National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China.
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410008, China.
Hum Mol Genet. 2022 Jun 4;31(11):1747-1761. doi: 10.1093/hmg/ddab358.
Increasing evidences suggest that mitochondrial dysfunction is implicated in diseases and aging, and whole-genome sequencing (WGS) is the most unbiased method in analyzing the mitochondrial genome (mtDNA). However, the genetic landscape of mtDNA in the Chinese population has not been fully examined. Here, we described the genetic landscape of mtDNA using WGS data from Chinese individuals (n = 3241). We identified 3892 mtDNA variants, of which 3349 (86%) were rare variants. Interestingly, we observed a trend toward extreme heterogeneity of mtDNA variants. Our study observed a distinct purifying selection on mtDNA, which inhibits the accumulation of harmful heteroplasmies at the individual level: (1) mitochondrial dN/dS ratios were much <1; (2) the dN/dS ratio of heteroplasmies was higher than homoplasmies; (3) heteroplasmies had more indels and predicted deleterious variants than homoplasmies. Furthermore, we found that haplogroup M (20.27%) and D (20.15%) had the highest frequencies in the Chinese population, followed by B (18.51%) and F (16.45%). The number of variants per individual differed across haplogroup groups, with a higher number of homoplasmies for the M lineage. Meanwhile, mtDNA copy number was negatively correlated with age but positively correlated with the female sex. Finally, we developed an mtDNA variation database of Chinese populations called MTCards (http://genemed.tech/mtcards/) to facilitate the query of mtDNA variants in this study. In summary, these findings contribute to different aspects of understanding mtDNA, providing a better understanding of the genetic basis of mitochondrial-related diseases.
越来越多的证据表明，线粒体功能障碍与疾病和衰老有关，全基因组测序（WGS）是分析线粒体基因组（mtDNA）最公正的方法。然而，中国人 mtDNA 的遗传图谱尚未得到充分研究。在这里，我们使用中国人（n=3241）的 WGS 数据描述了 mtDNA 的遗传图谱。我们确定了 3892 个 mtDNA 变体，其中 3349 个（86%）为罕见变体。有趣的是，我们观察到 mtDNA 变体的极端异质性趋势。我们的研究观察到 mtDNA 存在明显的纯化选择，抑制了个体水平有害异质体的积累：（1）线粒体 dN/dS 比值远<1；（2）异质体的 dN/dS 比值高于同质体；（3）异质体比同质体具有更多的插入和预测的有害变体。此外，我们发现中国人中 haplogroup M（20.27%）和 D（20.15%）的频率最高，其次是 B（18.51%）和 F（16.45%）。个体之间的变体数量因 haplogroup 群体而异，M 谱系的同质体数量更多。同时，mtDNA 拷贝数与年龄呈负相关，与女性呈正相关。最后，我们开发了一个中国人 mtDNA 变异数据库，称为 MTCards（http://genemed.tech/mtcards/），以方便查询本研究中的 mtDNA 变异。总之，这些发现有助于从不同方面理解 mtDNA，为线粒体相关疾病的遗传基础提供了更好的理解。
