O'Keefe Hannah, Queen Rachel, Lord Phillip, Elson Joanna L
Institute of Genetic Medicine Newcastle University Newcastle-upon-Tyne UK.
School of Computing Newcastle University Newcastle-upon-Tyne UK.
Evol Appl. 2019 Aug 27;12(10):1912-1930. doi: 10.1111/eva.12851. eCollection 2019 Dec.
Mitochondrial disorders are heterogeneous, showing variable presentation and penetrance. Over the last three decades, our ability to recognize mitochondrial patients and diagnose these mutations, linking genotype to phenotype, has greatly improved. However, it has become increasingly clear that these strides in diagnostics have not benefited all population groups. Recent studies have demonstrated that patients from genetically understudied populations, in particular those of black African heritage, are less likely to receive a diagnosis of mtDNA disease. It has been suggested that haplogroup context might influence the presentation and penetrance of mtDNA disease; thus, the spectrum of mutations that are associated with disease in different populations. However, to date there is only one well-established example of such an effect: the increased penetrance of two Leber's hereditary optic neuropathy mutations on a haplogroup J background. This paper conducted the most extensive investigation to date into the importance of haplogroup context on the pathogenicity of mtDNA mutations. We searched for proven human point mutations across 726 multiple sequence alignments derived from 33 non-human species absent of disease. A total of 58 pathogenic point mutations arise in the sequences of these species. We assessed the sequence context and found evidence of population variants that could modulate the phenotypic expression of these point mutations masking the pathogenic effects seen in humans. This supports the theory that sequence context is influential in the presentation of mtDNA disease and has implications for diagnostic practices. We have shown that our current understanding of the pathogenicity of mtDNA point mutations, primarily built on studies of individuals with haplogroups HVUKTJ, will not present a complete picture. This will have the effect of creating a diagnostic inequality, whereby individuals who do not belong to these lineages are less likely to receive a genetic diagnosis.
线粒体疾病具有异质性，表现出可变的临床表现和外显率。在过去三十年中，我们识别线粒体疾病患者并诊断这些突变、将基因型与表型联系起来的能力有了很大提高。然而，越来越明显的是，这些诊断方面的进展并未惠及所有人群。最近的研究表明，来自基因研究较少人群的患者，特别是那些有非洲黑人血统的患者，被诊断为线粒体DNA疾病的可能性较小。有人提出，单倍群背景可能会影响线粒体DNA疾病的表现和外显率；因此，不同人群中与疾病相关的突变谱也会不同。然而，迄今为止，只有一个这样的效应得到了充分证实的例子：在单倍群J背景下，两种Leber遗传性视神经病变突变的外显率增加。本文对单倍群背景对线粒体DNA突变致病性的重要性进行了迄今为止最广泛的研究。我们在来自33种无疾病的非人类物种的726个多序列比对中搜索已证实的人类点突变。在这些物种的序列中总共出现了58个致病点突变。我们评估了序列背景，发现了可能调节这些点突变表型表达的群体变异证据，从而掩盖了在人类中看到的致病效应。这支持了序列背景对线粒体DNA疾病表现有影响的理论，并对诊断实践有启示意义。我们已经表明，我们目前对线粒体DNA点突变致病性的理解主要基于对单倍群HVUKTJ个体的研究，并不全面。这将导致诊断不平等，即不属于这些谱系的个体获得基因诊断的可能性较小。
