Background sequence characteristics influence the occurrence and severity of disease-causing mtDNA mutations

Inherited mitochondrial DNA (mtDNA) mutations have emerged as a common cause of human disease, with mutations occurring multiple times in the world population. The clinical presentation of three pathogenic mtDNA mutations is strongly associated with a background mtDNA haplogroup, but it is not clear whether this is limited to a handful of examples or is a more general phenomenon. To address this, we determined the characteristics of 30,506 mtDNA sequences sampled globally. After performing several quality control steps, we ascribed an established pathogenicity score to the major alleles for each sequence. The mean pathogenicity score for known disease-causing mutations was significantly different between mtDNA macro-haplogroups. Several mutations were observed across all haplogroup backgrounds, whereas others were only observed on specific clades. In some instances this reflected a founder effect, but in others, the mutation recurred but only within the same phylogenetic cluster. Sequence diversity estimates showed that disease-causing mutations were more frequent on young sequences, and genomes with two or more disease-causing mutations were more common than expected by chance. These findings implicate the mtDNA background more generally in recurrent mutation events that have been purified through natural selection in older populations. This provides an explanation for the low frequency of mtDNA disease reported in specific ethnic groups.Author summary: MtDNA mutations are a major cause of genetic disease. Many of these variants have recurred several times in different populations and on diverse haplogroup backgrounds, but the clinical presentation of mutations causing Leber Hereditary Optic Neuropathy (LHON: m.14484T>C, m.3460G>A, m.11778G>A) are strongly associated with a specific mtDNA haplogroup. This raises the possibility that many pathogenic mtDNA mutations are subject to the same effects. Here, our analysis of 30,506 human mtDNA sequences shows that the association between disease-causing mtDNA mutations and background mtDNA haplogroups is not only restricted to three disease-causing mtDNA mutations known to cause LHON. The frequent recurrence of the same mutations on a population clade, and the reduced frequency of European mtDNAs harboring two or more diseases-causing mutations, suggest that the population mtDNA background influences the risk of developing mtDNA mutations. Our analysis also shows that disease-causing mtDNA mutations also occur more frequently on younger mtDNAs. This implies that, once formed, the mutations are selected against. These findings indicate that the clinical interpretation of mtDNA variants should be performed within an ethnogeographic context.