Membrane-bound receptor proteins are cellular sensors involved in the initiation of various signal transduction pathways. Not all but some amino acid variants in these proteins cause numerous disorders. The major approach in predicting disease-causing mutations has been to evaluate the evolutionary constraint on the amino acid of interest. A residue which is conserved throughout the receptor evolution is considered functionally important, and therefore any substitution on a conserved residue changingthe physiochemical property of the protein results in a malformed activity. Despite the apparent power of benefiting from the evolutionary history of a gene, establishing it precisely is a grand challenge due to the overwhelming effect of gene duplication and loss in human receptors. The current automated methods in orthology classification cause the inclusion of functionally diverged homologs in the analysis which mislead the disease-causing mutation predictor towards a poorer sensitivity. Here, we established the precise evolutionary history of NPC1 and GPRC6A, predicted amino acid substitutions disrupting protein function. We revealed and understand the evolutionary events by analyzing the phylogenetic clades of the genes. We obtained a clean set of homologs for each human receptor, including the functionally equivalent orthologs only, from other organisms by using existing and novel bioinformatics approaches. After building the accurate multiple sequence alignments edited manually, we will evaluate the true effect of each possible amino acid substitution on protein function and therefore health and disease. We anticipate our research to result in developing more accurate predictions of the disease-causing amino acid substitutions in the human receptor families and therefore yielding tools improving the precision in the diagnosis of genetic disorders associated with other protein families as well.
Tuesday, August 27, 2019 at 4:00 PM