Sinigaglia, BarbaraEscudero, JorgeBiagini, Simone Andrea, 1983-García Calleja, JorgeMoreno, JosepDobón Berenguer, Begoña, 1987-Acosta, SandraMondal, Mayukh, 1989-Walsh Capdevila, Sandra, 1991-Aguileta, GabrielaVallès, MònicaForrow, StephenMartín Caballero, JuanMigliano, Andrea BambergBertranpetit, Jaume, 1952-Muñoz López, Francisco José, 1964-Bosch Fusté, Elena2024-03-272024-03-272024Sinigaglia B, Escudero J, Biagini SA, Garcia-Calleja J, Moreno J, Dobon B, et al. Exploring adaptive phenotypes for the human calcium-sensing receptor polymorphism R990G. Mol Biol Evol. 2024 Feb 1;41(2):msae015. DOI: 10.1093/molbev/msae0150737-4038http://hdl.handle.net/10230/59599Rainforest hunter-gatherers from Southeast Asia are characterized by specific morphological features including a particularly dark skin color (D), short stature (S), woolly hair (W), and the presence of steatopygia (S)-fat accumulation localized in the hips (DSWS phenotype). 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-gatherers 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-gatherer groups during periods of nutritional stress in the challenging conditions of the Southeast Asian tropical rainforests.application/pdfeng© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.cominfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1093/molbev/msae015CaSRSE Asian populationsGenetic adaptationPygmy phenotypeinfo:eu-repo/semantics/openAccess