Department of Biology, Northeastern University, Boston, MA 02115, USA.
Wellcome Centre for Mitochondrial Research and Institute for Translational and Clinical Research, Newcastle University and Newcastle Medical School, Newcastle-upon-Tyne NE2 4HH, UK.
Hum Mol Genet. 2022 Nov 28;31(23):4075-4086. doi: 10.1093/hmg/ddac149.
The A-to-G point mutation at position 3243 in the human mitochondrial genome (m.3243A > G) is the most common pathogenic mtDNA variant responsible for disease in humans. It is widely accepted that m.3243A > G levels decrease in blood with age, and an age correction representing ~ 2% annual decline is often applied to account for this change in mutation level. Here we report that recent data indicate that the dynamics of m.3243A > G are more complex and depend on the mutation level in blood in a bi-phasic way. Consequently, the traditional 2% correction, which is adequate 'on average', creates opposite predictive biases at high and low mutation levels. Unbiased age correction is needed to circumvent these drawbacks of the standard model. We propose to eliminate both biases by using an approach where age correction depends on mutation level in a biphasic way to account for the dynamics of m.3243A > G in blood. The utility of this approach was further tested in estimating germline selection of m.3243A > G. The biphasic approach permitted us to uncover patterns consistent with the possibility of positive selection for m.3243A > G. Germline selection of m.3243A > G shows an 'arching' profile by which selection is positive at intermediate mutant fractions and declines at high and low mutant fractions. We conclude that use of this biphasic approach will greatly improve the accuracy of modelling changes in mtDNA mutation frequencies in the germline and in somatic cells during aging.
位于人类线粒体基因组（m.3243A > G）位置 3243 的 A 到 G 点突变是最常见的致病性 mtDNA 变体，导致人类疾病。人们普遍认为，随着年龄的增长，血液中的 m.3243A > G 水平会降低，并且通常应用年龄校正来表示约 2%的每年下降，以解释这种突变水平的变化。在这里，我们报告说，最近的数据表明，m.3243A > G 的动态更为复杂，并且以双相方式依赖于血液中的突变水平。因此，传统的 2%校正虽然平均而言是充分的，但在高突变水平和低突变水平下会产生相反的预测偏差。需要进行无偏的年龄校正以避免标准模型的这些缺陷。我们建议通过使用一种方法来消除这些偏差，该方法以双相方式使年龄校正取决于突变水平，以解释血液中 m.3243A > G 的动态。这种方法的实用性进一步通过估计 m.3243A > G 的种系选择来测试。双相方法使我们能够发现与 m.3243A > G 的正选择可能性一致的模式。m.3243A > G 的种系选择表现出“拱形”模式，其中在中间突变分数下选择是阳性的，而在高和低突变分数下选择则下降。我们得出结论，使用这种双相方法将大大提高建模生殖系和体细胞中线粒体 DNA 突变频率随年龄变化的准确性。
