A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations
A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations
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DOI：
10.1126/science.1147786
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发表时间：
2008-02-15
期刊：
影响因子：
56.9
通讯作者：
Wallace, Douglas C.
中科院分区：
文献类型：
--
作者：
Fan, Weiwei;Waymire, Katrina G.;Wallace, Douglas C.
大多数导致人类疾病的线粒体DNA （mtDNA）突变是轻微到中度有害的，然而许多随机的mtDNA突变预计是严重的。为了确定更严重的mtDNA突变的命运，我们将包含两种影响氧化磷酸化的突变的mtDNA引入雌性小鼠生殖系。严重的ND6突变在四代内的卵发生过程中被选择性地消除，而轻微的COI突变在多代中保留，即使后代一直发展为线粒体肌病和心肌病。因此，严重的mtDNA突变似乎被选择性地从雌性生殖系中消除，从而最大限度地减少了它们对种群适应性的影响。
The majority of mitochondrial DNA ( mtDNA) mutations that cause human disease are mild to moderately deleterious, yet many random mtDNA mutations would be expected to be severe. To determine the fate of the more severe mtDNA mutations, we introduced mtDNAs containing two mutations that affect oxidative phosphorylation into the female mouse germ line. The severe ND6 mutation was selectively eliminated during oogenesis within four generations, whereas the milder COI mutation was retained throughout multiple generations even though the offspring consistently developed mitochondrial myopathy and cardiomyopathy. Thus, severe mtDNA mutations appear to be selectively eliminated from the female germ line, thereby minimizing their impact on population fitness.