TEX13B is essential for metabolic reprogramming during germ cell differentiation.

STUDY QUESTION: What is the functional significance of Tex13b in male germ cell development and differentiation? SUMMARY ANSWER: Tex13b regulates male germ cell differentiation by metabolic reprogramming during spermatogenesis. WHAT IS KNOWN ALREADY: Studies in mice and humans suggest that TEX13B is a transcription factor and is exclusively expressed in germ cells. STUDY DESIGN, SIZE, DURATION: We sequenced the coding regions of TEX13B in 628 infertile men and 427 ethnically matched fertile control men. Further, to identify the molecular function of Tex13b, we created a Tex13b knockout and conditional overexpression system in GC-1spg (hereafter, GC-1) cells. PARTICIPANTS/MATERIALS, SETTING, METHODS: Our recent exome sequencing study identified novel candidate genes for male infertility. TEX13B was found to be one of the potential candidates, hence we explored the role of TEX13B in male infertility within a large infertile case-control cohort. We performed functional analyses of Tex13b in a GC-1 cell line using CRISPR-Cas9. We differentially labelled the cell proteins by stable isotope labelling of amino acids in cell culture (SILAC) and performed mass spectrometry-based whole-cell proteomics to identify the differential protein regulation in knockout cells compared to wild-type cells. We found that Tex13b knockout leads to downregulation of the OXPHOS complexes and upregulation of glycolysis genes, which was further validated by western blotting. These results were further confirmed by respirometry analysis in Tex13b knockout cells. Further, we also performed a conditional overexpression of TEX13B in GC-1 cells and studied the expression of OXPHOS complex proteins by western blotting. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a rare variant, rs775429506 (p.Gly237Glu), exclusively in two non-obstructive-azoospermia (NOA) men, that may genetically predispose these men for infertility. Further, we demonstrated that Tex13b functions in the transcription regulation of OXPHOS complexes. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: We examined the function of Tex13b in GC-1 in vitro by knocking out and conditional overexpression, for understanding the function of Tex13b in germ cells. Unfortunately, this could not be replicated in either an animal model or in patient-derived tissue due to the non-availability of an animal model or patient's testis biopsies. WIDER IMPLICATIONS OF THE FINDINGS: This study identified that Tex13b plays an important role in male germ cell development and differentiation. The findings of this study would be useful for screening infertile males with spermatogenic failure and counselling them before the implementation of assisted reproduction technique(s). STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the Council of Scientific and Industrial Research (CSIR) under the network project (BSC0101 and MLP0113) and SERB, the Department of Science and Technology, Government of India (J C Bose Fellowship: JCB/2019/000027). The authors do not have any competing interest.

The maternal genetic origin and diversity of the extant populations of the Ladakh region in India.

Ladakh lies at a strategic location between the Indus River valley and the Hindu Khush Mountains, which makes the "Land of high passes" one of the major routes of movement. Through the years the region has faced multi-layered cultural movements, genetic assimilation and demographic changes. The initial settlement in the years goes back to the early Neolithic age and still continues despite its harsh, unhospitable and cold climate. Previous studies mostly covered the patrilineal markers of the region and an in-depth study lacked to represent the matrilineal ancestry and possible genetic inflow in the region. Hence, our current study first time generated complete mitogenomes of 108 unrelated individuals from Ladakh belonging to three population groups namely, Changpa (n = 38), Brokpa (n = 32) and Monpa (n = 38). In the in-depth analysis, we found that the mitogenome of the three Ladakhi groups are highly diverse in terms of maternal haplogroup distribution carrying lineages specific to East Asia (M9a), Tibbet (A21) and South Asia (M3, M30, U2). In our analysis we found that Changpa and Monpa probably have shared maternal ancestry compared to Brokpa, which is very distinct and also later suffered possible historical Bottleneck. Bayesian evolutionary and Network analysis indicates more ancient maternal lineage of Changpa and Monpa in terms of M9a haplotypes, but they also share some genetic history with Tibeto-Burman speakers in past. These findings conclusively indicate possible matrilineal genetic inflow in Ladakh from three directions, primarily from East Asia or South East Asia during post-glacial, West Eurasia and also from South Asia.

Mitochondria in biology and medicine - 2023.

Mitochondria are an indispensable part of the cell that plays a crucial role in regulating various signaling pathways, energy metabolism, cell differentiation, proliferation, and cell death. Since mitochondria have their own genetic material, they differ from their nuclear counterparts, and dysregulation is responsible for a broad spectrum of diseases. Mitochondrial dysfunction is associated with several disorders, including neuro-muscular disorders, cancer, and premature aging, among others. The intricacy of the field is due to the cross-talk between nuclear and mitochondrial genes, which has also improved our knowledge of mitochondrial functions and their pathogenesis. Therefore, interdisciplinary research and communication are crucial for mitochondrial biology and medicine due to the challenges they pose for diagnosis and treatment. The ninth annual conference of the Society for Mitochondria Research and Medicine (SMRM)- India, titled "Mitochondria in Biology and Medicine" was organized at the Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India, on June 21-23, 2023. The latest advancements in the field of mitochondrial biology and medicine were discussed at the conference. In this article, we summarize the entire event for the benefit of researchers working in the field of mitochondrial biology and medicine.

The genetic identity of the Vedda: A language isolate of South Asia.

Linguistic data from South Asia identified several language isolates in the subcontinent. The Vedda, an indigenous population of Sri Lanka, are the least studied amongst them. Therefore, to understand the initial peopling of Sri Lanka and the genetic affinity of the Vedda with other populations in Eurasia, we extensively studied the high-resolution autosomal and mitogenomes from the Vedda population of Sri Lanka. Our autosomal analyses suggest a close genetic link of Vedda with the tribal populations of India despite no evidence of close linguistic affinity, thus suggesting a deep genetic link of the Vedda with these populations. The mitogenomic analysis supports this association by pointing to an ancient link with Indian populations. We suggest that the Vedda population is a genetically drifted group with limited gene flow from neighbouring Sinhalese and Sri Lankan Tamil populations. Interestingly, the genetic ancestry sharing of Vedda neglects the isolation-by-distance model. Collectively, the demography of Sri Lanka is unique, where Sinhalese and Sri Lankan Tamil populations excessively admixed, whilst Vedda largely preserved their isolation and deep genetic association with India.

Investigating linguistic and genetic shifts in East Indian tribal groups.

South Asia is home to almost a quarter of the world's total population and is home to significant ethnolinguistic diversity. Previous studies of linguistic and genetic affiliations of Indian populations suggest that the formation of these distinct groups was a protracted and complex phenomenon involving multiple waves of migration, cultural assimilation, and genetic admixture. The evolutionary processes of migration, mixing and merging of populations thus impact the culture and linguistic diversity of different groups, some of which may retain their linguistic affinities despite genetic admixture with other groups, or vice versa. Our study examines the relationship of genetic and linguistic affinities between Austroasiatic and Indo-European speakers in adjacent geographical regions of Eastern India. We analyzed 224 mitogenomes and 0.65 million SNP genotypes from 40 unrelated individuals belonging to the Bathudi, Bhumij, Ho, and Mahali ethnic groups from the Eastern Indian state of Odisha. These four groups are speakers of Austroasiatic languages who have adopted elements from Indo-European languages spoken in neighbouring regions. Our results suggest that these groups have the greatest maternal genetic affinity with other Austroasiatic-speaking groups in India. Allele frequency-based analyses, genome-wide SNPs, haplotype-based methods and IBD sharing further support the genetic similarity of these East Indian groups to Austroasiatic speakers of South Asia rather than regional populations speaking Indo-European and Dravidian languages. Our study shows that these populations experienced linguistic mixing, likely due to industrialization and modernization that brought them into close cultural contact with neighbouring Indo-European-speaking groups. However, linguistic change in these groups is not reflected in genetic mixing in these populations, as they appear to maintain strict genetic boundaries while simultaneously experiencing cultural mixing.