Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution

Abstract

BackgroundCytochrome 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.ResultsBifurcation 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 < = 0.037, p <0.001.ConclusionsWe found some evidence that the slow metabolizing allele CYP2C19*2 is subject to positive selective forces worldwide. Similar evidence was also found for CYP2C19*3 which is frequent only in Asia. FST 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.

Relevance of the ancestry for the variability of the Drug-Metabolizing Enzymes CYP2C9, CYP2C19 and CYP2D6 polymorphisms in a multiethnic Costa Rican population

“…The increased-activity CYP2C19*17 allele frequency of the Afro-Caribbean population is consistent with its high frequency in the West African Gambia population (23.0 %) (Janha et al, 2014), which is in accordance to the predominant Western African origin of the African diaspora to the Americas (Madrigal, 2006). The ascertainment of CYP2C19 gUMs by genotyping of the CYP2C19*17 allele has only been performed in other two Latin American admixed populations from Brazil and Ecuador (26.8 and 41.4 %, respectively) (Santos et al, 2011;Vicente et al, 2014), and both frequencies are higher than that of the Costa Rican admixed population (17.7 %; P<0.05).…”

TheCYP2C19Intron 2 Branch Point SNP is the Ancestral Polymorphism Contributing to the Poor Metabolizer Phenotype in Livers withCYP2C19*35andCYP2C19*2Alleles

“…In addition, a recent study of 2203 African Americans (Gordon et al, 2014) found that CYP2C19 had the highest number of putative novel functional variants compared with 11 other drug metabolizing CYP genes. This result was interesting because it was recently reported that the CYP2C19*2 nonfunctional allele may have been positively selected in human evolution (Janha et al, 2014), and that inactivation of CYP2C19 might have afforded some survival advantage. Conversely, because CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular events among clopidogrel-treated patients, Clinical Pharmacogenetic Implementation Consortium guidelines were issued for CYP2C19 genotype-directed drug therapy (Scott et al, 2013).…”

“…Second, we used extended haplotype homozygosity statistics and uncovered significant evidence that the haplotypes with rs12769205 alone (CYP2C19*35) and with rs4244285 on CYP2C19*2 have undergone positive selection, and that natural selection was not limited to YRI but was seen across African populations, having probably arisen in earlier human ancestors from which all other groups of Africans descended. Notably, the magnitude of evolutionary pressure for both haplotypes with rs12769205 was as great as that exerted on the human genome by infectious diseases (Janha et al, 2014), and implies that rs12769205 on both haplotypes confers an evolutionary advantage. Indeed, the signature of positive selection on the haplotype with rs12769205 alone (CYP2C19*35) reinforces that this polymorphism has a significant functional effect independent of rs4244285.…”

“…It was recently reported that the CYP2C19*2 nonfunctional allele may be under positive selection with CYP2C19 inactivation, conferring an evolutionary advantage in Africa (Janha et al, 2014). To investigate if the signal for selection could be attributed to rs12769205, we used Sweep-a program that uses large-scale analysis of haplotype structure in the genome to detect evidence of natural selection-in order to reanalyze CYP2C19*2 in 108 YRI, and we included rs12769205.…”

“…The Sweep program (http://www.broadinstitute.org/mpg/ sweep/) was used to determine haplotypes and to generate REHH plots in order to look for positive selection in the YRI population and then in other African populations. All 216 chromosomes from the YRI in the 1000 Genomes phase 3 data (release #20130502) were used, compared with a recent study (Janha et al, 2014), which used 120 YRI chromosomes. The coordinates were lifted from hg19 to hg17 using the LiftOver program (https://genome.ucsc.edu/cgi-bin/ hgLiftOver), and then data in chr10:96486608-96688055 (hg17 coordinates) were used for subsequent analysis, totaling 201,447 bp.…”