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
1. Stewart JB, Chinnery PF. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat Rev Genet. 2015;16(9):530–42. doi: 10.1038/nrg3966 26281784.
2. DiMauro S, Schon EA, Carelli V, Hirano M. The clinical maze of mitochondrial neurology. Nat Rev Neurol. 2013;9(8):429–44. doi: 10.1038/nrneurol.2013.126 23835535; PubMed Central PMCID: PMCPMC3959773.
3. Brown MD, Torroni A, Reckord CL, Wallace DC. Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations. Hum Mutat. 1995;6(4):311–25. doi: 10.1002/humu.1380060405 8680405.
4. Hudson G, Carelli V, Spruijt L, Gerards M, Mowbray C, Achilli A, et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet. 2007;81(2):228–33. doi: 10.1086/519394 17668373; PubMed Central PMCID: PMCPMC1950812.
5. Torroni A, Campos Y, Rengo C, Sellitto D, Achilli A, Magri C, et al. Mitochondrial DNA haplogroups do not play a role in the variable phenotypic presentation of the A3243G mutation. Am J Hum Genet. 2003;72(4):1005–12. doi: 10.1086/373936 12612863; PubMed Central PMCID: PMCPMC1180329.
6. van Oven M, Kayser M. Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum Mutat. 2009;30(2):E386–94. doi: 10.1002/humu.20921 18853457.
7. Weissensteiner H, Pacher D, Kloss-Brandstatter A, Forer L, Specht G, Bandelt HJ, et al. HaploGrep 2: mitochondrial haplogroup classification in the era of high-throughput sequencing. Nucleic Acids Res. 2016;44(W1):W58–63. doi: 10.1093/nar/gkw233 27084951; PubMed Central PMCID: PMCPMC4987869.
8. Hudson G, Panoutsopoulou K, Wilson I, Southam L, Rayner NW, Arden N, et al. No evidence of an association between mitochondrial DNA variants and osteoarthritis in 7393 cases and 5122 controls. Ann Rheum Dis. 2013;72(1):136–9. doi: 10.1136/annrheumdis-2012-201932 22984172; PubMed Central PMCID: PMCPMC3551219.
9. Ruiz-Pesini E, Mishmar D, Brandon M, Procaccio V, Wallace DC. Effects of purifying and adaptive selection on regional variation in human mtDNA. Science. 2004;303(5655):223–6. doi: 10.1126/science.1088434 14716012.
10. Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF. Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet. 2008;83(2):254–60. doi: 10.1016/j.ajhg.2008.07.004 18674747; PubMed Central PMCID: PMCPMC2495064.
11. Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44(D1):D862–8. doi: 10.1093/nar/gkv1222 26582918; PubMed Central PMCID: PMCPMC4702865.
12. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21. doi: 10.1038/nature12477 23945592; PubMed Central PMCID: PMCPMC3776390.
13. Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA [letter]. Nat Genet. 1999;23(2):147. doi: 10.1038/13779 10508508
14. Behar DM, van Oven M, Rosset S, Metspalu M, Loogvali EL, Silva NM, et al. A "Copernican" reassessment of the human mitochondrial DNA tree from its root. Am J Hum Genet. 2012;90(4):675–84. doi: 10.1016/j.ajhg.2012.03.002 22482806; PubMed Central PMCID: PMCPMC3322232.
15. Liu B, Du Q, Chen L, Fu G, Li S, Fu L, et al. CpG methylation patterns of human mitochondrial DNA. Scientific reports. 2016;6:23421. Epub 2016/03/22. doi: 10.1038/srep23421 26996456; PubMed Central PMCID: PMCPMC4800444.
16. Tang WW, Dietmann S, Irie N, Leitch HG, Floros VI, Bradshaw CR, et al. A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development. Cell. 2015;161(6):1453–67. doi: 10.1016/j.cell.2015.04.053 26046444; PubMed Central PMCID: PMCPMC4459712.
17. Ren L, Zhang C, Tao L, Hao J, Tan K, Miao K, et al. High-resolution profiles of gene expression and DNA methylation highlight mitochondrial modifications during early embryonic development. J Reprod Dev. 2017;63(3):247–61. Epub 2017/04/04. doi: 10.1262/jrd.2016-168 28367907; PubMed Central PMCID: PMCPMC5481627.
18. Forster P, Harding R, Torroni A, Bandelt HJ. Origin and evolution of Native American mtDNA variation: a reappraisal. Am J Hum Genet. 1996;59(4):935–45. 8808611; PubMed Central PMCID: PMCPMC1914796.
19. Cox MP. Accuracy of molecular dating with the rho statistic: deviations from coalescent expectations under a range of demographic models. 2008. Hum Biol. 2009;81(5–6):911–33. Epub 2010/05/28. doi: 10.3378/027.081.0631 20504206.
20. McFarland R, Elson JL, Taylor RW, Howell N, Turnbull DM. Assigning pathogenicity to mitochondrial tRNA mutations: when "definitely maybe" is not good enough. Trends Genet. 2004;20(12):591–6. doi: 10.1016/j.tig.2004.09.014 15522452.
21. Rubino F, Piredda R, Calabrese FM, Simone D, Lang M, Calabrese C, et al. HmtDB, a genomic resource for mitochondrion-based human variability studies. Nucleic Acids Res. 2012;40(Database issue):D1150–9. doi: 10.1093/nar/gkr1086 22139932; PubMed Central PMCID: PMCPMC3245114.
22. Stewart JB, Freyer C, Elson JL, Wredenberg A, Cansu Z, Trifunovic A, et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol. 2008;6(1):e10. doi: 10.1371/journal.pbio.0060010 18232733; PubMed Central PMCID: PMCPMC2214808.
23. Howell N, Elson JL, Howell C, Turnbull DM. Relative rates of evolution in the coding and control regions of African mtDNAs. Mol Biol Evol. 2007;24(10):2213–21. Epub 2007/07/24. doi: 10.1093/molbev/msm147 17642471.
24. Posth C, Renaud G, Mittnik A, Drucker DG, Rougier H, Cupillard C, et al. Pleistocene Mitochondrial Genomes Suggest a Single Major Dispersal of Non-Africans and a Late Glacial Population Turnover in Europe. Curr Biol. 2016;26(6):827–33. Epub 2016/02/09. doi: 10.1016/j.cub.2016.01.037 26853362.
25. Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet. 1999;23(2):147. doi: 10.1038/13779 10508508.
26. Li B, Krishnan VG, Mort ME, Xin F, Kamati KK, Cooper DN, et al. Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics. 2009;25(21):2744–50. doi: 10.1093/bioinformatics/btp528 19734154; PubMed Central PMCID: PMCPMC3140805.
27. Pereira L, Freitas F, Fernandes V, Pereira JB, Costa MD, Costa S, et al. The diversity present in 5140 human mitochondrial genomes. Am J Hum Genet. 2009;84(5):628–40. doi: 10.1016/j.ajhg.2009.04.013 19426953; PubMed Central PMCID: PMCPMC2681004.
Štítky
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PLOS Genetics
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