当前位置： SCI文献检索 > Pharmacogenetics and Genomics期刊下所有文献 > Molecular evolution and balancing selection in the flavin-containing monooxygenase 3 gene (FMO3).

Molecular evolution and balancing selection in the flavin-containing monooxygenase 3 gene (FMO3).

Abstract：

OBJECTIVES: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. CONCLUSION:The results provide evidence that FMO3 has been the subject of balancing selection. Finally, we identify mutations that are potential targets for selection.

journal_name

Pharmacogenet Genomics

journal_title

Pharmacogenetics and genomics

authors

Allerston CK,Shimizu M,Fujieda M,Shephard EA,Yamazaki H,Phillips IR

doi

10.1097/FPC.0b013e328256b198

subject

Has Abstract

pub_date

2007-10-01 00:00:00

pages

827-39

issue

eissn

1744-6872

issn

1744-6880

pii

01213011-200710000-00004

journal_volume

pub_type

杂志文章

在线工具

Molecular evolution and balancing selection in the flavin-containing monooxygenase 3 gene (FMO3).