Genetic variation in the FMO2 gene: evolution & functional consequences

Abstract

Flavin-containing monooxygenase 2 (FMO2) is involved in the metabolism of xenobiotics, including therapeutic drugs. FMO2 exists in two forms: a functional and a non-functional form. The functional allele is found only in Africa and individuals of recent African origin. The aims of the project were to determine the frequency of functional FMO2 in Africa and obtain insights into the evolutionary history of the FMO2 gene. Six hundred and eighty nine samples from nine African population groups were genotyped for six high-frequency SNPs, and the genetic diversity within FMO2 was characterized by sequencing 3.44 kb of genomic DNA, encompassing the entire coding sequence and some flanking intronic sequences in 48 African individuals. Haplotypes were inferred using Phase and the relationship between mutations was revealed using reduced-median and median-joining Network. Test statistics were used to determine whether the genetic variation is compatible with neutral evolution. Genotyping indicated that deleterious SNPs occur mostly on a non-functional allele and that the frequencies of three were significantly different (P<0.05) among populations. Resequencing identified 32 variants. Genetree was used to estimate the time to the most recent common ancestral sequence (~0.928 million years) and the ages of some of the mutations. Results indicate that the frequency of full-length 23238C alleles is relatively uniform across sub-Saharan Africa. Interestingly, this is not the case for the inferred potentially functional 23238C alleles, which frequency differed significantly (P<0.05) across sub-Saharan Africa. iv The results also provide evidence that the frequency of functional FMO2 in east and west-Africa is high (≥0.54), which has important implications for therapy with drugs that are substrates for FMO2. A Ka/Ks > 1, and low nucleotide sequence diversity of intronic regions of 23238C alleles indicate a possible selective sweep.