Biology subjects

Thangaraj, K.

Publications and source records attributed to Thangaraj, K..

13 recordsLinked to original sources

bioRxiv2025

Revisiting the Evolution of Lactase Persistence: Insights from South Asian Genomes

Lactase persistence (LP), the ability to digest lactose from milk into adulthood, is a classic example of natural selection in humans. Multiple mutations upstream of the LCT gene are associated with LP and have been previously shown to be under selection in Europeans and Africans. South Asia is the worlds largest producer of dairy, and milk and dairy products are widely consumed throughout the subcontinent. However, the origin, evolutionary history and selective pressures associated with LP in South Asia remain elusive. We assembled genome-wide data from [~]8,000 present-day and ancient genomes from India, Pakistan, and Bangladesh, spanning diverse timescales ([~]3300 BCE-1650 CE), geographic regions, and ethnolinguistic and subsistence groups. We find that the Eurasian LP-associated variant,-13.910:C>T, is widespread across South Asia, exhibiting clinal variation along north-south and east-west gradients. Ancient DNA analysis reveals that this variant first appeared in South Asia during the historical and medieval periods through Steppe pastoralist-related gene flow. Interestingly, unlike in other worldwide populations, the LP prevalence is almost entirely explained by Steppe ancestry--not selection--in most contemporary South Asians. A notable exception is the only two pastoralist groups, Toda in South India and Gujjar in Pakistan, that have unexpectedly high frequencies of-13.910*T, comparable to estimates in Northern Europeans. By performing local ancestry inference, we find significant enrichment for Steppe pastoralist ancestry around the LCT locus in these two geographically-distant pastoralist groups, indicative of strong selection. Together, these findings highlight the complex role of ancestry and natural selection in shaping the prevalence of lactase persistence on the subcontinent.

evolutionary biology↗

bioRxiv2025

An efficient protocol to derive primordial germ cell like cells in vitro from murine embryonic stem cells.

Primordial germ cells (PGCs) are the precursors of germ cells, specified from a subset of epiblast stem cells at the post-implantation stage of mammalian embryonic development. Over the past decade, primordial germ cell-like cells (PGCLCs) have been successfully derived in vitro from mouse and human embryonic stem cells (ESCs). These PGCLCs can further differentiate into mature sperm upon transplantation into neonatal testes. Such advancements offer promising strategies to address male infertility, which affects approximately 15% of couples worldwide. The discovery of induced pluripotent stem cells (iPSCs), which possess similar potential to ESCs, further raises hope for patient-specific therapeutic interventions. However, a major challenge remains: the low efficiency of in vitro PGCLC differentiation. To overcome this, we developed an optimized PGCLC differentiation strategy using a Dppa3-mCherry knock-in reporter mouse ESC line, TDM11. By testing various culture conditions, we identified ascorbic acid as a potent inducer of PGCLC differentiation from ESCs, providing a potential avenue for enhancing in vitro germ cell derivation.

developmental biology↗

bioRxiv2025

Investigating the demographic history of Sindhi population inhabited in West coast India

BackgroundSouth Asian populations are genetically well stratified due to multiple waves of migration, admixture events, and endogamy. India remains a rich resource for population genomics studies with many small and socioculturally homogeneous communities whose origins and demographic histories are largely unknown. In this study, we analysed such a small Sindhi settlement in the Thane district in Maharashtra of West coast India using genome-wide autosomal SNP data using both frequency- and haplotype-based approaches. ResultsOur analyses suggest that the West coast Indian Sindhi community is very unique and has significant population affinity with a group more closely related to the Pakistani Burusho than to the Pakistani Sindhi, as it has an additional East/Southeast Asian component. Furthermore, the sharing of haplotype and IBD suggests recent gene flow from the local Konkani population on the west coast of India into Indian Sindhi. Admixture modelling suggested that Indian Sindhi admixture with the East/Southeast Asian source group could be 40-50 GBP, explaining their current unique demographics. However, apart from this additional admixture, they share the basic genetic composition of the Pakistan/NWI groups, as reflected in PCA, outgroup F3 and IBD sharing. ConclusionThese new findings suggest that Indian Sindhi settlement from the Thane in Maharashtra in West coast of India derive their genetic ancestry not directly from Pakistani Sindhis but from other groups related to Burusho in Pakistan. The study therefore encourages further research to identify the heterogeneous nature of migrations to the Indian subcontinent and thus further decipher its unique demographics.

genetics↗

bioRxiv2024

Maternal genetic affinities of Konkani population in the southwest coast of India

Ko[n]kan region on the west coast of India is a hotspot of culture, folklore and ethnolinguistic diversity. The genetic landscape of this region remains understudied. The present study features Ko[n]kan[i] population residing along the Ko[n]kan Malabar coast. We have sequenced complete mitogenomes of 85 and the hypervariable region of 210 Ko[n]kan[i] individuals to understand the maternal gene pool of this region. Comparative analysis of the over 5000 mitogenomes revealed that the Ko[n]kan[i] population clustered at a convergence point on the PCA plot, presumably due to a diverse maternal gene pool with both autochthonous and West Eurasian components. A distinct clustering pattern was observed within the subgroups of S[a]rasvata and non-S[a]rasvata Ko[n]kan[i] groups, indicating unique ancestral maternal lineages in them. This distinction is majorly due to the N macrohaplogroup lineages found in this population. We observe low haplotype and nucleotide diversity in Citrapur S[a]rasvata Brahmins (CSB), R[a]j[a]pur S[a]rasvata Brahmins (RSB), Kh[a]rvi and Kudubi compared to Gauda S[a]rasvata Brahmins (GSB) and Roman Catholics. The assimilation of both pre and post Last Glacial Maximum (LGM) haplogroups like M57, M36, M37, M3, M30, R8 and U2 in the Ko[n]kan[i] population suggests active movement and settlement along the Ko[n]kan region on the west coast of India since the Late Pleistocene through the Holocene.

genetics↗

bioRxiv2024

The genetic landscape, gene flow and adaptation in Ladakh highlanders of trans-Himalayas

Trans-Himalayan Ladakh has witnessed complex cultural movements and demographic changes since the Neolithic period, which is still continue despite the harsh, inhospitable and cold climate. Although geographically isolated from mainland South Asia, Ladakh has historic trade routes and is well connected and accessible to travelers from Tibet and Central Asia. Despite its rich cultural heritage, a detailed description of the genetic landscape of the Ladakh region is completely lacking, particularly with regard to genome-wide analysis and larger sample sizes. Therefore, in the current study, we genotyped 80 individuals from Kargil and Leh districts of the Union Territory of Ladakh, India. Here, we performed a comprehensive genetic analysis based on allele frequency and haplotype sharing. Our analysis revealed the presence of two distinct genetic lineages in the region with quite distinct genetic composition. The population of Leh Region is more similar to East Asian and Southeast Asian populations. In contrast, the population of the Kargil Region (LDKLA) is more similar to Indo-European populations. Demographic modeling suggests that the Leh group shares a genetic history with Tibetans, while the Kargil group showed great affinities with Kashmiri Muslims, Gujjars and Nepalese Brahmins, and both showed recent admixture. Both groups have experienced a founder event around during 11th to 22nd generations ago, the duration of which coincided with the Mughal invasion. The genome-wide scan for a signal of positive selection revealed genetic signatures of high-altitude adaptation (EPAS1 and ELMO2) in the Leh population, while in the Kargil population the key gene signatures were associated with immunity and female fertility.

genetics↗

bioRxiv2022

Genetic affinities and sub-structuring in Coorg population of Southern India

The Coorgs, also known as Kodavas, are one of the smallest religious and socio-culturally homogenous communities in the world, currently residing in the state of Karnataka, India. Due to a stark contrast with the surrounding subpopulations, their genetic architecture and population & demographic history have been a matter of debate for long. To better understand the population structure and demographic history of this caste group, we analysed the population, using high-resolution autosomal (n=70) as well uniparentally inherited markers (Y-chromosomal and mitochondrial DNA) (n=144). Our first ever findings elucidate that origin of Coorgs traces back to early or middle Bronze Age. We further found population substructure among Coorgs, which manifested as three distinct clusters in a Principal component analysis. One of these subgroups has undergone a rare and immense amount of population-specific drift but all three eventually admixed, both genetically and socio-culturally. The mtDNA analysis showed 40% South Asian-specific mitochondrial lineages among Coorgs; while the Y-chromosomal analysis revealed predominant presence of Eurasian, Middle-Eastern and Indian-specific haplogroups suggesting male-centric migration and eventual assimilation with local females. Our results for the first time identify these ancient and distinct genealogies that make up the contemporary Coorgs and may explain the socio-cultural differences with their immediate and distant neighbours in the country and the prevalent narrative history. In a wider context, the study also reveals an ancient, yet unknown, Middle Eastern source population that might have contributed to an early west to east migration into India.

genetics↗

bioRxiv2022

Genetic affinities and adaptation of the South West coast populations of India

Evolutionary event has not only transformed the genetic structure of human populations but also associated with social and cultural transformation. South Asian populations were formed as a result of such evolutionary events of migration and admixture of genetically and culturally distinct groups. Most of the genetic studies pointed to large-scale admixture event between Ancestral North Indian (ANI) and Ancestral South Indian (ASI) groups, also additional layers of recent admixture. In the present study we have analyzed 213 individuals inhabited in South West coast India with traditional warriors and feudal lord status and historically associated with recent migrations events and possible admixture with Indo-Scythians, Saka, Huns and Kushans, whose genetic links are still missing. Analysis of autosomal SNP markers suggests that these groups possibly derived their ancestry from some groups of North West India having additional Middle Eastern genetic component and also their separation history suggests very early separation from North West Indian and Gangetic plain Indo-Europeans during late bronze or Iron age, most probably following central India and Godavari basin to South West coast. Higher distribution of west Eurasian mitochondrial haplogroups also points to admixture through maternal lineage. Selection screen using genome wide genealogy approach revealed genetic signatures related to their long-term coastal food habits. Thus, our study suggests that the South West coastal groups with traditional warriors and feudal lords status are of a distinct lineage compared to Dravidian and Gangetic plain Indo-Europeans and are remnants of very early migrations from North West India following Godavari basin to Karnataka and Kerala.

genetics↗

bioRxiv2022

TEX13B is important for germ cell development and male fertility

The recent epidemiological studies suggest that nearly one out of every 7 reproductive age couples face problem to conceive a child after trying for at least one year. Impaired fertility of the male partner is causative in approximately 50% of the infertile couples. However, the etiologies of large proportion of male infertility are still unclear. Our unpublished exome sequencing data identified several novel genes including TEX13B, which motivated us to further explore the role of TEX13B in male infertility in large infertile case control cohort. Hence in this study, we have examined the role of TEX13B in male infertility by whole gene sequencing 628 infertile and 427 control men and have demonstrated the functional role of Tex13b in spermatogonia GC1spg (GC1) cells. We identified 2 variants on TEX13B which are tightly associated with male infertility. TEX13B gene exclusively expressed in germ cells, but its molecular functions in germ cells are still unknown. Hence, we demonstrated the functional importance of Tex13b in GC1 cell line by genomic manipulation via CRISPR-Cas9 and mass spectrometry-based whole cell proteomics. The gene knock out in GC1 cell line clearly shows that Tex13b play an important role in germ cell growth and morphology. We demonstrate that Tex13b knockout or conditional overexpression in GC1 cells reprograms the metabolic status from an oxidative phosphorylation to glycolysis state and vice versa. In conclusion, our study clearly showed the importance of Tex13b in germ cells development and Its association with male infertility.

genetics↗

bioRxiv2021

Invivo and systematic analysis of random multigenic deletions associated with human diseases during epithelial morphogenesis using Drosophila

Random loss of multigenic loci on chromosomes, a crucial drive for evolution, occurs frequently in all living organisms. Analysis of such chromosomal disruption and understanding the consequences of their impact on the growth and development of multicellular organisms is challenging. In this report, we have addressed this issue using invivo mosaic analysis of deficiency lines in Drosophila. Genes on fly deficiency lines were compared with human orthologs for their implications in disease development during cytoskeletal processes and epithelial morphogenesis. The cytoskeletal phenotypes from the fly has been utilized to predict the function of human orthologs. In addition, as these Drosophila deficiency lines are equivalent to human microdeletions, based on the clonal behaviour and phenotypes generated, a systematic analysis has been carried out to establish the critical loci that correspond to Microdeletion Syndromes and Mendelian Disorders in humans. Further we have drawn the synteny that exists between these chromosomes and have identified critical region corresponding to defects. A few potential candidates that might have an implication in epithelial morphogenesis are also identified.

genetics↗

bioRxiv2020

Hematological parameters of high and low altitude Tibetan populations

High altitude hypoxia is believed to be experienced at elevations more than 2500 meters. A few studies have shed light on the biochemical aspects of high altitude acclimatization that profoundly included the subjects sojourning to the high altitude from low altitude and observation of the transient changes. However, information regarding the difference between the adapted people in high altitude and their counterpart, who reside in the low altitude are lacking. To address that issue, we have measured various hematological parameters and level of serum erythropoietin (EPO) in Tibetan population, who are residing in both high and low altitudes. We observed significant difference (p value < 0.0001) between high and low altitude Tibetan, in various hematological parameters, including red blood cells (RBC) count, hematocrit (HCT) or packed cell volume (PCV), and hemoglobin concentration (Hb). In case of mean corpuscular volume (MCV), significant difference was observed only in females (p value < 0.0001). Mean corpuscular hemoglobin concentration (MCHC) was significantly different between both males and females, but age was a potential confounder. There was no significant difference in serum EPO level between these two groups, either in males or females, which might be due to blunted erythropoietin response in the Tibetan population. We have also analyzed correlation between serum EPO with Hb and serum EPO with HCT and found no significant correlation. In multiple regression analysis, low altitude and male-gender showed significant impact on both Hb and HCT. In conclusion, our study suggests significant perturbation of hematological parameters, when native high altitude populations migrated to low altitude and inhabited for a long period.

physiology↗

bioRxiv2017

Like Sugar in Milk: Reconstructing the genetic history of the Parsi population

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.\n\nResultsOur 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.\n\nConclusionsWe 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-continents 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.

evolutionary biology↗

bioRxiv2017

Genetic polymorphism of Cytochrome-P450-2C9 (CYP2C9) in Indian populations

Cytochrome-P450-2C9 (CYP2C9) metabolizes wide range of drugs and highly express in human liver. Various mutations of CYP2C9 (R144C, I359L etc.), associated with drug-response, are highly diverse. We aimed to investigate the genetic diversity of CYP2C9 in Indian-subcontinent, using 1278 subjects from 36 populations. High frequency of CYP2C9*3 (0-0.179) was observed, comparative to other populations, including Europeans. Subjects having CYP2C9*3/*3 requires lower dose of warfarin, comparative to CYP2C9*1/*3 or CYP2C9*1/*1. Since, Indians are practicing marriage among their caste system, we predicted and observed high frequency (0-0.05) of CYP2C9*3/*3. Out of 21 populations, living outside of Indian subcontinent, only Toscani and Southern Han-Chinese have 0.009 and 0.01 CYP2C9*3/*3, respectively, lower than Indians. We found a non-synonymous mutation (L362V), observed only in Indian-subcontinent, and have 0-0.056 allelic, 0-0.037 L/V and 00.037 V/V genotype frequency. We observed unfavorable interatomic interactions between hydroxylation sites of warfarin and reactive oxyferryl heme in mutant, comparative to wild-type CYP2C9, in molecular dynamic simulations; and predict lower kinetic activity.

evolutionary biology↗

bioRxiv2017

Signatures of natural selection in the drug metabolizing enzyme genes: Opportunity for developing personalized and precision medicine

Modern human experienced various selective pressures; including range of xenobiotics which contributed to heterogeneity of drug response. Many genes involve in pharmacokinetics and dynamics of drug, have been reported under natural selection. However, none of the studies have utilized comprehensive information of drug-centered PharmGKB pathways. We have extended this work and aimed to investigate sweep signals, using 1,798 subjects, from 53 Indian and 15 other world populations. We observed that modifiers which alters the biochemical function of other genes, have excess of natural selection (median std-z score=0.033{+/-}0.95; p-value=1.7x10-9-3.7x10-3). Taxane and statin primarily used for chemotherapy and lowering cholesterol level, respectively; and well known for heterogeneous drug response. We observed that pharmacokinetic pathway of taxane and statins are under natural selection (p-value=2.53x10-9and 2.73x10-9-1.09x10-4; q-value=1.28x10-7 and 6.91x10-6-1.1x10-3). We also observed signal of selection in Ibuprofen pharmacokinetics (p-value=1.76x10-5; q-value =2.22x10-4), beta-agonist/beta-blocker pharmacodynamics (p-value=4.79x10-4; q-value =4.04x10-4) and Zidovudin pharmacokinetics/dynamic pathway (p-value=7.0x10-4; q-value =5.06x10-4). Hard sweeps signals were observed in a total of 322 loci. Of which, 53 affect mRNA expression (p-value<0.001) and 16 were already reported with therapeutic response. Interestingly, we observed that Africans have experience 2 phases of natural selection, one at ~30,000 another at ~10,000 years before present.

evolutionary biology↗