Interference of nuclear mitochondrial DNA segments in mitochondrial DNA testing resembles biparental transmission of mitochondrial DNA in humans
Interference of nuclear mitochondrial DNA segments in mitochondrial DNA testing resembles biparental transmission of mitochondrial DNA in humans
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DOI：
10.1038/s41436-021-01166-1
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发表时间：
2021-04-12
影响因子：
8.8
通讯作者：
Suchy, Sharon F.
中科院分区：
文献类型：
--
作者：
Bai, Renkui;Cui, Hong;Suchy, Sharon F.
有报道质疑人类线粒体DNA （mtDNA）的纯母系遗传教条，包括最近在来自三个多代家庭的个体中发现两个mtDNA单倍群的混合。这被解释为与常染色体显性样模式的双代mtDNA遗传一致。这些发现的真实性和频率存在争议。方法回顾性分析2017 - 2019年2个mtDNA单倍群的个体，选择4个家族进行进一步研究。结果我们在104/27,388（约1/263）个不相关个体中发现了这种现象。进一步研究表明：(1)具有两个线粒体单倍群的雄性只将其中一个单倍群遗传给其后代，与核遗传一致；(2)父系遗传变异的异质性水平在同一个体的血液中最高，在口腔中较低，在肌肉或尿液中不存在，表明其与mtDNA含量呈负相关；(3)父系传播的明显的大规模mtDNA缺失/重复与疾病表型无关。结论这些发现有力地表明，观察到的来自父系起源的线粒体单倍群是在检测过程中，罕见的、连接的核mtDNA片段与真正的mtDNA共扩增所致。对其他标本类型的评估有助于阐明观察结果的临床意义。
Purpose Reports have questioned the dogma of exclusive maternal transmission of human mitochondrial DNA (mtDNA), including the recent report of an admixture of two mtDNA haplogroups in individuals from three multigeneration families. This was interpreted as being consistent with biparental transmission of mtDNA in an autosomal dominant-like mode. The authenticity and frequency of these findings are debated. Methods We retrospectively analyzed individuals with two mtDNA haplogroups from 2017 to 2019 and selected four families for further study. Results We identified this phenomenon in 104/27,388 (approximately 1/263) unrelated individuals. Further study revealed (1) a male with two mitochondrial haplogroups transmits only one haplogroup to some of his offspring, consistent with nuclear transmission; (2) the heteroplasmy level of paternally transmitted variants is highest in blood, lower in buccal, and absent in muscle or urine of the same individual, indicating it is inversely correlated with mtDNA content; and (3) paternally transmitted apparent large-scale mtDNA deletions/duplications are not associated with a disease phenotype. Conclusion These findings strongly suggest that the observed mitochondrial haplogroup of paternal origin resulted from coamplification of rare, concatenated nuclear mtDNA segments with genuine mtDNA during testing. Evaluation of additional specimen types can help clarify the clinical significance of the observed results.