MtDNA segregation in heteroplasmic tissues is common in vivo and modulated by haplotype differences and developmental stage.
MtDNA segregation in heteroplasmic tissues is common in vivo and modulated by haplotype differences and developmental stage.
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DOI：
10.1016/j.celrep.2014.05.020
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发表时间：
2014-06-26
期刊：
影响因子：
8.8
通讯作者：
Brem G
中科院分区：
文献类型：
--
作者：
Burgstaller JP;Johnston IG;Jones NS;Albrechtová J;Kolbe T;Vogl C;Futschik A;Mayrhofer C;Klein D;Sabitzer S;Blattner M;Gülly C;Poulton J;Rülicke T;Piálek J;Steinborn R;Brem G
线粒体DNA（mtDNA）在生物体内进化的动力学仍然知之甚少，尽管突变mtDNA的遗传和增殖会导致致命和不治之症。当一个细胞中存在两种mtDNA单倍型时，通常认为分离（一种单倍型相对于另一种单倍型的增殖）是可以忽略的。我们挑战这一假设表明，分离取决于单倍型之间的遗传距离。我们通过创建四个新的小鼠模型，包含不同多样性的mtDNA单倍型对提供证据。我们发现在所有模型中的组织特异性隔离在广泛的组织。关键发现是有丝分裂后组织的分离（对疾病模型很重要），以及从产前到老年的所有发育阶段的分离。我们确定了四个新的动态机制的mtDNA分离。我们建议“单倍型匹配”作为一种手段，以避免并发症的治疗，在人类群体中，我们的研究结果暗示。
The dynamics by which mitochondrial DNA (mtDNA) evolves within organisms are still poorly understood, despite the fact that inheritance and proliferation of mutated mtDNA causes fatal and incurable diseases. When two mtDNA haplotypes are present in a cell, it is usually assumed that segregation (the proliferation of one haplotype over another) is negligible. We challenge this assumption showing that segregation depends on the genetic distance between haplotypes. We provide evidence by creating four new mouse models containing mtDNA haplotype pairs of varying diversity. We find tissue-specific segregation in all models over a wide range of tissues. Key findings are segregation in post mitotic tissues (important for disease models), and segregation covering all developmental stages from prenatal up to old age. We identify four new dynamic regimes of mtDNA segregation. We suggest “haplotype matching” as a means to avoid complications for therapies in human populations that our findings imply.