title: Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution.
abstract: 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 < = 0.037, p <0.001.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Medical Research Council Unit The Gambia, The Gambia, West Africa. touliej@yahoo.co.uk.
authors.forename: Ramatoulie E
authors.initials: RE
authors.lastname: Janha
authors.forename: Archibald
authors.initials: A
authors.lastname: Worwui
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Linton
authors.forename: Seif O
authors.initials: SO
authors.lastname: Shaheen
authors.forename: Fatoumatta
authors.initials: F
authors.lastname: Sisay-Joof
authors.forename: Robert T
authors.initials: RT
authors.lastname: Walton
mesh_terms: D000354:Africa, Western; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D005787:Gene Frequency; D005826:Genetics, Medical; D005828:Genetics, Population; D060148:HapMap Project; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D044465:White People / Q000235:genetics
chemical_list: D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19