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After the completion of the Human Genome Project in 2003, the field of genetics has witnessed massive progress that spanned research in high-altitude biology also. Especially the decade of 2010s witnessed the most of it and revealed various genetic signatures of high-altitude adaptation in Tibetans, Andeans and Ethiopians. High-altitude area, with its extreme environment, harbors a tremendous potential for gene-environment interaction, an aspect that could be explored by epigenetic studies. There are only four original articles till now which explore the epigenetic aspect of high-altitude adaptation or acclimatization. However, there is no comprehensive review to provide complete information on the genetic and epigenetic aspects of high-altitude adaptations. Hence, we have prepared this mini-review to summarize the genetic and epigenetic studies that have correlated the high-altitude adaptation or acclimatization, until recently.

Epitranscriptomic systems enable post-transcriptional modifications of cellular RNA that are essential for regulating gene expression. Of the ~ 170 known RNA chemical modifications, methylation is among the most common. Loss of function mutations in NSUN3, encoding the 5-methylcytosine (m5C) methyltransferase NSun3, have been linked to multisystem mitochondrial disease associated with combined oxidative phosphorylation deficiency. Here, we report a patient with early-onset mitochondrial encephalomyopathy and seizures in whom the novel biallelic NSUN3 missense variants c.421G>C (p.A141P) and c.454T>A (p.C152S) were detected. Segregation studies and in silico functional analysis confirmed the likely pathogenic effects of both variants. These findings expand the molecular and phenotypic spectrum of NSUN3-related mitochondrial disease.

Background South 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 socio-culturally homogeneous communities whose origins and demographic histories are largely unknown. Methods 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 from 13 healthy Sindhi individuals using both frequency- and haplotype-based approaches. Results Our 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 haplotypes and Identity by Descent (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 generations before present (GBP), explaining their current unique demographics. However, apart from this additional admixture, they share the basic genetic composition of the Pakistan/Northwest Indian groups, as reflected in Principal Component Analysis (PCA), outgroup F3 and IBD sharing. Conclusion Our 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.

Kumarasamy Thangaraj, David Reich and colleagues identify 81 South Asian groups descended from extreme founder events, including 14 with a census size of over 1 million people, thus providing an opportunity to test for and decrease the burden of recessive genetic diseases in these populations. 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.

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.

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.

PurposeTo identify the contribution of mutations in the Desert Hedgehog (DHH) gene to the disorders of sexual differentiation (DSD) and male infertility.MethodsThe study included a total 430 subjects, including 47 gonadal dysgenesis cases, 6 patients with undescended testis and infertility characterized by azoospermia, 125 infertile male patients characterized by oligoasthenozoospermia, 24 patients with oligoasthenoteratozoospermia, and 200 ethnically matched normozoospermic fertile men who had fathered a child in the last two years. Sequencing of the complete coding region of the DHH gene was undertaken to find its contribution to the DSD and male infertility.ResultsWe observed four novel mutations in the DHH gene in the cases with different reproductive anomalies. A synonymous substitution, c. 543C>T (p.His181His) was observed in 6.6% oligoasthenozoospermic infertile males and 1.5% normozoospermic fertile control samples (RR = 4.4077, 95%CI 1.19–16.29). Another synonymous substitution, c.990G>A (p.Ala330Ala) was observed in an infertile patient with unilateral undescended testis (case #12). Insertion of G at c.1156insG (p.Arg385fs) was observed in a case with bilateral undescended testis and azoospermia (case #23). In gonadal dysgenesis category, two mutations, insertion of G at c.1156insG (p.Arg385fs) and c.997A>G (p.Thr333Ala) substitution were observed in one case (case #34). These mutations were completely absent in control samples.ConclusionMutations in the DHH gene impact reproduction with mild mutations affecting fertility, and severe or multiple mutations resulting in gonadal dysgenesis.

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.

Sixty billion chickens are produced worldwide each year, and all are at risk from Eimeria , parasites that cause coccidiosis. Control relies widely on chemoprophylaxis, but pressure to reduce drug use in farming urges development of cost-effective vaccines. Antigens such as apical membrane antigen 1 (AMA1) offer promise as anticoccidial vaccine candidates, but experience with related apicomplexans such as Plasmodium , in which pre-existing antigenic diversity and incompatible population structure have undermined vaccine development, tempers confidence. Parasite genotyping identified enormous region-specific variation in haplotype diversity for Eimeria tenella but a contrastingly low level of polymorphism for Et AMA1. Although high levels of polyclonal Eimeria infection and hybridization indicate an ability to disseminate vaccine resistance rapidly, the low level of Et AMA1 diversity promotes vaccine development. The phylum Apicomplexa includes serious pathogens of humans and animals. Understanding the distribution and population structure of these protozoan parasites is of fundamental importance to explain disease epidemiology and develop sustainable controls. Predicting the likely efficacy and longevity of subunit vaccines in field populations relies on knowledge of relevant preexisting antigenic diversity, population structure, the likelihood of coinfection by genetically distinct strains, and the efficiency of cross-fertilization. All four of these factors have been investigated for Plasmodium species parasites, revealing both clonal and panmictic population structures with exceptional polymorphism associated with immunoprotective antigens such as apical membrane antigen 1 (AMA1). For the coccidian Toxoplasma gondii only genomic diversity and population structure have been defined in depth so far; for the closely related Eimeria species, all four variables are currently unknown. Using Eimeria tenella , a major cause of the enteric disease coccidiosis, which exerts a profound effect on chicken productivity and welfare, we determined population structure, genotype distribution, and likelihood of cross-fertilization during coinfection and also investigated the extent of naturally occurring antigenic diversity for the E . tenella AMA1 homolog. Using genome-wide Sequenom SNP-based haplotyping, targeted sequencing, and single-cell genotyping, we show that in this coccidian the functionality of Et AMA1 appears to outweigh immune evasion. This result is in direct contrast to the situation in Plasmodium and most likely is underpinned by the biology of the direct and acute coccidian life cycle in the definitive host.

BackgroundMitochondrial disorders are clinically complex and have highly variable phenotypes among all inherited disorders. Mutations in mitochon drial DNA (mtDNA) and nuclear genome or both have been reported in mitochondrial diseases suggesting common pathophysiological pathways. Considering the clinical heterogeneity of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) phenotype including focal neurological deficits, it is important to look beyond mitochondrial gene mutation.MethodsThe clinical, histopathological, biochemical analysis for OXPHOS enzyme activity, and electron microscopic, and neuroimaging analysis was performed to diagnose 11 patients with MELAS syndrome with a multisystem presentation. In addition, whole exome sequencing (WES) and whole mitochondrial genome sequencing were performed to identify nuclear and mitochondrial mutations.ResultsAnalysis of whole mtDNA sequence identified classical pathogenic mutation m.3243A > G in seven out of 11 patients. Exome sequencing identified pathogenic mutation in several nuclear genes associated with mitochondrial encephalopathy, sensorineural hearing loss, diabetes, epilepsy, seizure and cardiomyopathy (POLG, DGUOK, SUCLG2, TRNT1, LOXHD1, KCNQ1, KCNQ2, NEUROD1, MYH7) that may contribute to classical mitochondrial disease phenotype alone or in combination with m.3243A > G mutation.ConclusionIndividuals with MELAS exhibit clinical phenotypes with varying degree of severity affecting multiple systems including auditory, visual, cardiovascular, endocrine, and nervous system. This is the first report to show that nuclear genetic factors influence the clinical outcomes/manifestations of MELAS subjects alone or in combination with m.3243A > G mutation.