Evidence from human oocytes for a genetic bottleneck in an mtDNA disease
Evidence from human oocytes for a genetic bottleneck in an mtDNA disease
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DOI：
10.1086/302009
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发表时间：
1998-09-01
影响因子：
9.8
通讯作者：
Poulton, J
中科院分区：
文献类型：
--
作者：
Marchington, DR;Macaulay, V;Poulton, J
我们检查了一个由mtDNA重排引起的Kearn-Sayre综合征患者的卵母细胞。在mtDNA疾病中，突变型和野生型mtDNA经常在受影响的个体中共存（异质性的条件）。由于遗传瓶颈，突变mtDNA从母亲传给后代的比例是可变的，并且突变mtDNA的“剂量”影响表型的严重程度。产前诊断的可行性关键取决于这一瓶颈的性质和时机。通过使用多重PCR，在大多数患者的卵母细胞中可检测到显著水平的重排mtDNA，在单个卵母细胞之间，突变体和野生型分子的水平存在很大差异。我们还使用了长度变化的同源聚合物C道，这往往是异质性的正常对照，以确定创始人亚群的mtDNA在这个病人的卵母细胞。我们提出的直接证据表明，在人类女性卵母细胞中，分离单位（n）的数量比线粒体的数量少三到五个数量级。在某些情况下，它的最佳估计可能对应于一个单一的染色体，如果它被假定为mtDNA的代际传递可以被视为一个单一的采样事件。瓶颈似乎有助于从母亲到卵母细胞的变量传输的主要组成部分，在这个病人和控制。这一瓶颈在卵母细胞成熟时已经发生，这为mtDNA疾病的产前诊断提供了前景。
We have examined oocytes from a patient with Kearn-Sayre syndrome caused by mtDNA rearrangements. In mtDNA diseases, mutant and wild-type mtDNA frequently coexist in affected individuals (the condition of heteroplasmy). The proportion of mutant mtDNA transmitted from mother to offspring is variable because of a genetic bottleneck, and the "dose" of mutant mtDNA received influences the severity of the phenotype. The feasibility of prenatal diagnosis is critically dependent on the nature and timing of this bottleneck. Significant levels of rearranged mtDNA were detectable in the majority of the patient's oocytes, by use of multiplex PCR, with wide variation, in the levels of mutant and wildtype molecules, between individual oocytes. We also used length variation in a homopolymeric C tract, which is often heteroplasmic in normal controls, to identify founder subpopulations of mtDNAs in this patient's oocytes. We present direct evidence that the number of segregating units (n) is three to five orders of magnitude less than the number of mitochondria in the human female oocyte. In some cases, the best estimate of it may correspond to a single mitochondrion, if it is assumed that intergenerational transmission of mtDNA can be treated as a single sampling event. The bottleneck appears to contribute a major component of the variable transmission from mother to oocyte, in this patient and in a control. That this bottleneck had occurred by the time that oocytes were mature advances the prospects for prenatal diagnosis of mtDNA diseases.