Signatures of co-evolution and co-regulation in the CYP3A and CYP4F genes in humans

1 Abstract Cytochromes P450 (CYP450) are hemoproteins generally involved in the detoxification of the body of xenobiotic molecules. They participate in the metabolism of many drugs and genetic polymorphisms in humans have been found to impact drugs responses and metabolic functions. In this study, we investigate the genetic diversity for CYP450 genes. We found that two clusters, CYP3A and CYP4F , are notably differentiated across human populations with evidence for selective pressures acting on both clusters: we found signals of recent positive selection in CYP3A and CYP4F genes and signals of balancing selection in CYP4F genes. Furthermore, unusual linkage disequilibrium pattern is detected in both clusters, suggesting co-evolution of genes within clusters. Several of these selective signals co-localize with expression quantitative trait loci, which suggest co-regulation and epistasis within these highly important gene families. We also found that SNPs under selection in Africans within the CYP3A cluster are associated to CYP3A5 expression levels which are causally associated with reticulocytes count, as established by mendelian randomization. Furthermore, as the CYP3A and CYP4F subfamilies are involved in the metabolism of nutrients and drugs, our findings linking natural selection and gene expression in these gene clusters are of importance in understanding population differences in human health.