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Based on previous evidence in the Andamanese population, we first characterized signatures of adaptive natural selection around the calcium-sensing receptor gene in Southeast Asian rainforest groups presenting the DSWS phenotype and identified the R990G substitution (rs1042636) as a putative adaptive variant for experimental follow-up. Although the calcium-sensing receptor has a critical role in calcium homeostasis by directly regulating the parathyroid hormone secretion, it is expressed in different tissues and has been described to be involved in many biological functions. Previous works have also characterized the R990G substitution as an activating polymorphism of the calcium-sensing receptor associated with hypocalcemia. Therefore, we generated a knock-in mouse for this substitution and investigated organismal phenotypes that could have become adaptive in rainforest hunter\u2013gatherers from Southeast Asia. Interestingly, we found that mouse homozygous for the derived allele show not only lower serum calcium concentration but also greater body weight and fat accumulation, probably because of enhanced preadipocyte differentiation and lipolysis impairment resulting from the calcium-sensing receptor activation mediated by R990G. We speculate that such differential features in humans could have facilitated the survival of hunter\u2013gatherer groups during periods of nutritional stress in the challenging conditions of the Southeast Asian tropical rainforests.<\/jats:p>","DOI":"10.1093\/molbev\/msae015","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T18:06:23Z","timestamp":1706551583000},"source":"Crossref","is-referenced-by-count":4,"title":["Exploring Adaptive Phenotypes for the Human Calcium-Sensing Receptor Polymorphism R990G"],"prefix":"10.1093","volume":"41","author":[{"given":"Barbara","family":"Sinigaglia","sequence":"first","affiliation":[{"name":"Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ci\u00e8ncies de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biom\u00e8dica de Barcelona , Barcelona 08003 , 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