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)
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DOI：
10.1097/fpc.0b013e328256b198
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发表时间：
2007-10-01
影响因子：
2.6
通讯作者：
Phillips, Ian R.
中科院分区：
文献类型：
--
作者：
Allerston, Charles K.;Shimizu, Makiko;Phillips, Ian R.
目的含黄素单加氧酶3（Flavin-containing monooxygenase 3，FMO 3）参与外源性化学物质（包括治疗药物）的代谢，并介导人体与化学环境之间的相互作用。该基因的功能丧失突变导致遗传性疾病三甲基氨基尿症，或鱼腥味综合征。方法对23例可能患有三甲基氨基尿症的日本人和45例正常日本人的6.3kb基因组DNA进行测序，分析FMO 3基因的遗传多样性，包括完整的编码序列、部分内含子和3 '端非翻译区以及3.4kb的5'端侧翼序列。单倍型之间的突变关系是从减少中位数网络推断的。通过最大似然合并分析估计变异的时间深度和个体突变的年龄。结果共发现16个单核苷酸多态性（SNPs）位点，分为7个不同的单倍型。这些突变的估计年龄表明，几乎所有突变都发生在非洲移民之前。FMO 3 SNP的杂合性分析表明，大陆种群之间的遗传分化较低（F（ST）=0.050）。测试统计，等位基因频率谱，数量和多样性的单倍型，连锁不平衡和种间序列比较的基础上，表现出显着偏离中性的期望，因为过量的中频SNP和单倍型，参差不齐的配对错配分布和过量的替代polymorphis.Conclusion结果提供证据，FMO 3一直是平衡选择的主题。最后，我们确定突变是选择的潜在目标。
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'-untransiated 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 (F(ST)=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.