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

BACKGROUND AND OBJECTIVES: 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. RESULTS AND CONCLUSIONS: 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.

Multiple rare variants as a cause of a common phenotype: several different lactase persistence associated alleles in a single ethnic group.

Persistence of intestinal lactase into adulthood allows humans to use milk from other mammals as a source of food and water. This genetic trait has arisen by convergent evolution and the derived alleles of at least three different single nucleotide polymorphisms (-13910C>T, -13915T>G, -14010G>C) are associated with lactase persistence in different populations. Each allele occurs on an extended haplotype, consistent with positive directional selection. The SNPs are located in an 'enhancer' sequence in an intron of a neighboring gene (MCM6) and modulate lactase transcription in vitro. However, a number of lactase persistent individuals carry none of these alleles, but other low-frequency single nucleotide polymorphisms have been observed in the same region. Here we examine a cohort of 107 milk-drinking Somali camel-herders from Ethiopia. Eight polymorphic sites are identified in the enhancer. -13915*G and -13907*G (a previously reported candidate) are each significantly associated with lactase persistence. A new allele, -14009*G, has borderline association with lactase persistence, but loses significance after correction for multiple testing. Sequence diversity of the enhancer is significantly higher in the lactase persistent members of this and a second cohort compared with non-persistent members of the two groups (P = 7.7 x 10(-9) and 1.0 x 10(-3)). By comparing other loci, we show that this difference is not due to population sub-structure, demonstrating that increased diversity can accompany selection. This contrasts with the well-documented observation that positive selection decreases diversity by driving up the frequency of a single advantageous allele, and has implications for association studies.