Exploring adaptive phenotypes for the human calcium-sensing receptor polymorphism R990G

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• dc.contributor.author Sinigaglia, Barbara
• dc.contributor.author Escudero, Jorge
• dc.contributor.author Biagini, Simone Andrea, 1983-
• dc.contributor.author García Calleja, Jorge
• dc.contributor.author Moreno, Josep
• dc.contributor.author Dobón Berenguer, Begoña, 1987-
• dc.contributor.author Acosta, Sandra
• dc.contributor.author Mondal, Mayukh, 1989-
• dc.contributor.author Walsh Capdevila, Sandra, 1991-
• dc.contributor.author Aguileta, Gabriela
• dc.contributor.author Vallès, Mònica
• dc.contributor.author Forrow, Stephen
• dc.contributor.author Martín Caballero, Juan
• dc.contributor.author Migliano, Andrea Bamberg
• dc.contributor.author Bertranpetit, Jaume, 1952-
• dc.contributor.author Muñoz López, Francisco José, 1964-
• dc.contributor.author Bosch Fusté, Elena
• dc.date.accessioned 2024-03-27T13:47:49Z
• dc.date.available 2024-03-27T13:47:49Z
• dc.date.issued 2024
• dc.description.abstract Rainforest 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.
• dc.description.sponsorship This work was supported by Agencia Estatal de Investigación (AEI, DOI: 10.13039/501100011033), Fondo Europeo de Desarrollo Regional, Ministerio de Ciencia e Innovación, and Ministerio de Ciencia, Innovación y Universidades with project grants BFU2016-77961-P, PID2019-110933GB-I00, and the Unidad de Excelencia María de Maeztu Ref. CEX2018-000792-M; and by Agència de Gestió d'Ajuts Universitaris i de la Recerca, Generalitat de Catalunya (2017SGR00702). B.S. was supported with an FPI-MINECO PhD fellowship (BES-2017-080343). S.A. was supported by Beatriu de Pinós 2017 BP 00176 and by the Serra Hunter Fellowship from Generalitat de Catalunya.
• dc.format.mimetype application/pdf
• dc.identifier.citation Sinigaglia 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/msae015
• dc.identifier.doi http://dx.doi.org/10.1093/molbev/msae015
• dc.identifier.issn 0737-4038
• dc.identifier.uri http://hdl.handle.net/10230/59599
• dc.language.iso eng
• dc.publisher Oxford University Press
• dc.relation.ispartof Mol Biol Evol. 2024 Feb 1;41(2):msae015
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-77961-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-110933GB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2018-000792-M
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BES-2017-080343
• dc.rights © 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.com
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.keyword CaSR
• dc.subject.keyword SE Asian populations
• dc.subject.keyword Genetic adaptation
• dc.subject.keyword Pygmy phenotype
• dc.title Exploring adaptive phenotypes for the human calcium-sensing receptor polymorphism R990G
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion