Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA
Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA
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DOI：
10.1073/pnas.1409328111
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发表时间：
2014-10-28
影响因子：
11.1
通讯作者：
Makova, Kateryna D.
中科院分区：
文献类型：
--
作者：
Rebolledo-Jaramillo, Boris;Su, Marcia Shu-Wei;Makova, Kateryna D.
线粒体DNA （mtDNA）疾病的表现取决于异质性（个体中存在几个等位基因）的频率，但由于缺乏关于卵子发生过程中mtDNA瓶颈大小的数据，因此无法轻易预测其跨代传播。对于有害的异质，严重的瓶颈可能会突然将母亲体内的良性（低）频率转变为其孩子体内的致病（高）频率。在这里，我们提出了一项高分辨率的异质传播研究，对39对健康的欧洲血统母子对的血液和口腔mtDNA进行了研究（总共156个样本，每个样本的测序量接近每个位点20000倍）。平均每个个体携带一种异质，每8个人中就有1个人携带一种与疾病相关的异质，小等位基因频率>= 1%。我们观察到代与代之间频繁的剧烈异质性频率转移，并估计种系mtDNA瓶颈的有效大小仅类似于30-35（四分位数范围为9至141）。考虑到异质性，我们估计mtDNA种系突变率为每年每个位点1.3 x 10(-8)（四分位数范围为4.2 x 10（-9）至4.1 x 10(-8)）突变，比核DNA高一个数量级。值得注意的是，我们发现儿童的异质数量与母亲受精时的年龄呈正相关，这可能归因于卵母细胞老化。本研究还利用液滴数字PCR （ddPCR）来验证异质体并确认新生突变。我们的研究结果可用于预测致病mtDNA变异的传播，并阐明线粒体基因组的进化动力学。
The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother-child pairs of European ancestry (a total of 156 samples, each sequenced at similar to 20,000x per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease- associated heteroplasmy, with minor allele frequency >= 1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germline mtDNA bottleneck at only similar to 30-35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 x 10(-8) (interquartile range from 4.2 x 10(-9) to 4.1 x 10(-8)) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome.