Selective propagation of functional mitochondrial DNA during oogenesis restricts the transmission of a deleterious mitochondrial variant
Selective propagation of functional mitochondrial DNA during oogenesis restricts the transmission of a deleterious mitochondrial variant
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DOI：
10.1038/ng.2920
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发表时间：
2014-04-01
期刊：
影响因子：
30.8
通讯作者：
Xu, Hong
中科院分区：
文献类型：
--
作者：
Hill, Jahda H.;Chen, Zhe;Xu, Hong
虽然线粒体DNA(MtDNA)很容易发生突变，而且几乎没有线粒体DNA修复机制(1)，但致残的线粒体突变是极其罕见的(2)。最近的研究表明，在小鼠雌性生殖系(3，4)中有很强的净化选择。然而，健康线粒体正向选择的机制仍有待阐明。我们可视化了果蝇卵子发生过程中mtDNA的复制，发现mtDNA复制在卵子发育后期的卵子确定之前就开始了，并且依赖于线粒体的适合性。我们分离到了一个对温度敏感的致死线粒体DNA等位基因mt：CoIT300I，该等位基因在有限的温度下导致了细菌中mtDNA复制的减少。此外，在限制性温度下，异质果蝇mt：CoIT300I等位基因的频率在卵子发生过程中和在多代中都降低了。此外，我们确定了针对mt：CoIT300I的选择与细菌中mtDNA选择性复制的时间重叠。这些发现为野生型mtDNA的选择性扩增建立了一种以前未知的发育机制，这种机制可能在进化上是保守的，以限制有害突变的传播。
Although mitochondrial DNA (mtDNA) is prone to mutation and few mtDNA repair mechanisms exist(1), crippling mitochondrial mutations are exceedingly rare(2). Recent studies have demonstrated strong purifying selection in the mouse female germline(3,4). However, the mechanisms underlying positive selection of healthy mitochondria remain to be elucidated. We visualized mtDNA replication during Drosophila melanogaster oogenesis, finding that mtDNA replication commenced before oocyte determination during the late germarium stage and was dependent on mitochondrial fitness. We isolated a temperature- sensitive lethal mtDNA allele, mt:CoIT300I, which resulted in reduced mtDNA replication in the germarium at the restrictive temperature. Additionally, the frequency of the mt:CoIT300I allele in heteroplasmic flies was decreased, both during oogenesis and over multiple generations, at the restrictive temperature. Furthermore, we determined that selection against mt:CoIT300I overlaps with the timing of selective replication of mtDNA in the germarium. These findings establish a previously uncharacterized developmental mechanism for the selective amplification of wild-type mtDNA, which may be evolutionarily conserved to limit the transmission of deleterious mutations.