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Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution
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Janha, Ramatoulie E, Worwui, Archibald, Linton, Kenneth J, Shaheen, Seif O, Sisay-Joof, Fatoumatta and Walton, Robert T. (2014) Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution. BMC Evolutionary Biology, 14 (1). 71. doi:10.1186/1471-2148-14-71 ISSN 1471-2148.
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Official URL: http://dx.doi.org/10.1186/1471-2148-14-71
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.
Item Type: | Journal Article | ||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences > Population, Evidence & Technologies (PET) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Journal or Publication Title: | BMC Evolutionary Biology | ||||||
Publisher: | BioMed Central Ltd. | ||||||
ISSN: | 1471-2148 | ||||||
Official Date: | 1 April 2014 | ||||||
Dates: |
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Volume: | 14 | ||||||
Number: | 1 | ||||||
Article Number: | 71 | ||||||
DOI: | 10.1186/1471-2148-14-71 | ||||||
Status: | Peer Reviewed | ||||||
Publication Status: | Published | ||||||
Access rights to Published version: | Open Access (Creative Commons) |
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