Distinct positions of genetic and oral histories: Perspectives from India.

Over the past decade, genomic data have contributed to several insights on global human population histories. These studies have been met both with interest and critically, particularly by populations with oral histories that are records of their past and often reference their origins. While several studies have reported concordance between oral and genetic histories, there is potential for tension that may stem from genetic histories being prioritized or used to confirm community-based knowledge and ethnography, especially if they differ. To investigate the interplay between oral and genetic histories, we focused on the southwestern region of India and analyzed whole-genome sequence data from 156 individuals identifying as Bunt, Kodava, Nair, and Kapla. We supplemented limited anthropological records on these populations with oral history accounts from community members and historical literature, focusing on references to non-local origins such as the ancient Scythians in the case of Bunt, Kodava, and Nair, members of Alexander the Great's army for the Kodava, and an African-related source for Kapla. We found these populations to be genetically most similar to other Indian populations, with the Kapla more similar to South Indian tribal populations that maximize a genetic ancestry related to Ancient Ancestral South Indians. We did not find evidence of additional genetic sources in the study populations than those known to have contributed to many other present-day South Asian populations. Our results demonstrate that oral and genetic histories may not always provide consistent accounts of population origins and motivate further community-engaged, multi-disciplinary investigations of non-local origin stories in these communities.

Corrigendum: The maternal U1 haplogroup in the Koraga tribe as a correlate of their North Dravidian linguistic affinity.

[This corrects the article DOI: 10.3389/fgene.2023.1303628.].

Identifying Biomarkers and Therapeutic Targets by Multiomic Analysis for HNSCC: Precision Medicine and Healthcare Management.

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the major types of cancer, with 900,000 cases and over 400,000 deaths annually. It constitutes 3-4% of all cancers in Europe and western countries. As early diagnosis is the key to treating the disease, reliable biomarkers play an important role in the precision medicine of HNSCC. Despite treatments, the survival rate of cancer patients remains unchanged, and this is mainly due to the failure to detect the disease early. Thus, the objective of this study is to identify reliable biomarkers for head and neck cancers for better healthcare management. Methods: In this study, all available, curated human genes were screened for their expression against HNSCC TCGA patient samples using genomic and proteomic data by various bioinformatic approaches and datamining. Docking studies were performed using AutoDock or online virtual screening tools for identifying potential ligands. Results: Sixty genes were short-listed, and most of them show a consistently higher expression in head and neck patient samples at both the mRNA and the protein level. Irrespective of human papillomavirus (HPV) status, all of them show a higher expression in cancer samples. The higher expression of 30 genes shows adverse effects on patient survival. Out of the 60 genes, 12 genes have crystal structures and druggable potential. We show that genes such as GTF2H4, HAUS7, MSN, and MNDA could be targets of Pembrolizumab and Nivolumab, which are approved monoclonal antibodies for HNSCC. Conclusion: Sixty genes are identified as potential biomarkers for head and neck cancers based on their consistent and statistically significantly higher expression in patient samples. Four proteins have been identified as potential drug targets based on their crystal structure. However, the utility of these candidate genes has to be further tested using patient samples.

Genetic evidence for a single founding population of the Lakshadweep Islands.

Lakshadweep is an archipelago of 36 islands located in the Southeastern Arabian Sea. In the absence of a detailed archaeological record, the human settlement timing of this island is vague. Previous genetic studies on haploid DNA makers suggested sex-biased ancestry linked to North and South Indian populations. Maternal ancestry suggested a closer link with the Southern Indian, while paternal ancestry advocated the Northern Indian genetic affinity. Since the haploid markers are more sensitive to genetic drift, which is evident for the Island populations, we have used the biparental high-resolution single-nucleotide polymorphic markers to reconstruct the population history of Lakshadweep Islands.  Using the fine-scaled analyses, we specifically focused on (A) the ancestry components of Lakshadweep Islands populations; (B) their relation with East, West Eurasia and South Asia; (C) the number of founding lineages and (D) the putative migration from Northern India as the paternal ancestry was closer to the North Indian populations. Our analysis of ancestry components confirmed relatively higher North Indian ancestry among the Lakshadweep population. These populations are closely related to the South Asian populations. We identified mainly a single founding population for these Islands, geographically divided into two sub-clusters. By examining the population's genetic composition and analysing the gene flow from different source populations, this study contributes to our understanding of Lakshadweep Island's evolutionary history and population dynamics. These findings shed light on the complex interactions between ethnic groups and their genetic contributions in making the Lakshadweep population.

Genetic Affinities and Adaptation of the South-West Coast Populations of India.

Evolutionary event has not only altered the genetic structure of human populations but also associated with social and cultural transformation. South Asian populations were the result of migration and admixture of genetically and culturally diverse groups. Most of the genetic studies pointed to large-scale admixture events 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 migratory events from North/North West India and possible admixture with West Eurasian populations, whose genetic links are still missing. Analysis of autosomal Single Nucleotide Polymorphism (SNP) markers suggests that these groups possibly derived their ancestry from some groups of North West India having additional Middle Eastern genetic components. Higher distribution of West Eurasian mitochondrial haplogroups also points to female-mediated admixture. Estimation of Effective Migration Surface (EEMS) analysis indicates Central India and Godavari basin as a crucial transition zone for population migration from North and North West India to South-west coastal India. Selection screen using 3 distinct outlier-based approaches revealed genetic signatures related to Immunity and protection from Viral infections. 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 the Godavari basin to Karnataka and Kerala.

TAS2R38 bitter taste perception in the Konkani Sarasvata Brahmin population.

BACKGROUND: The TAS2R38 gene carries markers for phenylthiocarbamide (PTC) sensitivity. Various studies have investigated the genotype-phenotype association pattern for bitter tasting ability and other factors in different populations. However, a paucity of such information for endogamous Indian populations is the reason behind this study. OBJECTIVE: To study the association of phenylthiocarbamide (PTC) sensitivity with TAS2R38 gene variations in Konkani Sarasvata Brahmin population. METHODS: We studied the association of the alleles rs714598, rs1726866, rs10246939 with PTC sensitivity and other factors in the Konkani Sarasvata Brahmin population. DNA was extracted from 114 individuals belonging to the Konkani Sarasvata Brahmin community. The TAS2R38 gene was sequenced to find the genotype distribution pattern. The association between genotype and phenotype was checked using the Chi-Square test and multifactorial logistical regression. RESULTS: We observed a 58.8% frequency of the AVI haplotype, which is the most prevalent in European populations. A higher number of non-taster haplotypes and diplotypes were observed in Konkani Sarasvata Brahmins, with the allele rs10246939 showing a significant association with PTC bitter taste sensitivity in both allelic (p = 8.6 × 10-4; Allele-G, OR = 3.57 [95% CI = 1.66-7.69]) and genotype-based (p = 6.9 × 10-4; genotype-AG, OR = 3.11 [95% CI = 0.73-13.20]; genotype-GG, OR = 40 [95% CI = 3.58-447.03]) tests. CONCLUSION: Our results are in line with earlier studies, which report an association between PTC sensitivity and the TAS2R38 gene in different populations. In the global context, Konkani Sarasvata Brahmins, who are mostly distributed along the southwestern coast of India, show a PTC sensitivity pattern slightly similar to that of West Eurasian populations. Our findings suggest ancestry specific selection in TAS2R38 gene variations for taste sensitivity at global level.

Identification of novel biomarkers for lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is the second most common subtype of lung cancer, accounting for a majority of lung cancer-related deaths. Detection or diagnosis of cancer at an early stage is an unmet clinical need that is being actively explored. In this study, we aimed to identify potential biomarkers for LUSC, by screening expression status of all human genes against LUSC patient samples available with The Cancer Genome Atlas (TCGA). This led to the identification of several genes that are upregulated in LUSC. Further analysis revealed that many of these genes also show higher expression at the protein level not only in lung cancer but also in other cancers. Additionally, some of these genes show stage-dependent higher expression and are associated with statistically significant poor survival of LUSC patients. As per our results, more than 60 genes are overexpressed in LUSC at the level of mRNA and some at the protein level. Thus, we identified genes such as MCC1, MRPL47, CRYGS, HSP40, DNAJC19, GMPS and PARL as novel potential biomarkers for LUSC in this study. We believe that these genes hold great potential as LUSC biomarkers for early detection as the data are derived from patient samples. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03489-z.

Maternal Transmission of the PAX7 Single Nucleotide Polymorphisms among Indian Cleft Trios.

Cleft lip and/or cleft palate (CL/P) is one of the most common congenital anomalies of the human face with a complex etiology involving multiple genetic and environmental factors. Several studies have shown the association of the paired box 7 ( PAX7 ) gene with CL/P in different populations worldwide. However, the current literature reveals no reported case-parent trio studies to evaluate the association between the PAX7 gene and the risk of nonsyndromic cleft lip and/or palate (NSCL/P) in the Indian population. Hence, the purpose of this study was to assess the PAX7 gene single nucleotide polymorphisms (SNPs) in the etiology of NSCL/P among the Indian cleft trios. Forty Indian case-parent trios of NSCL/P were included. The cases and their parents' genomic DNA were extracted. The SNPs rs9439714, rs1339062, rs6695765, rs742071, and rs618941of the PAX7 gene were genotyped using the Agena Bio MassARRAY analysis. The allelic transmission disequilibrium test was performed using PLINK software while pair-wise linkage disequilibrium by the Haploview program. The SNP rs9439714 showed evidence of association ( p -value = 0.02, odds ratio = 3) with NSCL/P. Considering the parent-of-origin effects, the SNPs rs9439714 and rs618941 showed an excess maternal transmission of allele C at rs9439714 ( p -value = 0.05) and G allele at rs618941 ( p -value = 0.04). The results of the present study suggested that the SNPs rs9439714 and rs618941 showed an excess maternal transmission of alleles suggestive of the possible role of the PAX7 gene involvement in the etiology of NSCL/P in the Indian population.

The maternal U1 haplogroup in the Koraga tribe as a correlate of their North Dravidian linguistic affinity.

Introduction: The Koraga tribe are an isolated endogamous tribal group found in the southwest coastal region of India. The Koraga language shares inherited grammatical features with North Dravidian languages. To seek a possible genetic basis for this exceptionality and understand the maternal lineage pattern, we have aimed to reconstruct the inter-population and intra-population relationships of the Koraga tribal population by using mtDNA markers for the hypervariable regions along with a partial coding region sequence analysis. Methods and Results: Amongst the 96 individuals studied, we observe 11 haplogroups, of which a few are shared and others are unique to the clans Soppu, Onti and Kuntu. In addition to several deep rooted Indian-specific lineages of macrohaplogroups M and U, we observe a high frequency of the U1 lineage (∼38%), unique to the Koraga. A Bayesian analysis of the U1 clade shows that the Koraga tribe share their maternal lineage with ancestral populations of the Caucasus at the cusp of the Last Glacial Maximum. Discussion: Our study suggests that the U1 lineage found in the Indian subcontinent represents a remnant of a post-glacial dispersal. The presence of West Asian U1 when viewed along with historical linguistics leads us to hypothesise that Koraga represents a mother tongue retained by a vanquished population group that fled southward at the demise of the Indus civilisation as opposed to a father tongue, associated with a particular paternal lineage.

Seasonal dynamics and polyphenism of butterfly communities in the coastal plains of central Western Ghats, India.

Long-term socioeconomic progress requires a healthy environment/ecosystem, but anthropogenic activities cause environmental degradation and biodiversity loss. Constant ecological monitoring is, therefore, necessary to assess the state of biodiversity and ecological health. However, baseline data are lacking even for ecologically sensitive regions such as the Western Ghats. We looked at the seasonality and polyphenism of butterflies of the central Western Ghats to obtain baseline population patterns on these charismatic taxa. We recorded 43118 individuals (175 species) using fortnightly time-constrained counts for two consecutive years and found the peak abundance (49% of the total individuals) in the post-monsoon period (October to January). Seasonal abundance was correlated with the overall increase in species richness. Habitat differences were stronger than seasonality as samples clustered based on sites. Several species also displayed polyphenism with distinct distributions of wet and dry season forms. Seasonal equitability and indicator species analysis showed distinct inter-species differences in seasonality patterns. This work provides key baseline data on the seasonal dynamics of butterflies of the Western Ghats in the context of climate change and conservation. It will help monitor this ecologically sensitive region using butterflies.

Dissecting the genetic history of the Roman Catholic populations of West Coast India.

Migration and admixture history of populations have always been curious and an interesting theme. The West Coast of India harbours a rich diversity, bestowing various ethno-linguistic groups, with many of them having well-documented history of migrations. The Roman Catholic is one such distinct group, whose origin was much debated. While some historians and anthropologists relating them to ancient group of Gaud Saraswat Brahmins, others relating them for being members of the Jews Lost Tribes in the first Century migration to India. Historical records suggests that this community was later forcibly converted to Christianity by the Portuguese in Goa during the Sixteenth Century. Till date, no genetic study was done on this group to infer their origin and genetic affinity. Hence, we analysed 110 Roman Catholics from three different locations of West Coast of India including Goa, Kumta and Mangalore using both uniparental and autosomal markers to understand their genetic history. We found that the Roman Catholics have close affinity with the Indo-European linguistic groups, particularly Brahmins. Additionally, we detected genetic signal of Jews in the linkage disequilibrium-based admixture analysis, which was absent in other Indo-European populations, who are inhabited in the same geographical regions. Haplotype-based analysis suggests that the Roman Catholics consist of South Asian-specific ancestry and showed high drift. Ancestry-specific historical population size estimation points to a possible bottleneck around the time of Goan inquisition (fifteenth century). Analysis of the Roman Catholics data along with ancient DNA data of Neolithic and bronze age revealed that the Roman Catholics fits well in a basic model of ancient ancestral composition, typical of most of the Indo-European caste groups of India. Mitochondrial DNA (mtDNA) analysis suggests that most of the Roman Catholics have aboriginal Indian maternal genetic ancestry; while the Y chromosomal DNA analysis indicates high frequency of R1a lineage, which is predominant in groups with higher ancestral North Indian (ANI) component. Therefore, we conclude that the Roman Catholics of Goa, Kumta and Mangalore regions are the remnants of very early lineages of Brahmin community of India, having Indo-Europeans genetic affinity along with cryptic Jewish admixture, which needs to be explored further.

Heterogeneity in Hematological Parameters of High and Low Altitude Tibetan Populations.

INTRODUCTION: High altitude hypoxia is believed to be experienced at elevations of more than 2500 meters above sea level. Several studies have shed light on the biochemical aspects of high altitude acclimatization, where participants were sojourners to the high altitude from low altitude areas. However, information regarding the difference between the high altitude adapted Tibetans living at high altitude and their counterparts who reside at low altitude are lacking. To understand this, we have measured various hematological parameters in the Tibetan populations, who are residing in both high and low altitudes in India. METHODS: A total of 168 individuals (79 from high altitude (≥4500 meters) and 89 from low altitude (~850 meters) were recruited for this study. Hematological parameters such as red blood cells (RBC) count, hematocrit (HCT), hemoglobin concentration (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) were measured from the individuals from high and low altitudes. Serum erythropoietin (EPO) was measured by ELISA. Statistical analyses were performed to compare data from both of the altitudes. Gender-wise comparison of data was reported. Correlation analysis was performed within relevant parameters. RESULTS: Highly significant differences (p <0.0001) between high and low altitude Tibetans were detected in RBC count, HCT, Hb, MCHC in both males and females and in MCV in females. In the case of MCHC, however, age and BMI were potential confounders. Nominally significant differences (p <0.05) were detected in MCV and MCH within males. No significant difference in serum EPO level was found between altitude groups, in any gender. No significant correlation was found between serum EPO with Hb as well as serum EPO with HCT. DISCUSSION: Our study explores significantly lower RBC count, HCT, Hb, MCH, MCHC and higher MCV in long-term Tibetan residents living at low altitude compared to their high altitude counterparts, which is likely due to the outcome of hematological adaptation to a relatively hyperoxic environment in low altitude areas.

The peopling of Lakshadweep Archipelago.

The archipelago of Lakshadweep is considered as a stopover to the maritime route since ancient time. It is not very clear when the human first occupied these islands, however in the long history of the islands, the local legends suggest that Lakshadweep has been ruled by different kingdoms. To have a better understanding of peopling of Lakshadweep, we have analysed 557 individuals from eight major islands for mitochondrial DNA and 166 individuals for Y chromosome markers. We found a strong founder effect for both paternal and maternal lineages. Moreover, we report a close genetic link of Lakshadweep islanders with the Maldives, Sri Lanka and India. Most of the Lakshadweep islands share the haplogroups specific to South Asia and West Eurasia, except Minicoy Island that also shares haplogroups of East Eurasia. The paternal and maternal ancestries of the majority of island populations suggest their arrival from distinct sources. We found that the maternal ancestry was closer to South Indian populations, whereas the paternal ancestry was overwhelmed with the haplogroups, more common in the Maldives and North of India. In conclusion, our first genetic data suggest that the majority of human ancestry in Lakshadweep is largely derived from South Asia with minor influences from East and West Eurasia.

Neuroprotective effect of quercetin against radiation-induced endoplasmic reticulum stress in neurons.

The endoplasmic reticulum (ER) plays an important role in the regulation and maintenance of cellular homeostasis. However, unresolved ER stress leads to deleterious effects by inducing the accumulation of unfolded proteins in the cell. Here we have demonstrated the protective aspects of quercetin against radiation-induced ER stress and against inflammation in primary cultured dorsal root ganglion (DRG) neurons. The mature DRG neurons were pretreated with different concentrations of quercetin (5-100 µM) for 24 hours before 2 Gy gamma radiation exposure and then subjected to a cytotoxicity assay, quantitative real-time polymerase chain reaction and Western blot analysis. The results showed that quercetin decreased the expression of BiP and C/EBP-homologous protein, the ER stress marker genes along with downregulation of tumor necrosis factor-α, JNK in irradiated DRG neurons. Furthermore, quercetin pretreatment significantly increased the cytoskeletal protein Tuj1 and the neurotrophin brain-derived neurotrophic factor in the neuron. These results indicate that quercetin plays a neuroprotective role against radiation-mediated ER stress and inflammatory responses.

ER stress and genomic instability induced by gamma radiation in mice primary cultured glial cells.

Ionizing radiation induces various pathophysiological conditions by altering central nervous system (CNS) homeostasis, leading to neurodegenerative diseases. However, the potential effect of ionizing radiation response on cellular physiology in glial cells is unclear. In the present study, micronucleus test, comet assay, and RT-PCR were performed to investigate the potential effect of gamma radiation in cultured oligodendrocytes and astrocytes with respect to genomic instability, Endoplasmic Reticulum (ER) stress, and inflammation. Further, we studied the effect of alteration in ER stress specific gene expression in cortex post whole body radiation in mice. Results showed that exposure of gamma radiation of 2Gy in-vitro cultured astrocytes and oligodendrocytes and 7Gy in-vivo induced ER stress and Inflammation along with profuse DNA damage and Chromosomal abnormality. Additionally, we observed downregulation of myelin basic protein levels in cultured oligodendrocytes exposed to radiation. The present data suggests that ER stress and pro inflammatory cytokines serve as the major players in inducing glial cell dysfunction post gamma irradiation along with induction of genomic instability. Taken together, these results indicate that ER stress, DNA damage, and inflammatory pathways may be critical events leading to glial cell dysfunction and subsequent cell death following exposure to ionizing radiation.

TG haplotype in the LRP8 is associated with myocardial infarction in south Indian population.

Myocardial infarction (MI) is a complex multifactorial cardiovascular disease. India experiences a much greater burden of MI, also suggesting an experimental increase of this burden in the future. The absolute reasons for MI are context dependent and differ with different geographical settings. Several reports indicate that SNPs that are associated with certain diseases in other populations may not be associated with Indian population. It is, therefore, important to validate the association of SNPs. Low density lipoprotein receptor related protein 8 (LRP8) gene plays central role in human lipoprotein metabolism as it facilitates the clearance of bad cholesterol LDL, VLDL from plasma and is reported to be associated with MI in the western population. However, this gene has not been studied in the South Indian population. We aim to test the role of the LRP8 gene variants correlating with the lipid profile in MI patients in South Indian population. We sequenced regions of SNPs rs10788952, rs7546246, rs2297660 and rs5174 of LRP8 in 100 MI patients and 100 age-matched controls. Our result revealed a total of 4 variations. None of the SNPs were significantly associated with MI (p>0.973). Interestingly, haplotype based association analysis showed TG and CG of rs10788952 and rs7546246 significantly associated with MI (p<0.01 and p<0.00005) and in particular, haplotype TG was positively correlated with the risk of MI, as this increased the LDL and total cholesterol level in MI patients in south Indians. Our results suggest that haplotype TG is a risk factor for MI in South Indian population.

The promise of discovering population-specific disease-associated genes in South Asia.

The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identified 81 unique groups, 14 of which had estimated census sizes of more than 1 million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identified multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an underappreciated opportunity for decreasing disease burden among South Asians through discovery of and testing for recessive disease-associated genes.

Indian Siddis: African descendants with Indian admixture.

The Siddis (Afro-Indians) are a tribal population whose members live in coastal Karnataka, Gujarat, and in some parts of Andhra Pradesh. Historical records indicate that the Portuguese brought the Siddis to India from Africa about 300-500 years ago; however, there is little information about their more precise ancestral origins. Here, we perform a genome-wide survey to understand the population history of the Siddis. Using hundreds of thousands of autosomal markers, we show that they have inherited ancestry from Africans, Indians, and possibly Europeans (Portuguese). Additionally, analyses of the uniparental (Y-chromosomal and mitochondrial DNA) markers indicate that the Siddis trace their ancestry to Bantu speakers from sub-Saharan Africa. We estimate that the admixture between the African ancestors of the Siddis and neighboring South Asian groups probably occurred in the past eight generations (∼200 years ago), consistent with historical records.