Background sequence characteristics influence the occurrence and severity of disease-causing mtDNA mutations
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.3460A<G, m.11778A>G) 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.
Vyšlo v časopise:
Background sequence characteristics influence the occurrence and severity of disease-causing mtDNA mutations. PLoS Genet 13(12): e32767. doi:10.1371/journal.pgen.1007126
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1007126
Souhrn
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.3460A<G, m.11778A>G) 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.
Zdroje
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Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2017 Číslo 12
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