
Complex genetic origin of Indian populations and its implications
(2012) Rakesh Tamang; Lalji Singh; Kumarasamy Thangaraj
Indian populations are classified into various caste, tribe and religious groups, which altogether makes them very unique compared to rest of the world. The long-term firm socio-religious boundaries and the strict endogamy practices along with the evolutionary forces have further supplemented the existing high-level diversity. As a result, drawing definite conclusions on its overall origin, affinity, health and disease conditions become even more sophisticated than was thought earlier. In spite of these challenges, researchers have undertaken tireless and extensive investigations using various genetic markers to estimate genetic variation and its implication in health and diseases. We have demonstrated that the Indian populations are the descendents of the very first modern humans, who ventured the journey of out-of-Africa about 65,000 years ago. The recent gene flow from east and west Eurasia is also evident. Thus, this review attempts to summarize the unique genetic variation among Indian populations as evident from our extensive study among approximately 20,000 samples across India. © Indian Academy of Sciences.
COVID-19: Impact on linguistic and genetic isolates of India
(Springer Nature, 2022) Prajjval Pratap Singh; Prashanth Suravajhala; Chandana Basu Mallick; Rakesh Tamang; Ashutosh Kumar Rai; Pratheusa Machha; Royana Singh; Abhishek Pathak; Vijay Nath Mishra; Pankaj Shrivastava; Keshav K. Singh; Kumarasamy Thangaraj; Gyaneshwer Chaubey
The rapid expansion of coronavirus SARS-CoV-2 has impacted various ethnic groups all over the world. The burden of infectious diseases including COVID-19 are generally reported to be higher for the Indigenous people. The historical knowledge have also suggested that the indigenous populations suffer more than the general populations in the pandemic. Recently, it has been reported that the indigenous groups of Brazil have been massively affected by COVID-19. Series of studies have shown that many of the indigenous communities reached at the verge of extinction due to this pandemic. Importantly, South Asia also has several indigenous and smaller communities, that are living in isolation. Till date, despite the two consecutive waves in India, there is no report on the impact of COVID-19 for indigenous tribes. Since smaller populations experiencing drift may have greater risk of such pandemic, we have analysed Runs of Homozygosity (ROH) among South Asian populations and identified several populations with longer homozygous segments. The longer runs of homozygosity at certain genomic regions may increases the susceptibility for COVID-19. Thus, we suggest extreme careful management of this pandemic among isolated populations of South Asia. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
Dopamine transporter (DAT1) VNTR polymorphism and alcoholism in two culturally different populations of South India
(2012) Lakkakula V. K. S. Bhaskar; Kumarasamy Thangaraj; Samiksha Wasnik; Lalji Singh; Vadlamudi Raghavendra Rao
It is well established that the central dopaminergic reward pathway is likely involved in alcohol intake and the progression of alcohol dependence. Dopamine transporter (DAT1) mediates the active re-uptake of DA from the synapse and is a principal regulator of dopaminergic neurotransmission. The gene for the human DAT1 displays several polymorphisms, including a 40-bp variable number of tandem repeats (VNTR) ranging from 3 to 16 copies in the 3'-untranslated region (UTR) of the gene. To assess the role of this gene in alcoholism, we genotyped the VNTR of DAT1 gene in a sample of 206 subjects from the Kota population (111 alcohol dependence cases and 95 controls) and 142 subjects from Badaga population (81 alcohol dependence cases and 61 controls). Both populations inhabit a similar environmental zone, but have different ethnic histories. Phenotype was defined based on the DSM-IV criteria. Genotyping was performed using PCR and electrophoresis. The association of DAT1 with alcoholism was tested by using the Clump v1.9 program which uses the Monte Carlo method. In both Kota and Badaga populations, the allele A10 was the most frequent allele followed by allele A9. The genotypic distribution is in Hardy-Weinberg equilibrium in both cases and control groups of Kota and Badaga populations. The DAT1 VNTR was significantly associated with alcoholism in Badaga population but not in Kota population. Our results suggest that the A9 allele of the DAT gene is involved in vulnerability to alcoholism, but that these associations are population specific. Copyright © American Academy of Addiction Psychiatry.
Forensic and phylogenetic characterization of 24 autosomal STR in the Sindhi population of India
(Elsevier Inc., 2025) Khushboo Gautam; Chanchal Devnani; Shivani Dixit; Pankaj Shrivastav; Shruti Dasgupta; Madhusudan Reddy Nandineni; Kumarasamy Thangaraj; Rakesh Mahesh Rawal; G. Chaubey
Short Tandem Repeats (STR) genotyping is of utmost importance in forensic casework. Thus, this study, for the first time, explores the forensic profile of the Sindhi population of India, a community with deep historical roots in the Indus Valley Civilization, through the analysis of 24 autosomal short tandem repeat (STR) loci. We found a total of 292 alleles for 24 STRs, and for each locus, the number of alleles ranged from 8 to 22. Out of 24 loci analysed, we obtained the highest genetic diversity for SE33 (0.947) and the lowest for TPOX (0.646) loci. We observed the highest Power of Discrimination (PD) for SE33 (0.988) and the lowest for TPOX (0.79) loci. SE33 locus has the highest number of alleles (36), while the CSF1PO, D5S818, TH01, and TPOX loci have the lowest (6 each). Research has revealed a significant genetic link between the Indian Sindhi population and their ancestral homeland. Based on the present analysis, we conclude that these 24 STR makers used in the present study are highly informative for individual identification, paternity testing, and population genetic studies. © 2025 Elsevier Inc.
Genetic affinities of the central Indian tribal populations
(2012) Gunjan Sharma; Rakesh Tamang; Ruchira Chaudhary; Vipin Kumar Singh; Anish M. Shah; Sharath Anugula; Deepa Selvi Rani; Alla G. Reddy; Muthukrishnan Eaaswarkhanth; Gyaneshwer Chaubey; Lalji Singh; Kumarasamy Thangaraj
Background: The central Indian state Madhya Pradesh is often called as 'heart of India' and has always been an important region functioning as a trinexus belt for three major language families (Indo-European, Dravidian and Austroasiatic). There are less detailed genetic studies on the populations inhabited in this region. Therefore, this study is an attempt for extensive characterization of genetic ancestries of three tribal populations, namely; Bharia, Bhil and Sahariya, inhabiting this region using haploid and diploid DNA markers. Methodology/Principal Findings: Mitochondrial DNA analysis showed high diversity, including some of the older sublineages of M haplogroup and prominent R lineages in all the three tribes. Y-chromosomal biallelic markers revealed high frequency of Austroasiatic-specific M95-O2a haplogroup in Bharia and Sahariya, M82-H1a in Bhil and M17-R1a in Bhil and Sahariya. The results obtained by haploid as well as diploid genetic markers revealed strong genetic affinity of Bharia (a Dravidian speaking tribe) with the Austroasiatic (Munda) group. The gene flow from Austroasiatic group is further confirmed by their Y-STRs haplotype sharing analysis, where we determined their founder haplotype from the North Munda speaking tribe, while, autosomal analysis was largely in concordant with the haploid DNA results. Conclusions/Significance: Bhil exhibited largely Indo-European specific ancestry, while Sahariya and Bharia showed admixed genetic package of Indo-European and Austroasiatic populations. Hence, in a landscape like India, linguistic label doesn't unequivocally follow the genetic footprints. © 2012 Sharma et al.
Genetic and functional evaluation of the role of CXCR1 and CXCR2 in susceptibility to visceral leishmaniasis in north-east India
(2011) Sanjana Mehrotra; Michaela Fakiola; Joyce Oommen; Sarra E. Jamieson; Anshuman Mishra; Medhavi Sudarshan; Puja Tiwary; Deepa S. Rani; Kumarasamy Thangaraj; Madhukar Rai; Shyam Sundar; Jenefer M. Blackwell
Background: IL8RA and IL8RB, encoded by CXCR1 and CXCR2, are receptors for interleukin (IL)-8 and other CXC chemokines involved in chemotaxis and activation of polymorphonuclear neutrophils (PMN). Variants at CXCR1 and CXCR2 have been associated with susceptibility to cutaneous and mucocutaneous leishmaniasis in Brazil. Here we investigate the role of CXCR1/CXCR2 in visceral leishmaniasis (VL) in India.Methods: Three single nucleotide polymorphisms (SNPs) (rs4674259, rs2234671, rs3138060) that tag linkage disequilibrium blocks across CXCR1/CXCR2 were genotyped in primary family-based (313 cases; 176 nuclear families; 836 individuals) and replication (941 cases; 992 controls) samples. Family- and population-based analyses were performed to look for association between CXCR1/CXCR2 variants and VL. Quantitative RT/PCR was used to compare CXCR1/CXCR2 expression in mRNA from paired splenic aspirates taken before and after treatment from 19 VL patients.Results: Family-based analysis using FBAT showed association between VL and SNPs CXCR1_rs2234671 (Z-score = 2.935, P = 0.003) and CXCR1_rs3138060 (Z-score = 2.22, P = 0.026), but not with CXCR2_rs4674259. Logistic regression analysis of the case-control data under an additive model of inheritance showed association between VL and SNPs CXCR2_rs4674259 (OR = 1.15, 95%CI = 1.01-1.31, P = 0.027) and CXCR1_rs3138060 (OR = 1.25, 95%CI = 1.02-1.53, P = 0.028), but not with CXCR1_rs2234671. The 3-locus haplotype T_G_C across these SNPs was shown to be the risk haplotype in both family- (TRANSMIT; P = 0.014) and population- (OR = 1.16, P = 0.028) samples (combined P = 0.002). CXCR2, but not CXCR1, expression was down regulated in pre-treatment compared to post-treatment splenic aspirates (P = 0.021).Conclusions: This well-powered primary and replication genetic study, together with functional analysis of gene expression, implicate CXCR2 in determining outcome of VL in India. © 2011 Mehrotra et al; licensee BioMed Central Ltd.
Genetic and functional evaluation of the role of DLL1 in susceptibility to visceral leishmaniasis in India
(2012) Sanjana Mehrotra; Michaela Fakiola; Anshuman Mishra; Medhavi Sudarshan; Puja Tiwary; Deepa Selvi Rani; Kumarasamy Thangaraj; Madhukar Rai; Shyam Sundar; Jenefer M. Blackwell
Chromosome 6q26-27 is linked to susceptibility to visceral leishmaniasis (VL) in Brazil and Sudan. DLL1 encoding the Delta-like 1 ligand for Notch 3 was implicated as the etiological gene. DLL1 belongs to the family of Notch ligands known to selectively drive antigen-specific CD4 T helper 1 cell responses, which are important in protective immune response in leishmaniasis. Here we provide further genetic and functional evidence that supports a role for DLL1 in a well-powered population-based study centred in the largest global focus of VL in India. Twenty-one single nucleotide polymorphisms (SNPs) at . PHF10/C6orf70/DLL1. /FAM120B/PSMB1/TBP were genotyped in 941 cases and 992 controls. Logistic regression analysis under an additive model showed association between VL and variants at DLL1 and . FAM120B, with top associations (rs9460106, OR. =. 1.17, 95%CI 1.01-1.35, . P=. 0.033; rs2103816, OR. =. 1.16, 95%CI 1.01-1.34, . P=. 0.039) robust to analysis using caste as a covariate to take account of population substructure. Haplotype analysis taking population substructure into account identified a common 2-SNP risk haplotype (frequency 0.43; . P=. 0.028) at . FAM120B, while the most significant protective haplotype (frequency 0.18; . P=. 0.007) was a 5-SNP haplotype across the interval 5' of both DLL1 (negative strand) and . FAM120B (positive strand) and extending to intron 4 of DLL1. Quantitative RT/PCR was used to compare expression of 6q27 genes in paired pre- and post-treatment splenic aspirates from VL patients (. N=. 19). DLL1 was the only gene to show differential expression that was higher (. P<. 0.0001) in pre- compared to post-treatment samples, suggesting that regulation of gene expression was important in disease pathogenesis. This well-powered genetic and functional study in an Indian population provides evidence supporting DLL1 as the etiological gene contributing to susceptibility to VL at Chromosome 6q27, confirming the potential for polymorphism at DLL1 to act as a genetic risk factor across the epidemiological divides of geography and parasite species. © 2012 .
Genetic architecture of the Sindhi Indian population: a 19X-STR forensic analysis
(BioMed Central Ltd, 2025) Khushboo Gautam; Chanchal Devnani; Shruti Dasgupta; Madhusudan Reddy Nandineni; Kumarasamy Thangaraj; G. Chaubey; Rakesh Mahesh Rawal
The X chromosome accounts for approximately 5% of the human genome and serves as a valuable marker in forensic and population genetics due to its uneven and asymmetrical pattern of inheritance. This unique trait enables significant applications, including kinship testing, half-sister paternity deficiency assessments, and analyzing relationships across generations. Notably, the unequal transmission of the X chromosome where females have two X chromosomes compared to males—contributes to sex-based disparities. The use of X-STRs offers additional evidence in cases where personal identification poses challenges in forensic investigations. In both population studies and forensic analyses, X-STRs are typically examined using commercially available kits, such as the Microreader 19X STR. The present study focuses on the Sindhi population, an ethnic group in India with ancestral roots in Pakistan. We analyzed 19 X-STR loci in the Sindhi Indian population, examining allele frequencies from 206 DNA samples derived from 144 unrelated males and 62 females. Among the 19 X-STR loci analyzed, DXS10135 showed the highest polymorphism with 19 observed alleles, while DXS7133 was the least polymorphic, with only 6 alleles. The Fst distance matrix analysis, which encompassed 26 global populations, revealed that the Sindhi Indian population shares the closest genetic affinity with Pathan, Baluchi, and other Pakistani groups, demonstrating an average genetic distance of approximately 0.006. These findings underscore the genetic proximity of the Sindhi population to Indo-European-speaking groups in the region. Notably, this study presents the first comprehensive X-STR reference dataset for the Sindhi population in India, providing novel data for forensic applications and enhancing the understanding of regional population structure and differentiation in South Asia. © The Author(s) 2025.
Genetic evidence for recent population mixture in India
(2013) Priya Moorjani; Kumarasamy Thangaraj; Nick Patterson; Mark Lipson; Po-Ru Loh; Periyasamy Govindaraj; Bonnie Berger; David Reich; Lalji Singh
Most Indian groups descend from a mixture of two genetically divergent populations: Ancestral North Indians (ANI) related to Central Asians, Middle Easterners, Caucasians, and Europeans; and Ancestral South Indians (ASI) not closely related to groups outside the subcontinent. The date of mixture is unknown but has implications for understanding Indian history. We report genome-wide data from 73 groups from the Indian subcontinent and analyze linkage disequilibrium to estimate ANI-ASI mixture dates ranging from about 1,900 to 4,200 years ago. In a subset of groups, 100% of the mixture is consistent with having occurred during this period. These results show that India experienced a demographic transformation several thousand years ago, from a region in which major population mixture was common to one in which mixture even between closely related groups became rare because of a shift to endogamy. © 2013 The American Society of Human Genetics.
Genetic Structure of Tibeto-Burman Populations of Bangladesh: Evaluating the Gene Flow along the Sides of Bay-of-Bengal
(2013) Nurun Nahar Gazi; Rakesh Tamang; Vipin Kumar Singh; Ahmed Ferdous; Ajai Kumar Pathak; Mugdha Singh; Sharath Anugula; Pandichelvam Veeraiah; Subburaj Kadarkaraisamy; Brijesh Kumar Yadav; Alla G. Reddy; Deepa Selvi Rani; Syed Saleheen Qadri; Lalji Singh; Gyaneshwer Chaubey; Kumarasamy Thangaraj
Human settlement and migrations along sides of Bay-of-Bengal have played a vital role in shaping the genetic landscape of Bangladesh, Eastern India and Southeast Asia. Bangladesh and Northeast India form the vital land bridge between the South and Southeast Asia. To reconstruct the population history of this region and to see whether this diverse region geographically acted as a corridor or barrier for human interaction between South Asia and Southeast Asia, we, for the first time analyzed high resolution uniparental (mtDNA and Y chromosome) and biparental autosomal genetic markers among aboriginal Bangladesh tribes currently speaking Tibeto-Burman language. All the three studied populations; Chakma, Marma and Tripura from Bangladesh showed strikingly high homogeneity among themselves and strong affinities to Northeast Indian Tibeto-Burman groups. However, they show substantially higher molecular diversity than Northeast Indian populations. Unlike Austroasiatic (Munda) speakers of India, we observed equal role of both males and females in shaping the Tibeto-Burman expansion in Southern Asia. Moreover, it is noteworthy that in admixture proportion, TB populations of Bangladesh carry substantially higher mainland Indian ancestry component than Northeast Indian Tibeto-Burmans. Largely similar expansion ages of two major paternal haplogroups (O2a and O3a3c), suggested that they arose before the differentiation of any language group and approximately at the same time. Contrary to the scenario proposed for colonization of Northeast India as male founder effect that occurred within the past 4,000 years, we suggest a significantly deep colonization of this region. Overall, our extensive analysis revealed that the population history of South Asian Tibeto-Burman speakers is more complex than it was suggested before. © 2013 Gazi et al.
High frequencies of Non Allelic Homologous Recombination (NAHR) events at the AZF loci and male infertility risk in Indian men
(Nature Publishing Group, 2019) Deepa Selvi Rani; Singh Rajender; Kadupu Pavani; Gyaneshwer Chaubey; Avinash A. Rasalkar; Nalini J. Gupta; Mamta Deendayal; Baidyanath Chakravarty; Kumarasamy Thangaraj
Deletions in the AZoospermia Factor (AZF) regions (spermatogenesis loci) on the human Y chromosome are reported as one of the most common causes of severe testiculopathy and spermatogenic defects leading to male infertility, yet not much data is available for Indian infertile men. Therefore, we screened for AZF region deletions in 973 infertile men consisting of 771 azoospermia, 105 oligozoospermia and 97 oligoteratozoospermia cases, along with 587 fertile normozoospermic men. The deletion screening was carried out using AZF-specific markers: STSs (Sequence Tagged Sites), SNVs (Single Nucleotide Variations), PCR-RFLP (Polymerase Chain Reaction - Restriction Fragment Length Polymorphism) analysis of STS amplicons, DNA sequencing and Southern hybridization techniques. Our study revealed deletion events in a total of 29.4% of infertile Indian men. Of these, non-allelic homologous recombination (NAHR) events accounted for 25.8%, which included 3.5% AZFb deletions, 2.3% AZFbc deletions, 6.9% complete AZFc deletions, and 13.1% partial AZFc deletions. We observed 3.2% AZFa deletions and a rare long AZFabc region deletion in 0.5% azoospermic men. This study illustrates how the ethnicity, endogamy and long-time geographical isolation of Indian populations might have played a major role in the high frequencies of deletion events. © 2019, The Author(s).
High prevalence of Arginine to Glutamine Substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians
(2012) Deepa S. Rani; Pratibha Nallari; Singh Priyamvada; Calambur Narasimhan; Lalji Singh; Kumarasamy Thangaraj
Background: Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study.Methods: We have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM), along with 160 healthy controls, inhabited in the same geographical region of southern India.Results: Our study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q) mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM). The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++). The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E) mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85%) with a rare codon (GAA: 14%). Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E) of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T) exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing.Conclusion: Our study has provided valuable information regarding the prevalence of TNNI3 mutations in Indian HCM patients and its risk assessment, these will help in genetic counseling and to adopt appropriate treatment strategies. © 2012 Rani et al.; licensee BioMed Central Ltd.
IL-4 Haplotype -590T, -34T and Intron-3 VNTR R2 Is Associated with Reduced Malaria Risk among Ancestral Indian Tribal Populations
(2012) Aditya Nath Jha; Vipin Kumar Singh; Namrata Kumari; Ashish Singh; Justin Antony; Hoang van Tong; Sakshi Singh; Sudhanshu S. Pati; Pradeep K. Patra; Rajender Singh; Nguyen L. Toan; Le H. Song; Amal Assaf; Iara J. T. Messias-Reason; Thirumalaisamy P. Velavan; Lalji Singh; Kumarasamy Thangaraj
Background: Interleukin 4 (IL-4) is an anti-inflammatory cytokine, which regulates balance between TH1 and TH2 immune response, immunoglobulin class switching and humoral immunity. Polymorphisms in this gene have been reported to affect the risk of infectious and autoimmune diseases. Methods: We have analyzed three regulatory IL-4 polymorphisms; -590C>T, -34C>T and 70 bp intron-3 VNTR, in 4216 individuals; including: (1) 430 ethnically matched case-control groups (173 severe malaria, 101 mild malaria and 156 asymptomatic); (2) 3452 individuals from 76 linguistically and geographically distinct endogamous populations of India, and (3) 334 individuals with different ancestry from outside India (84 Brazilian, 104 Syrian, and 146 Vietnamese). Results: The -590T, 34T and intron-3 VNTR R2 alleles were found to be associated with reduced malaria risk (P<0.001 for -590C>T and -34C>T, and P = 0.003 for VNTR). These three alleles were in strong LD (r2>0.75) and the TTR2 (-590T, -34T and intron-3 VNTR R2) haplotype appeared to be a susceptibility factor for malaria (P = 0.009, OR = 0.552, 95% CI = 0.356 -0.854). Allele and genotype frequencies differ significantly between caste, nomadic, tribe and ancestral tribal populations (ATP). The distribution of protective haplotype TTR2 was found to be significant (χ23 = 182.95, p-value <0.001), which is highest in ATP (40.5%); intermediate in tribes (33%); and lowest in caste (17.8%) and nomadic (21.6%). Conclusions: Our study suggests that the IL-4 polymorphisms regulate host susceptibility to malaria and disease progression. TTR2 haplotype, which gives protection against malaria, is high among ATPs. Since they inhabited in isolation and mainly practice hunter-gatherer lifestyles and exposed to various parasites, IL-4 TTR2 haplotype might be under positive selection. © 2012 Jha et al.
Is MTHFR 677 C>T polymorphism clinically important in Polycystic Ovarian Syndrome (PCOS)? A case-control study, meta-analysis and trial sequential analysis
(Public Library of Science, 2016) S. Justin Carlus; Saumya Sarkar; Sandeep Kumar Bansal; Vertika Singh; Kiran Singh; Rajesh Kumar Jha; Nirmala Sadasivam; Sri Revathy Sadasivam; P.S. Gireesha; Kumarasamy Thangaraj; Singh Rajender
Background: Optimum efficiency of the folate pathway is considered essential for adequate ovarian function. 677 C>T substitution in the 5, 10-methylene tertrahydrofolatereductase (MTHFR) gene compromises activity of the MTHFR enzyme by about 50%. The significance of correlation between 677C>T substitution and PCOS remains dubious due to the low power of published studies. Methods and Results: We analyzed MTHFR 677 C>T site in ethnically two different PCOS case-control groups (total 261 cases and 256 controls) from India. The data analysis revealed a lack of association between this polymorphism and PCOS [OR = 1.11 (95%CI = 0.71-1.72), P = 0.66]. Group-wise analysis on the basis of ethnicity also revealed no association in any of the ethnic groups [Indo-Europeans, P = 1; Dravidians, P = 0.70]. Homocysteine levels did not differ significantly between cases (15.51 μmol/L, SD = 2.89) and controls (15.89 μmol/L, SD = 2.23). We also undertook a meta-analysis on 960 cases and 1028 controls, which suggested a significant association of the substitution with PCOS in the dominant model of analysis (OR = 1.47 (95%CI = 1.04-2.09), P = 0.032]. Trial sequential analysis corroborated findings of the traditional meta-analysis. However, we found that the conclusions of meta-analysis were strongly influenced by studies that deviated from the Hardy Weinberg equilibrium. A careful investigation of each study and a trial sequential analysis suggested that 677 C>T substitution holds no clinical significance in PCOS in most of the populations. Conclusion: In conclusion, MTHFR 677 C>T polymorphism does not affect PCOS risk in India. The association seen in the meta-analysis is due to an outlier study and studies showing deviation from the Hardy Weinberg equilibrium. © 2016 Carlus et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
L712V mutation in the androgen receptor gene causes complete androgen insensitivity syndrome due to severe loss of androgen function
(2013) Singh Rajender; Nalini J. Gupta; Baidyanath Chakrabarty; Lalji Singh; Kumarasamy Thangaraj
Inability to respond to the circulating androgens is named as androgen insensitivity syndrome (AIS). Mutations in the androgen receptor (AR) gene are the most common cause of AIS. A cause and effect relationship between some of these mutations and the AIS phenotype has been proven by in vitro studies. Several other mutations have been identified, but need to be functionally validated for pathogenicity. Screening of the AR mutations upon presumptive diagnosis of AIS is recommended. We analyzed a case of complete androgen insensitivity syndrome (CAIS) for mutations in the AR gene. Sequencing of the entire coding region revealed C > G mutation (CTT-GTT) at codon 712 (position according to the NCBI database) in exon 4 of the gene, resulting in replacement of leucine with valine in the ligand-binding domain of the AR protein. No incidence of this mutation was observed in 230 normal male individuals analyzed for comparison. In vitro androgen binding and transactivation assays using mutant clone showed approximately 71% loss of ligand binding and about 76% loss of transactivation function. We conclude that CAIS in this individual was due to L712V substitution in the androgen receptor protein. © 2013 Elsevier Ltd. All rights reserved.
Mannose-binding Lectin (MBL) as a susceptible host factor influencing Indian Visceral Leishmaniasis
(Elsevier Ireland Ltd, 2015) Anshuman Mishra; Justin S. Antony; Prabhanjan Gai; Pandarisamy Sundaravadivel; Tong Hoang van; Aditya Nath Jha; Lalji Singh; Thirumalaisamy P. Velavan; Kumarasamy Thangaraj
Visceral Leishmaniasis (VL), caused by Leishmania donovani is endemic in the Indian sub-continent. Mannose-binding Lectin (MBL) is a complement lectin protein that binds to the surface of Leishmania promastigotes and results in activation of the complement lectin cascade. We utilized samples of 218 VL patients and 215 healthy controls from an Indian population. MBL2 functional variants were genotyped and the circulating MBL serum levels were measured. MBL serum levels were elevated in patients compared to the healthy controls (adjusted P=. 0.007). The MBL2 promoter variants -. 78C/T and +. 4P/Q were significantly associated with relative protection to VL (-. 78C/T, OR. =. 0.7, 95% CI. =. 0.5-0.96, adjusted P=. 0.026 and +. 4P/Q, OR. =. 0.66, 95% CI. =. 0.48-0.9, adjusted P=. 0.012). MBL2*. LYQA haplotypes occurred frequently among controls (OR. =. 0.69, 95% CI. =. 0.5-0.97, adjusted P=. 0.034). MBL recognizes Leishmania and plays a relative role in establishing L. donovani infection and subsequent disease progression. In conclusion, MBL2 functional variants were associated with VL. © 2015 Elsevier Ireland Ltd.