Pharmacogenetic variation in Neanderthals and Denisovans and implications for human health and response to medications

Abstract

Modern humans carry both Neanderthal and Denisovan (archaic) genome elements that are part of the human gene pool and affect the life and health of living individuals. The impact of archaic DNA may be particularly evident in pharmacogenes - genes responsible for the processing of exogenous substances such as food, pollutants, and medications. However, the health implications and contribution of archaic ancestry in pharmacogenes of modern humans remains understudied. Here, we explore eleven key cytochrome P450 genes (CYP450) involved in drug metabolizing reactions in three Neanderthal and one Denisovan individuals as well as examine archaic introgression in modern human populations. We infer the metabolizing efficiency of these eleven CYP450 genes in archaic individuals and find important phenotypic differences relative to modern human variants. We identify several single nucleotide variants shared between archaic and modern humans in each gene, including some potentially function-altering mutations in archaic CYP450 genes, which may result in altered metabolism in living people carrying these variants. We highlight three genes which show evidence for archaic introgression into modern humans, as well as one additional gene that shows evidence for a gene duplication found only in Neanderthals and modern Africans.