PDF(Pubmed)
Abstract：
Genetic screens have been used extensively to probe interactions between nuclear genes and their impact on phenotypes. Probing interactions between mitochondrial genes and their phenotypic outcome, however, has not been possible due to a lack of tools to map the responsible polymorphisms. Here, using a toolkit we previously established in Drosophila, we isolate over 300 recombinant mitochondrial genomes and map a naturally occurring polymorphism at the cytochrome c oxidase III residue 109 (CoIII109) that fully rescues the lethality and other defects associated with a point mutation in cytochrome c oxidase I (CoIT300I). Through lipidomics profiling, biochemical assays and phenotypic analyses, we show that the CoIII109 polymorphism modulates cardiolipin binding to prevent complex IV instability caused by the CoIT300I mutation. This study demonstrates the feasibility of genetic interaction screens in animal mitochondrial DNA. It unwraps the complex intra-genomic interplays underlying disorders linked to mitochondrial DNA and how they influence disease expression.
摘要：
遗传筛选已被广泛用于探测核基因之间的相互作用及其对表型的影响。探索线粒体基因之间的相互作用及其表型结果，然而,由于缺乏工具来绘制负责任的多态性，这是不可能的。这里,使用我们以前在果蝇中建立的工具包，我们分离了300多个重组线粒体基因组，并在细胞色素c氧化酶III残基109（CoIII109）上绘制了天然存在的多态性，该多态性完全挽救了与细胞色素c氧化酶I（CoIT300I）中的点突变相关的致死性和其他缺陷。通过脂质组学分析，生化测定和表型分析，我们显示CoIII109多态性调节心磷脂结合,以防止由CoIT300I突变引起的复合物IV不稳定.这项研究证明了在动物线粒体DNA中进行遗传相互作用筛选的可行性。它揭示了与线粒体DNA相关的潜在疾病的复杂基因组内相互作用以及它们如何影响疾病表达。
