title: Molecular evolution and balancing selection in the flavin-containing monooxygenase 3 gene (FMO3).
abstract: OBJECTIVE
  Flavin-containing monooxygenase 3 (FMO3) is involved in the metabolism of foreign chemicals, including therapeutic drugs, and thus mediates interactions between humans and their chemical environment. Loss-of-function mutations in the gene cause the inherited disorder trimethylaminuria, or fish-odour syndrome. The objective was to gain insights into the evolutionary history of FMO3.
  
  
  METHODS
  Genetic diversity within FMO3 was characterized by sequencing 6.3 kb of genomic DNA, encompassing the entire coding sequence, some intronic and 3'-untranslated region, and 3.4 kb of 5'-flanking sequence, in 23 potential trimethylaminuric Japanese, and the same 3.4 kb 5'-flanking region in 45 unaffected Japanese. Mutational relationships among haplotypes were inferred from a reduced-median network. The time depth of the variation and ages of individual mutations were estimated by maximum-likelihood coalescent analysis. Test statistics were used to investigate whether the variation is compatible with neutral evolution.
  
  
  RESULTS
  Sixteen single-nucleotide polymorphisms (SNPs) were identified, which segregated as seven distinct haplotypes. Estimated ages of the mutations indicate that almost all predated migration out of Africa. Analysis of the heterozygosity of FMO3 SNPs indicates that genetic differentiation among continental populations is low (FST=0.050). Test statistics, based on allele-frequency spectrum, number and diversity of haplotypes, linkage disequilibrium and interspecific sequence comparisons, showed a significant departure from neutral expectations, because of an excess of intermediate-frequency SNPs and haplotypes, a ragged pairwise mismatch distribution and an excess of replacement polymorphisms.
  
  
  CONCLUSIONS
  The results provide evidence that FMO3 has been the subject of balancing selection. Finally, we identify mutations that are potential targets for selection.
authors: Department of Biochemistry and Molecular Biology, University College London, UK.
authors: Charles K
authors: CK
authors: Allerston
authors: Makiko
authors: M
authors: Shimizu
authors: Masaki
authors: M
authors: Fujieda
authors: Elizabeth A
authors: EA
authors: Shephard
authors: Hiroshi
authors: H
authors: Yamazaki
authors: Ian R
authors: IR
authors: Phillips
mesh_terms: D000328:Adult; D000483:Alleles; D001483:Base Sequence; D019143:Evolution, Molecular; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010105:Oxygenases / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D013045:Species Specificity; D013997:Time Factors
chemical_list: D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)