Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan.
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan.
Commun Biol. 2020 Mar 5;3(1):104. doi: 10.1038/s42003-020-0812-9.
The genetic landscape of mitochondrial DNA (mtDNA) has been elusive. By analyzing mtDNA using the whole genome sequence (WGS) of Japanese individuals (n = 1928), we identified 2023 mtDNA variants and high-resolution haplogroups. Frequency spectra of the haplogroups were population-specific and were heterogeneous among geographic regions within Japan. Application of machine learning methods could finely classify the subjects corresponding to the high-digit mtDNA sub-haplogroups. mtDNA had distinct genetic structures from that of nuclear DNA (nDNA), characterized by no distance-dependent linkage disequilibrium decay, sparse tagging of common variants, and the existence of common haplotypes spanning the entire mtDNA. We did not detect any evidence of mtDNA-nDNA (or mtDNA copy number-nDNA) genotype associations. Together with WGS-based mtDNA variant imputation, we conducted a phenome-wide association study of 147,437 Japanese individuals with 99 clinical phenotypes. We observed pleiotropy of mtDNA genetic risk on the five late-onset human complex traits including creatine kinase (P = 1.7 × 10).
线粒体 DNA（mtDNA）的遗传景观一直难以捉摸。通过对 1928 名日本个体的全基因组序列（WGS）进行 mtDNA 分析，我们鉴定出 2023 种 mtDNA 变体和高分辨率单倍群。单倍群的频率谱具有种群特异性，在日本内部的地理区域之间存在异质性。机器学习方法的应用可以对对应于高数位 mtDNA 亚单倍群的对象进行精细分类。mtDNA 的遗传结构与核 DNA（nDNA）明显不同，其特征为没有距离依赖性连锁不平衡衰减、常见变异的稀疏标记以及跨越整个 mtDNA 的常见单倍型的存在。我们没有检测到任何 mtDNA-nDNA（或 mtDNA 拷贝数-nDNA）基因型关联的证据。结合基于 WGS 的 mtDNA 变体推断，我们对 147437 名日本个体的 99 种临床表型进行了全基因组关联研究。我们观察到 mtDNA 遗传风险在包括肌酸激酶在内的 5 种晚发性人类复杂特征上的多效性（P=1.7×10）。
