Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution Genome evolution and evolutionary systems biology

© 2014 Janha et al.; licensee BioMed Central Ltd.Background: Cytochrome P450 CYP2C19 metabolizes a wide range of pharmacologically active substances and a relatively small number of naturally occurring environmental toxins. Poor activity alleles of CYP2C19 are very frequent worldwide, particularly in Asia, raising the possibility that reduced metabolism could be advantageous in some circumstances. The evolutionary selective forces acting on this gene have not previously been investigated. We analyzed CYP2C19 genetic markers from 127 Gambians and on 120 chromosomes from Yoruba, Europeans and Asians (Japanese + Han Chinese) in the Hapmap database. Haplotype breakdown was explored using bifurcation plots and relative extended haplotype homozygosity (REHH). Allele frequency differentiation across populations was estimated using the fixation index (FST) and haplotype diversity with coalescent models. Results: Bifurcation plots suggested conservation of alleles conferring slow metabolism (CYP2C19∗2 and ∗3). REHH was high around CYP2C19∗2 in Yoruba (REHH 8.3, at 133.3 kb from the core) and to a lesser extent in Europeans (3.5, at 37.7 kb) and Asians (2.8, at -29.7 kb). FST at the CYP2C19 locus was low overall (0.098). CYP2C19∗3 was an FST outlier in Asians (0.293), CYP2C19 haplotype diversity ST is low at the CYP2C19 locus, suggesting balancing selection overall. The biological factors responsible for these selective pressures are currently unknown. One possible explanation is that early humans were exposed to a ubiquitous novel toxin activated by CYP2C19. The genetic adaptation took place within the last 10,000 years which coincides with the development of systematic agricultural practices.This work was supported by the Medical Research Council Unit The Gambia and the European and Developing Countries Clinical Trials Partnership [grant number CG_ta_05_40204_018]

Is there adaptation in the human genome for taste perception and phase I biotransformation?

Background: During the modern human expansion, new environmental pressures may have driven adaptation, especially in genes related to the perception of ingested substances and their detoxification. Consequently, positive (adaptive) selection may have occurred in genes related to taste, and in those related to the CYP450 system due to its role in biotransformation of potentially toxic compounds. A total of 91 genes (taste receptors and CYP450 superfamily) have been studied using Hierarchical Boosting, a powerful combination of different selection tests, to detect signatures of recent positive selection in three continental human populations: Northern Europeans (CEU), East Asians (CHB) and Africans (YRI). Analyses have been refined with selection analyses of the 26 populations of 1000 Genomes Project Phase 3. Results: Genes related to taste perception have not been positively selected in the three continental human populations. This finding suggests that, contrary to results of previous studies, different allele frequencies among populations in genes such as TAS2R38 and TAS2R16 are not due to positive selection but to genetic drift. CYP1 and CYP2 genes, also previously considered to be under positive selection, did not show signatures of selective sweeps. However, three genes belonging to the CYP450 system have been identified by the Hierarchical Boosting as positively selected: CYP3A4 and CYP3A43 in CEU, and CYP27A1 in CHB. Conclusions: No main adaptive differences are found in known taste receptor genes among the three continental human populations studied. However, there are important genetic adaptations in the cytochrome P450 system related to the Out of Africa expansion of modern humans. We confirmed that CYP3A4 and CYP3A43 are under selection in CEU, and we report for the first time CYP27A1 to be under positive selection in CHB.This study has been possible thanks to grant BFU2016–77961-P (AEI/FEDER, UE) awarded by the Agencia Estatal de Investigación (Ministerio de Ciencia, Innovación y Universidades, Spain) and with the support of Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 702). Part of the “Unidad de Excelencia María de Maeztu” (MDM-2014-0370), funded by the Ministerio de Economía, Industria y Competividad (MINECO, Spain). BD is supported by F.P.U. grant FPU13/06813 from the Ministerio de Educación, Cultura y Deporte (Spain). SW is supported by F.P.I grant BES-2014-068994 from MINECO