Evolutionary history of Calcium-sensing receptors sheds light into hyper/hypocalcemia-causing mutations

The Calcium Sensing Receptor (CaSR) is very important in controlling the levels of calcium in the body by interacting with different types of G-protein. This receptor is highly conserved among other G-protein coupled receptors (GPCRs) and has been linked to disorders affecting the balance of calcium in the body, such as hypercalcemia and hypocalcemia. Although there has been progress in understanding the structure and function of CaSR, there is still a lack of knowledge about which specific residues are important for their function and how it differs from other receptors in the same class. In this study, we used phylogeny-based methods to identify functionally-equivalent orthologs of CaSR, predict the importance of each residue, and calculate specificity-determining position (SDP) scores to uncover the evolutionary basis of its function. Our results showed that the CaSR subfamily is highly conserved, with higher SDP scores than its closest receptor subfamilies. Residues with high SDP scores are likely to be critical in receptor activation and pathogenicity. We applied gradient-boosting trees with evolutionary metrics as inputs to predict the functional consequences of each substitution, and discriminate between gain and loss-of-function mutations those causing hypo- and hypercalcemia, respectively. Our study provides insight into the evolutionary fine-tuning of CaSR, which can help understand its role in calcium balance and related disorders.