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POSTER NO: 197 Evolutionary and population genetic analysis of CYP genes in humans
Scott E. Stanley, Julie Schneider, Chad Messer, Alison Anastasio, Rex Denton, J. Claiborne Stephens Cytochrome P450 genes (known as CYP genes), which make up a large gene superfamily, are known to play important roles in drug metabolism and are thought to be associated with human diseases, particularly several types of cancer. Thus, CYP genes are of great interest to the pharmaceutical industry and researchers studying the genetics of cancer. Here we analyzed CYP genes known to exist in the human genome from both a phylogenetic and population genetic perspective. First, we aligned all CYP genes for which a representative mRNA was available and analyzed that alignment phylogenetically. Our results demonstrate that the members of the currently recognized and named CYP subfamilies are descended from a single common ancestor (i.e. are monophyletic). Since the CYP subfamilies have been defined by functional similarity, this suggests that the function of CYP proteins has largely tracked the evolutionary history of the genes that code for them. Using likelihood ratio tests, we also looked for patterns of evolution along the CYP gene tree indicative of rate heterogeneity and unusual patterns of selection during CYP gene evolution. In addition, we used a sample of 93 humans, including 82 unrelated individuals, and a single chimp to detect non-neutral evolution for a select number of CYP genes. Although patterns of variation in the majority of CYP genes are consistent with neutral evolution, two genes, including the pharmaceutically important CYP3A5, show patterns consistent with the effects of natural selection. Our results demonstrate the power of an evolutionary and population level approach to characterizing genes with possible relevance to human disease and drug response. |