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

Rainforest hunter-gatherers from South-East Asia are characterized by specific morphological features including a particularly dark skin color (D), short stature (S), woolly hair (W), and presence of steatopygia (S) – fat accumulation localized in the hips (DSWS phenotype). Led by previous evidence in the Andamanese, we first characterized signatures of adaptive natural selection around the Calcium- Sensing Receptor (CaSR) gene in SE Asian rainforest groups presenting the DSWS phenotype and identified the R990G substitution (rs1042636) as a putative adaptive variant to experimentally follow up. Although CaSR 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 CaSR associated with hypocalcemia. Thus, we generated a knock-in mouse for this substitution and investigated organismal phenotypes that could have become adaptive in the rainforest hunter-gatherers from SE Asia. Interestingly, we found that mouse homozygotes for the derived allele show not only lower serum calcium concentration but greater body weight and fat accumulation, probably because of enhanced preadipocyte differentiation and lipolysis impairment resulting from the CaSR activation mediated by R990G. We speculate that such differential features in humans could facilitate survival during periods of nutritional stress but also an earlier sexual maturation, in agreement with the hypothesis that the short stature of the DSWS phenotype may result from selection for an early onset of reproduction in an environment with high mortality.