Project

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The cytochrome P450 (CYP450) genes encode oxidase enzymes that function in metabolism of endogenous small molecules and in detoxification of exogenous (or xenobiotic) compounds. The evolution of xenobiotic CYP450 enzymes may be driven by organisms’ need to metabolically detoxify foreign compounds - often toxic chemicals produced by plants, fungi, and bacteria - in the local environment. Interestingly, CYP450 enzymes show evidence of positive selection in humans. Although CYP450 genes have been studied in many populations, the extent of genetic variation and evolutionary pressures in archaic hominins and non-human primates has not been addressed. 

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Additional Information

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We have characterized variation in eleven pharmacogenes across four archaic hominin samples and are expanding our efforts to include additional pharmacogenes. High-coverage genome sequences for two archaic human lineages now exist: Neanderthals and Denisovans. Direct comparisons of archaic and modern human genomes have revealed a complex landscape of genetic admixture. It is widely accepted that most modern humans carry both Neanderthal and Denisovan genomic variants from introgression (the transfer of genetic information from one species to another as a result of hybridization between them), and that these variants have been the targets of natural selection. In the last decade, dozens of archaic variants of genes have been reported influencing modern human health and fitness, a few examples include BNC2 and OCA2 (skin pigmentation), TBX15/WARS2 (adipose metabolism), and OAS and STAT2 (immune system).

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Future Directions

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We plan to further study the introgression of archaic variation in the modern human population, unique introgressed haplotypes identified in modern human populations, and the evolution of pharmacogenes in non-human primate species. What are the evolutionary pressures acting on PGx, and do specific variants segregate within the primate and archaic hominin populations? Are specific variants adaptative and what are the implications for modern medicine?