Primates, poison, and cytochrome P450: Evolutionary dynamism of the CYP1-3 gene families within the primate order

Primates exhibit a high degree of among-species dietary diversity, which likely exposes them to varying levels of xenobiotic compounds. Many compounds in this category are known to be metabolized by enzymes in the cytochrome P450 superfamily, which has members in all kingdoms of life. Some of these enzymes have been shown to metabolize drugs and xenobiotic toxins and are therefore of great importance for biomedical research and applications. While the pharmacology of P450 enzymes has been studied extensively, our understanding of molecular evolution of this gene family is incomplete, in part because a great variation exists in the number of P450 homologs across genomes. In this dissertation, I aim to show that xenobiotic-metabolizing P450 genes vary in coherent or predictable ways. First, I show that the CYP2C subfamily, responsible for the breakdown of about 20% of pharmaceutical compounds in humans, has undergone a pattern of gene loss in great apes compared to Old World monkeys. Second, I show that P450 subfamilies involved in the largest proportions of pharmacological biotransformation — CYP2C, CYP2D, and CYP3, as well as CYP2E1 — show statistical signals of positive or diversifying selection on the portions of their genes that correspond to substrate-recognition sites. Finally, I illustrate how some of the most dietarily specialized primates in the entire order, the bamboo lemurs of Madagascar (Hapalemur spp. and Prolemur simus), have undergone a clear pattern of genic loss compared to other species of lemur and, especially, in comparison to their closest relative, the ringtail lemur (Lemur catta). Viewed in summary, these findings show that P450 variation exists in comprehensible patterns and that this topic, which has been relatively neglected by many molecular primatologists, deserves future study as more genome assembles and omic resources become available.