CYP1A2 is more variable than previously thought: a genomic biography of the gene behind the human drug-metabolizing enzyme

Abstract

CYP1A2 metabolizes various drugs, endogenous compounds and procarcinogens. As human genetic diversity has been reported to decrease with distance from Ethiopia, we resequenced CYP1A2 in five Ethiopian ethnic groups representing a rough northeast to southwest transect across Ethiopia to establish: (i) what variation exists in comparison with what is already known globally and (ii) what CYP1A2 pharmacogenetic profiles may be present as several CYP1A2-metabolized drugs are administered to Ethiopians. We found 49 different variable sites (30 of which are novel), nine nonsynonymous changes (seven of which are novel), one synonymous change and 55 different haplotypes, only three of which are previously reported. When haplotypes were constructed using only nonsynonymous polymorphisms to restrict haplotypes to those most likely to affect enzyme structure/function, 10 haplotypes were identified (seven contain previously unidentified nonsynonymous variants and four are predicted to alter the enzyme structure/function). Most individuals have at least one copy of the ancestral haplotype. Comparing these data with those from publically available databases, Ethiopian groups display twice the variation seen in all other populations combined (gene diversity using nonsynonymous variants): Ethiopia=0.17±0.02, other populations=0.08±0.03. Across the entire gene, Ethiopia also evidences all common variation found on a global scale. We provide evidence of weak purifying selection acting on CYP1A2 and show that the time to most recent common ancestor, calculated using variation in a nearby microsatellite, places several variants into a period predating the expansion of modern humans out of Africa less than 100,000 years ago.