@article {156536, title = {Mapping genetic diversity with the GenomeIndia project.}, journal = {Nat Genet}, volume = {57}, year = {2025}, month = {2025 Apr}, pages = {767-773}, chapter = {767}, abstract = {

The rich ethnolinguistic and sociocultural differences that exist in India offers a unique opportunity to study human diversity. With the whole genomes of 10,000 healthy and unrelated Indians from 83 populations, the GenomeIndia project captures the genetic diversity of one of the highly underrepresented populations in the global genomics landscape.

India, the most populous nation in the world with 1.44 billion people from over 4,600 distinct endogamous groups, represents an invaluable source of ethnolinguistic, sociocultural and genetic diversity. Deciphering the genetic makeup of human populations helps in understanding their ancestry, evolutionary history, admixture patterns, disease susceptibility and drug response. To this end, world over, genomics consortia have been established. Nevertheless, the global genomic landscape is predominantly Euro-centric1; although some projects have documented worldwide genetic diversity by discovering DNA sequence variation in several human populations, for example the 1000 Genomes project2, followed by others across the world, recent inclusions being at biobank scale3,4,5,6,7. Unfortunately, India has been severely underrepresented in these global studies. To address this lacuna, a few studies have been initiated to understand the human genetic diversity of Asia (GenomeAsia)8\ and India (IndiGen and LASI-DAD)9,10.

India experienced several waves of migration11,12\ with evidence of population expansion during the Paleolithic and Neolithic periods. The demographic history of India is also unique, with exposure to different environments and widespread admixture, followed by formation of numerous endogamous groups13. Many of the contemporary Indian populations have originated from a few founding groups and have maintained distinct identities through centuries of endogamy. These endogamous groups13,14, apart from sharing genetic similarities, possess unique variations, including distinct disease-causing mutations with amplified frequencies within specific groups.

}, issn = {1546-1718}, doi = {10.1038/s41588-025-02153-x}, url = {https://www.nature.com/articles/s41588-025-02153-x}, author = {Bhattacharyya, Chandrika and Subramanian, Krithika and Uppili, Bharathram and Biswas, Nidhan K and Ramdas, Shweta and Tallapaka, Karthik Bharadwaj and Arvind, Prathima and Rupanagudi, Khader Valli and Maitra, Arindam and Nagabandi, Tulasi and De, Tiyasha and Singh, Kuldeep and Sharma, Praveen and Sharma, Nanaocha and Raghav, Sunil K and Prasad, Punit and Soniya, E V and Jaleel, Abdul and Nelson Sathi, Shijulal and Joshi, Madhvi and Joshi, Chaitanya and Lahiri, Mayurika and Dixit, Santosh and Shashidhara, L S and Senthil Kumar, Nachimuthu and Lalhruaitluanga, H and Nundanga, Lal and Shivakumar, Venkataram and Venkatasubramanian, Ganesan and Rao, Naren P and Ganie, Mohd Ashraf and Wani, Imtiyaz Ahmad and Jha, Ganganath and Dalal, Ashwin and Bashyam, Murali Dharan and Varadwaj, Pritish Kumar and Bs, Sanjeev and Simmhan, Yogesh and Jain, Chirag and Sundar, Durai and Gupta, Ishaan and Yadav, Pankaj and Sinha, Himanshu and Narayanan, Manikandan and Raman, Karthik and Padinjat, Raghu and Sabarinathan, Radhakrishnan and Narahari, Yadati and Ravindranath, Vijayalakshmi and Kumarasamy, Thangaraj and Sowpati, Divya Tej and Faruq, Mohammed and Basu, Analabha and Kahali, Bratati} } @article {117969, title = {AP2 regulates Thickveins trafficking to attenuate NMJ growth signaling in .}, journal = {eNeuro}, year = {2022}, month = {2022 Sep 30}, abstract = {

Compromised endocytosis in neurons leads to synapse overgrowth and altered organization of synaptic proteins. However, the molecular players and the signaling pathways which regulate the process remain poorly understood. Here, we show that σ2-adaptin, one of the subunits of the AP2-complex, genetically interacts with Mad, Medea and Dad (components of BMP signaling) to control neuromuscular junction (NMJ) growth in Ultrastructural analysis of mutants show an accumulation of large vesicles and membranous structures akin to endosomes at the synapse. We found that mutations in lead to an accumulation of Tkv receptors at the presynaptic membrane. Interestingly, the level of small GTPase Rab11 was significantly reduced in the mutant synapses. However, expression of Rab11 does not restore the synaptic defects of mutations. We propose a model in which AP2 regulates Tkv internalization and endosomal recycling to control synaptic growth.Understanding the regulation of synaptic development and refinement could provide mechanistic insights into the neural basis of fundamental processes such as learning, memory and adaptation. In this study, we describe the role of σ-adaptin in attenuating NMJ growth signaling and show its involvement in the trafficking of Thickveins receptor at the NMJ. σ-adaptin interacts genetically with the BMP pathway components and NMJ synapses lacking σ-adaptin show reduced levels of the endosomal recycling marker, Rab11. Our study contributes to a broader understanding of AP2 complex-dependent regulation of synaptic growth signaling, which might have implications in neurodevelopment under conditions where endocytosis and trafficking of the BMP receptors are perturbed.

}, issn = {2373-2822}, doi = {10.1523/ENEURO.0044-22.2022}, author = {Choudhury, Saumitra Dey and Dwivedi, Manish Kumar and Pippadpally, Srikanth and Patnaik, Abhinandan and Mishra, Shirish and Padinjat, Raghu and Kumar, Vimlesh} } @article {89662, title = {Interdomain interactions regulate the localization of a lipid transfer protein at ER-PM contact sites.}, journal = {Biol Open}, year = {2021}, month = {2021 Feb 17}, abstract = {

During phospholipase C-β (PLC-β) signalling in photoreceptors, the phosphatidylinositol transfer protein (PITP) RDGB, is required for lipid transfer at endoplasmic reticulum (ER)-plasma membrane (PM) contact sites (MCS). Depletion of RDGB or its mis-localization away from the ER-PM MCS results in multiple defects in photoreceptor function. Previously, the interaction between the FFAT motif of RDGB and the integral ER protein dVAP-A was shown to be essential for accurate localization to ER-PM MCS. Here, we report that the FFAT/dVAP-A interaction alone is insufficient to localize RDGB accurately; this also requires the function of the C-terminal domains, DDHD and LNS2. Mutations in each of these domains results in mis-localization of RDGB leading to loss of function. While the LNS2 domain is necessary, it is not sufficient for the correct localization of RDGB, which also requires the C-terminal DDHD domain. The function of the DDHD domain is mediated through an intramolecular interaction with the LNS2 domain. Thus, interactions between the additional domains in a multi-domain PITP together lead to accurate localization at the MCS and signalling function.

}, issn = {2046-6390}, doi = {10.1242/bio.057422}, author = {Basak, Bishal and Krishnan, Harini and Padinjat, Raghu} } @article {64325, title = {Phosphoinositides: Regulators of Nervous System Function in Health and Disease}, journal = {FRONTIERS IN MOLECULAR NEUROSCIENCE}, volume = {12 }, year = {2019}, month = {08/2019}, abstract = {

Phosphoinositides, the seven phosphorylated derivatives of phosphatidylinositol have emerged as regulators of key sub-cellular processes such as membrane transport, cytoskeletal function and plasma membrane signaling in eukaryotic cells. All of these processes are also present in the cells that constitute the nervous system of animals and in this setting too, these are likely to tune key aspects of cell biology in relation to the unique structure and function of neurons. Phosphoinositides metabolism and function are mediated by enzymes and proteins that are conserved in evolution, and analysis of knockouts of these in animal models implicate this signaling system in neural function. Most recently, with the advent of human genome analysis, mutations in genes encoding components of the phosphoinositide signaling pathway have been implicated in human diseases although the cell biological basis of disease phenotypes in many cases remains unclear. In this review we evaluate existing evidence for the involvement of phosphoinositide signaling in human nervous system diseases and discuss ways of enhancing our understanding of the role of this pathway in the human nervous system{\textquoteright}s function in health and disease.

}, doi = {10.3389/fnmol.2019.00208}, author = {Padinjat, Raghu and Joseph, A and Krishnan, H and Singh, P and Saha, S} } @article {30018, title = {Evidence of sinks and sources in the phospholipase C activated PIP2 cycle.}, journal = {FEBS Lett}, year = {2018}, month = {2018 Feb 10}, abstract = {

In many eukaryotic signalling cascades, receptor mediated phospholipase C (PLC) activity triggers phosphatidylinositol-4,5-bisphosphate (PIP2 ) hydrolysis leading to information transfer. Coupled with PLC activation is a sequence of reactions spread across multiple compartments which resynthesize PIP2 , a process essential for supporting sustained PLC signalling. The biochemical strategies coordinating these reactions and, in particular, whether this is a closed cycle with no net addition or loss of metabolites, are poorly understood. Using mathematical models, we find that most closed PIP2 cycles cannot explain experimentally observed changes in key metabolic intermediates in particular mutants. Thus, we propose that the PIP2 cycle likely includes at least one metabolic source and one sink whose net activity results in the experimentally observed regulation of this key signalling pathway. This article is protected by copyright. All rights reserved.

}, issn = {1873-3468}, doi = {10.1002/1873-3468.12998}, author = {Suratekar, Rohit and Panda, Aniruddha and Padinjat, Raghu and Krishna, Sandeep} }