Archaic introgression and variation in pharmacogenes and implications for local adaptation

Abstract

AbstractModern humans carry Neanderthal and Denisovan (archaic) genome elements which may have been adaptive. These effects 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. We characterize eleven key cytochrome P450 (CYP450) genes involved in drug metabolizing reactions in three Neanderthal and one Denisovan individuals and examine archaic introgression in modern human populations. We infer the metabolizing efficiency of these eleven genes in archaic individuals and show important genetic differences relative to modern human variants. We identify archaic-specific SNVs in each CYP450 gene, including some that are potentially damaging, which may result in altered metabolism in modern human people carrying these variants. We highlight four genes which display interesting patterns of archaic variation: CYP2B6 – we find a large number of unique variants in the Vindija Neanderthal, some of which are shared with a small subset of African modern humans; CYP2C9 – containing multiple variants that are shared between Europeans and Neanderthals; CYP2A6*12 – a variant defined by a hybridization event that was found in humans and Neanderthals, suggesting the recombination event predates both species; and CYP2J2 – in which we hypothesize a Neanderthal variant was re-introduced in non-African populations by archaic admixture. The genetic variation identified in archaic individuals suggests that selective pressures from the environment may be involved in the evolution of CYP450 genes.