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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 (F ST ) 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). F ST  at the  CYP2C19  locus was low overall (0.098).  CYP2C19 * 3  was an F ST  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. F 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.

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