Exploring Adaptive Phenotypes for the Human Calcium-Sensing Receptor Polymorphism R990G

Area of Science:

• Human evolutionary genetics
• Physiological adaptations
• Calcium signaling

Background:

• Southeast Asian rainforest hunter-gatherers exhibit distinctive traits (DSWS phenotype): dark skin, short stature, woolly hair, and steatopygia.
• The calcium-sensing receptor gene (CaSR) is crucial for calcium homeostasis and has been implicated in various biological functions.
• Previous studies identified the R990G substitution (rs1042636) in CaSR as a potential adaptive variant in populations with the DSWS phenotype.

Purpose of the Study:

• To investigate the adaptive significance of the R990G CaSR variant in Southeast Asian rainforest hunter-gatherers.
• To explore the physiological effects of the R990G substitution on calcium levels, body weight, and fat accumulation.

Main Methods:

• Analysis of natural selection signatures around the CaSR gene in relevant human populations.
• Generation of a knock-in mouse model carrying the R990G CaSR substitution.
• Phenotypic characterization of the knock-in mice, including serum calcium levels, body weight, and fat composition.

Main Results:

• The R990G substitution was identified as a putative adaptive variant in Southeast Asian rainforest groups.
• Homozygous knock-in mice exhibited lower serum calcium concentrations.
• These mice also showed increased body weight and fat accumulation, linked to enhanced preadipocyte differentiation and impaired lipolysis due to CaSR activation.

Conclusions:

• The R990G CaSR variant may confer adaptive advantages by influencing metabolism and fat storage.
• These metabolic changes could have enhanced the survival of rainforest hunter-gatherer groups facing nutritional challenges.
• The study highlights the role of CaSR in human adaptation to specific environmental conditions.