Biology subjects

Phalke, S.

Publications and source records attributed to Phalke, S..

4 recordsLinked to original sources

bioRxiv2025

Mitochondrial fission regulates ROS for ventral furrow formation in Drosophila gastrulation

Mitochondrial dynamics are vital for embryogenesis, but their role in morphogenesis is largely unexplored. In this study, we elucidate the role of mitochondrial dynamics and function in regulating apical constriction at the ventral furrow in Drosophila gastrulation. We find that spatiotemporal redistribution of mitochondria from basal to apically constricting regions is coincident with Myosin II accumulation in ventral epithelial cells. This apical enrichment depends on intact microtubules and is regulated by Dorsal/NFkb signaling pathway. Embryos expressing mitochondrial fission protein, Drp1 mutants, contain larger, basally accumulated mitochondria, decreased apical constriction and ventral furrow defects. Transcriptomic and proteomic profiling of Drp1 mutants shows no change in Dorsal signaling, but an upregulation of antioxidant enzymes, decreased respiratory complexes, and reduced reactive oxygen species (ROS), confirming loss of mitochondrial activity and a reduced environment. Depleting mitochondrial SOD2 in Drp1 mutant embryos restores levels of antioxidant proteins and increases ROS, leading to an oxidized environment. These embryos also show rescue in apical mitochondrial migration and Myosin II accumulation, thereby enabling proper ventral furrow formation. Our study reveals the functional importance of localized mitochondrial dynamics, regulated by the Dorsal signaling pathway, and mitochondrial activity in a spatiotemporal manner for apical constriction during gastrulation.

developmental biology↗

bioRxiv2020

South Asian patient population genetics reveal strong founder effects and high rates of homozygosity - new resources for precision medicine

Population-scale genetic studies can identify drug targets and allow disease risk to be predicted with resulting benefit for management of individual health risks and system-wide allocation of health care delivery resources. Although population-scale projects are underway in many parts of the world, genetic variation between population groups means that additional projects are warranted. South Asia has a population whose genetics is the least characterized of any of the worlds major populations. Here we describe GenomeAsia studies that characterize population structure in South Asia and that create tools for economical and accurate genotyping at population-scale. Prior work on population structure characterized isolated population groups, the relevance of which to large-scale studies of disease genetics is unclear. For our studies we used whole genome sequence information from 4,807 individuals recruited in the health care delivery systems of Pakistan, India and Bangladesh to ensure relevance to population-scale studies of disease genetics. We combined this with WGS data from 927 individuals from isolated South Asian population groups, and developed a custom SNP array (called SARGAM) that is optimized for future human genetic studies in South Asia. We find evidence for high rates of reproductive isolation, endogamy and consanguinity that vary across the subcontinent and that lead to levels of homozygosity that approach 100 times that seen in outbred populations. We describe founder effects that increase the power to associate functional variants with disease processes and that make South Asia a uniquely powerful place for population-scale genetic studies.

genomics↗

bioRxiv2020

Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease (COVID-19) that has resulted in a global pandemic. It is a highly contagious positive strand RNA virus and its clinical presentation includes severe to critical respiratory disease that appears to be fatal in [~]3-5% of the cases. The viral spike (S) coat protein engages the human angiotensin-converting enzyme2 (ACE2) cell surface protein to invade the host cell. The SARS-CoV-2 S-protein has acquired mutations that increase its affinity to human ACE2 by [~]10-15-fold compared to SARS-CoV S-protein, making it highly infectious. In this study, we assessed if ACE2 polymorphisms might alter host susceptibility to SARS-CoV-2 by affecting the ACE2 S-protein interaction. Our comprehensive analysis of several large genomic datasets that included over 290,000 samples representing >400 population groups identified multiple ACE2 protein-altering variants, some of which mapped to the S-protein-interacting ACE2 surface. Using recently reported structural data and a recent S-protein-interacting synthetic mutant map of ACE2, we have identified natural ACE2 variants that are predicted to alter the virus-host interaction and thereby potentially alter host susceptibility. In particular, human ACE2 variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R are predicted to increase susceptibility. The T92I variant, part of a consensus NxS/T N-glycosylation motif, confirmed the role of N90 glycosylation in immunity from non-human CoVs. Other ACE2 variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y are putative protective variants predicted to show decreased binding to SARS-CoV-2 S-protein. Overall, ACE2 variants are rare, consistent with the lack of selection pressure given the recent history of SARS-CoV epidemics, however, are likely to play an important role in altering susceptibility to CoVs.

genetics↗

bioRxiv2019

Recent evolutionary history of tigers highlights contrasting roles of genetic drift and selection

Formulating strategies for species conservation requires knowledge of evolutionary and genetic history. Tigers are among the most charismatic of endangered species and garner significant conservation attention. However, the evolutionary history and genomic variation of tigers remain poorly known. With 70% of the worlds wild tigers living in India, such knowledge is critical for tiger conservation. We re-sequenced 65 individual tiger genomes across their extant geographic range, representing most extant subspecies with a specific focus on tigers from India. As suggested by earlier studies, we found strong genetic differentiation between the putative tiger subspecies. Despite high total genomic diversity in India, individual tigers host longer runs of homozygosity, potentially suggesting recent inbreeding, possibly because of small and fragmented protected areas. Surprisingly, demographic models suggest recent divergence (within the last 10,000 years) between populations, and strong population bottlenecks. Amur tiger genomes revealed the strongest signals of selection mainly related to metabolic adaptation to cold, while Sumatran tigers show evidence of evolving under weak selection for genes involved in body size regulation. Depending on conservation objectives, our results support the isolation of Amur and Sumatran tigers, while geneflow between Malayan and South Asian tigers may be considered. Further, the impacts of ongoing connectivity loss on the health and persistence of tigers in India should be closely monitored.

genomics↗