Genetic variation in the FMO2 gene: evolution & functional consequences
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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.
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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.
Authors
Al-Sulaimani, Maha SalehCollections
- Theses [3831]