Novel genetic association of the Furin gene polymorphism rs1981458 with COVID-19 severity among Indian populations.

SARS CoV-2, the causative agent for the ongoing COVID-19 pandemic, it enters the host cell by activating the ACE2 receptor with the help of two proteasesi.e., Furin and TMPRSS2. Therefore, variations in these genes may account for differential susceptibility and severity between populations. Previous studies have shown that the role of ACE2 and TMPRSS2 gene variants in understanding COVID-19 susceptibility among Indian populations. Nevertheless, a knowledge gap exists concerning the COVID-19 susceptibility of Furin gene variants among diverse South Asian ethnic groups. Investigating the role of Furin gene variants and their global phylogeographic structure is essential to comprehensively understanding COVID-19 susceptibility in these populations. We have used 450 samples from diverse Indian states and performed linear regression to analyse the Furin gene variant's with COVID-19 Case Fatality Rate (CFR) that could be epidemiologically associated with disease severity outcomes. Associated genetic variants were further evaluated for their expression and regulatory potential through various Insilco analyses. Additionally, we examined the Furin gene using next-generation sequencing (NGS) data from 393 diverse global samples, with a particular emphasis on South Asia, to investigate its Phylogeographic structure among diverse world populations. We found a significant positive association for the SNP rs1981458 with COVID-19 CFR (p < 0.05) among diverse Indian populations at different timelines of the first and second waves. Further, QTL and other regulatory analyses showed various significant associations for positive regulatory roles of rs1981458 and Furin gene, mainly in Immune cells and virus infection process, highlighting their role in host immunity and viral assembly and processing. The Furin protein-protein interaction suggested that COVID-19 may contribute to Pulmonary arterial hypertension via a typical inflammation mechanism. The phylogeographic architecture of the Furin gene demonstrated a closer genetic affinity of South Asia with West Eurasian populations. Therefore, it is worth proposing that for the Furin gene, the COVID-19 susceptibility of South Asians will be more similar to the West Eurasian population. Our previous studies on the ACE2 and TMPRSS2 genes showed genetic affinity of South Asian with East Eurasians and West Eurasians, respectively. Therefore, with the collective information from these three important genes (ACE2, TMPRSS2 and Furin) we modelled COVID-19 susceptibilityof South Asia in between these two major ancestries with an inclination towards West Eurasia. In conclusion, this study, for the first time, concluded the role of rs1981458 in COVID-19 severity among the Indian population and outlined its regulatory potential.This study also highlights that the genetic structure for COVID-19 susceptibilityof South Asia is distinct, however, inclined to the West Eurasian population. We believe this insight may be utilised as a genetic biomarker to identify vulnerable populations, which might be directly relevant for developing policies and allocating resources more effectively during an epidemic.

The genetic admixture and assimilation of Ahom: a historic migrant from Thailand to India.

The Northeastern region of India is considered a gateway for modern humans' dispersal throughout Asia. This region is a mixture of various ethnic and indigenous populations amalgamating multiple ancestries. One reason for such amalgamation is that, South Asia experienced multiple historic migrations from various parts of the world. A few examples explored genetically are Jews, Parsis and Siddis. Ahom is a dynasty that historically migrated to India during the 12th century. However, this putative migration has not been studied genetically at high resolution. Therefore, to validate this historical evidence, we genotyped autosomal data of the Modern Ahom population residing in seven sister states of India. Principal Component and Admixture analyses haave suggested a substantial admixture of the Ahom population with the local Tibeto-Burman populations. Moreover, the haplotype-based analysis has linked these Ahom individuals mainly with the Kusunda (a language isolated from Nepal) and Khasi (an Austroasiatic population of Meghalaya). Such unexpected presence of widespread population affinities suggests that Ahom mixed and assimilated a wide variety of Trans-Himalayan populations inhabiting this region after the migration. In summary, we observed a significant deviation of Ahom from their ancestral homeland (Thailand) and extensive admixture and assimilation with the local South Asian populations.

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.

Reconstructing the population history of the Sinhalese, the major ethnic group in Sri Lanka.

The Sinhalese are the major ethnic group in Sri Lanka, inhabiting nearly the whole length and breadth of the island. They speak an Indo-European language of the Indo-Iranian branch, which is held to originate in northwestern India, going back to at least the fifth century BC. Previous genetic studies on low-resolution markers failed to infer the genomic history of the Sinhalese population. Therefore, we have performed a high-resolution fine-grained genetic study of the Sinhalese population and, in the broader context, we attempted to reconstruct the genetic history of Sri Lanka. Our allele-frequency-based analysis showed a tight cluster of Sinhalese and Tamil populations, suggesting strong gene flow beyond the boundary of ethnicity and language. Interestingly, the haplotype-based analysis preserved a trace of the North Indian affiliation to the Sinhalese population. Overall, in the South Asian context, Sri Lankan ethnic groups are genetically more homogeneous than others.

Estimation of real COVID-19 cases in India during the first wave.

In 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread across the world within a few months. The SARS-CoV-2 pandemic has had a devastating effect on humanity, with social and economic consequences. The continents of Europe and America have been hit the hardest. However, there has also been a huge loss of life in India, with the country having the fourth highest number of total deaths worldwide. Nevertheless, the infection and death rates per million and the case fatality ratio in India are substantially lower than those in many developed nations. Several explanations for this have been proposed, including genetics. Mathematical modelling has suggested that the actual number of infections is much higher than the number of reported cases. Therefore, to understand the dynamics of actual infection and the population-level immunity against SARS-CoV-2, a serosurvey (antibody testing) was performed among 2301 individuals in urban regions of 14 districts in six states of India. A notable outcome of this study was that a large proportion of the Indian population had an asymptomatic SARS-CoV-2 infection. The real infection rate in India was several fold higher than the reported number of cases. Therefore, a large number of people in the country have developed SARS-CoV-2-specific antibodies. In this survey, the seroprevalence (frequency antibody-positive) varied between 0.01 (95% CI 0.002-0.054) and 0.477 (95% CI 0.392-0.563), suggesting a high variability in viral transmission between the states and the possibility of future waves. In this study population, the frequency of asymptomatic infection was highest in the younger age groups. It was also found that the numbers of cases reported by the government were several-fold lower than the real incidence of infection. It is likely that the high number of asymptomatic cases was the main driver of this discrepancy.

Studying C-reactive protein and D-dimer levels in blood may prevent severe complications: A study in Bangladeshi COVID-19 patients.

The ongoing COVID-19 pandemic has been a scientific, medical and social challenge. Since clinical course of this disease is largely unpredictable and can develop rapidly causing severe complications, it is important to identify laboratory biomarkers, which may help to classify patient's severity during initial stage. Previous studies have suggested C-reactive protein (inflammatory) and D-dimer (biochemical) as an effective biomarker. The differential severity in patients across the world and our limited understanding in the progression of the disease calls for a multi-country analysis for biomarkers. Therefore, we have analyzed these biomarkers among 228 Bangladeshi COVID-19 patients. We observed significant association of COVID-19 severity with these two biomarkers. Thus, we suggest to use these biomarkers for Bangladeshi COVID-19 patients for better disease monitoring. Such validated preventive measures may decrease the case fatality ratio substantially.

Vaccine hesitancy for coronavirus SARS-CoV-2 in Varanasi India.

With the rollout of the world's largest vaccine drive for SARS-CoV-2 by the Government of India on January 16 2021, India had targeted to vaccinate its entire population by the end of 2021. Struggling with vaccine procurement and production earlier, India overcome these hurdles, but the Indian population still did not seem to be mobilizing swiftly toward vaccination centers. The severe second wave has slowed the vaccination pace and was also one of the major contributing factors to vaccine hesitancy. To understand the nature of vaccine hesitancy and its underlying factors, we conducted extensive online and offline surveys in Varanasi and adjoining regions using structured questions. Most respondents were students (0.633). However, respondents from other occupations, such as government officials (0.10), have also participated in the study. Interestingly, most people (0.75) relied on fake news and did not take COVID-19 seriously. Most importantly, we noticed that a substantial proportion of respondents (relative frequency 0.151; mean age 24.8 years) reported that they were still not interested in vaccination. We observed a significant association between vaccine hesitancy and socioeconomic status (χ2 = 307.6, p < 0.001). However, we failed to detect any association between vaccine hesitancy and gender (χ2 = 0.007, p > 0.5). People who have neither been vaccinated nor have ever been infected may become the medium for spreading the virus and creating new variants, which may lead to the vaccine-resistant variant. We expect this extensive survey to help the Government upgrade their vaccination policies for COVID-19 in North India.

Genetic association of TMPRSS2 rs2070788 polymorphism with COVID-19 case fatality rate among Indian populations.

SARS-CoV-2, the causative agent for COVID-19, an ongoing pandemic, engages the ACE2 receptor to enter the host cell through S protein priming by a serine protease, TMPRSS2. Variation in the TMPRSS2 gene may account for the disparity in disease susceptibility between populations. Therefore, in the present study, we have used next-generation sequencing (NGS) data of world populations from 393 individuals and analyzed the TMPRSS2 gene using a haplotype-based approach with a major focus on South Asia to study its phylogenetic structure and their haplotype sharing among various populations worldwide. Our analysis of phylogenetic relatedness showed a closer affinity of South Asians with the West Eurasian populations therefore, host disease susceptibility and severity particularly in the context of TMPRSS2 will be more akin to West Eurasian instead of East Eurasian. This is in contrast to our prior study on the ACE2 gene which shows South Asian haplotypes have a strong affinity towards West Eurasians. Thus ACE2 and TMPRSS2 have an antagonistic genetic relatedness among South Asians. Considering the significance of the TMPRSS2 gene in the SARS-CoV-2 pathogenicity, COVID-19 infection and intensity trends could be directly associated with increased expression therefore, we have also tested the SNPs frequencies of this gene among various Indian state populations with respect to the case fatality rate (CFR). Interestingly, we found a significant positive association between the rs2070788 SNP (G Allele) and the CFR among Indian populations. Further our cis eQTL analysis of rs2070788 shows that the GG genotype of the rs2070788 tends to have a significantly higher expression of TMPRSS2 gene in the lung compared to the AG and AA genotypes thus validating the previous observation and therefore it might play a vital part in determining differential disease vulnerability. We trust that this information will be useful in understanding the role of the TMPRSS2 variant in COVID-19 susceptibility and using it as a biomarker may help to predict populations at risk.

COVID-19: Impact on linguistic and genetic isolates of India.

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.

The association of ABO blood group with the asymptomatic COVID-19 cases in India.

The COVID-19 pandemic resulted in multiple waves of infection worldwide. The large variations in case fatality rate among different geographical regions suggest that the human susceptibility against this virus varies substantially. Several studies from different parts of the world showed a significant association of ABO blood group and COVID-19 susceptibility. It was demonstrated that individuals with blood group O are at the lower risk of coronavirus infection. To establish the association of ABO blood group in SARS-CoV-2 susceptibility, we for the first time analysed SARS-CoV-2 neutralising antibodies among 509 individuals, collected from three major districts of Eastern Uttar Pradesh region of India. Interestingly, we found neutralising antibodies in a significantly higher percentage of people with blood group AB (0.36) followed by B (0.31), A (0.22) and lowest in people with blood group O (0.11). We further estimated that people with blood group AB are at comparatively higher risk of infection than other blood groups. Thus, among the asymptomatic SARS-CoV-2 recovered people blood group AB has highest, whilst individuals with blood group O has lowest risk of infection.

The major genetic risk factor for severe COVID-19 does not show any association among South Asian populations.

With the growing evidence on the variable human susceptibility against COVID-19, it is evident that some genetic loci modulate the severity of the infection. Recent studies have identified several loci associated with greater severity. More recently, a study has identified a 50 kb genomic segment introgressed from Neanderthal adding a risk for COVID-19, and this genomic segment is present among 16% and 50% people of European and South Asian descent, respectively. Our studies on ACE2 identified a haplotype present among 20% and 60% of European and South Asian populations, respectively, which appears to be responsible for the low case fatality rate among South Asian populations. This result was also consistent with the real-time infection rate and case fatality rate among various states of India. We readdressed this issue using both of the contrasting datasets and compared them with the real-time infection rates and case fatality rate in India. We found that the polymorphism present in the 50 kb introgressed genomic segment (rs10490770) did not show any significant correlation with the infection and case fatality rate in India.

Dissecting the paternal founders of Mundari (Austroasiatic) speakers associated with the language dispersal in South Asia.

The phylogenetic analysis of Y chromosomal haplogroup O2a-M95 was crucial to determine the nested structure of South Asian branches within the larger tree, predominantly present in East and Southeast Asia. However, it had previously been unclear that how many founders brought the haplogroup O2a-M95 to South Asia. On the basis of the updated Y chromosomal tree for haplogroup O2a-M95, we analysed 1437 male samples from South Asia for various novel downstream markers, carefully selected from the extant phylogenetic tree. With this increased resolution of genetic markers, we were able to identify at least three founders downstream to haplogroup O2a-M95, who are likely to have been associated with the dispersal of Austroasiatic languages to South Asia. The fourth founder was exclusively present amongst Tibeto-Burman speakers of Manipur and Bangladesh. In sum, our new results suggest the arrival of Austroasiatic languages in South Asia during last 5000 years.

Genetic Association of ACE2 rs2285666 Polymorphism With COVID-19 Spatial Distribution in India.

Studies on host-pathogen interaction have identified human ACE2 as a host cell receptor responsible for mediating infection by coronavirus (COVID-19). Subsequent studies have shown striking difference of allele frequency among Europeans and Asians for a polymorphism rs2285666, present in ACE2. It has been revealed that the alternate allele (TT-plus strand or AA-minus strand) of rs2285666 elevate the expression level of this gene upto 50%, hence may play a significant role in SARS-CoV-2 susceptibility. Therefore, we have first looked the phylogenetic structure of rs2285666 derived haplotypes in worldwide populations and compared the spatial frequency of this particular allele with respect to the COVID-19 infection as well as case-fatality rate in India. For the first time, we ascertained a significant positive correlation for alternate allele (T or A) of rs2285666, with the lower infection as well as case-fatality rate among Indian populations. We trust that this information will be useful to understand the role of ACE2 in COVID-19 susceptibility.

Most frequent South Asian haplotypes of ACE2 share identity by descent with East Eurasian populations.

It was shown that the human Angiotensin-converting enzyme 2 (ACE2) is the receptor of recent coronavirus SARS-CoV-2, and variation in this gene may affect the susceptibility of a population. Therefore, we have analysed the sequence data of ACE2 among 393 samples worldwide, focusing on South Asia. Genetically, South Asians are more related to West Eurasian populations rather than to East Eurasians. In the present analyses of ACE2, we observed that the majority of South Asian haplotypes are closer to East Eurasians rather than to West Eurasians. The phylogenetic analysis suggested that the South Asian haplotypes shared with East Eurasians involved two unique event polymorphisms (rs4646120 and rs2285666). In contrast with the European/American populations, both of the SNPs have largely similar frequencies for East Eurasians and South Asians, Therefore, it is likely that among the South Asians, host susceptibility to the novel coronavirus SARS-CoV-2 will be more similar to that of East Eurasians rather than to that of Europeans.

Genetic and linguistic non-correspondence suggests evidence for collective social climbing in the Kol tribe of South Asia.

Both classical and recent genetic studies have unanimously concluded that the genetic landscape of South Asia is unique. At long distances the 'isolation-by-distance' model appears to correspond well with the genetic data, whereas at short distances several other factors, including the caste, have been shown to be strong determinant factors. In addition with these, tribal populations speaking various languages add yet another layer of genetic complexity. The Kol are the third most populous tribal population in India, comprising communities speaking Austroasiatic languages of the Northern Munda branch. Yet, the Kol have not hitherto undergone in-depth genetic analysis. In the present study, we have analysed two Kol groups of central and western India for hundreds thousands of autosomal and several mitochondrial DNA makers to infer their fine genetic structure and affinities to other Eurasian populations. In contrast, with their known linguistic affinity, the Kol share their more recent common ancestry with the Indo-European and Dravidian speaking populations. The geographic-genetic neighbour tests at both the temporal and spatial levels have suggested some degree of excess allele sharing of Kol1 with Kol2, thereby indicating their common stock. Our extensive analysis on the Kol ethnic group shows South Asia to be a living genetics lab, where real-time tests can be performed on existing hypotheses.

Historic migration to South Asia in the last two millennia: A case of Jewish and Parsi populations.

The South Asian populations have a mosaic of ancestries likely due to the interactions of long-term populations of the landmass and those of East andWest Eurasia. Apart from prehistoric dispersals, there are some known population movements to India. In this study,we focussed on the migration of Jewish and Parsi populations on temporal and spatial scales. The existence of Jewish and Parsi communities in India are recorded since ancient times. However, due to the lack of high-resolution genetic data, their origin and affiliation with other Indian and non-Indian populations remains shrouded in legends. Earlier genetic studies on populations of Indian Jews have found evidence for a minor shared ancestry of Indian Jews with Middle Eastern (Jews) populations, whereas for Parsis, the Iranian link was proposed. Recently, in our high-resolution study, we were able to quantify the admixture dynamics of these groups, which has suggested a male-biased admixture. Here, we added the newly available ancient samples and revisited the interplay of genes and cultures. Thus, in this study we reconstructed a broad genetic profile of Indian Jews and Parsis to paint a fine-grained picture of these ethnic groups.

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.