Mutation signatures in germline mitochondrial genome provide insights into human mitochondrial evolution and disease
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Variations in mitochondrial DNA (mtDNA) have been fundamental for understanding human evolution and are causative for a plethora of inherited mitochondrial diseases, but the mutation signatures of germline mtDNA and their value in understanding mitochondrial pathogenicity remain unknown. Here, we carried out a systematic analysis of mutation patterns in germline mtDNA based on 97,566 mtDNA variants from 45,494 full-length sequences and revealed a highly non-stochastic and replication-coupled mutation signature characterized by nucleotide-specific mutation pressure (G > T>A > C) and position-specific selection pressure, suggesting the existence of an intensive mutation–selection interplay in germline mtDNA. We provide evidence that this mutation–selection interplay has strongly shaped the mtDNA sequence during evolution, which not only manifests as an oriented alteration of amino acid compositions of mitochondrial encoded proteins, but also explains the long-lasting mystery of CpG depletion in mitochondrial genome. Finally, we demonstrated that these insights may be integrated to better understand the pathogenicity of disease-implicated mitochondrial variants.
We are grateful to Prof. Tielin Yang, Prof. Xiaogang Liu (Xi’an Jiaotong University), Prof. Jianhua Zheng (Zhengzhou University), and Prof. Douglas C. Wallace (Children’s Hospital of Philadelphia) for helpful discussions and critical reading of the manuscript. This work was supported by the Fundamental Research Funds for the Central Universities (to XG), the Scientific Research Foundation for Returned Scholars of Shaanxi Province (to XG), the National Basic Research Program (973 Project 2015CB553602 to JL), and the National Natural Science Foundation of China (91649106, 31770917, 31570777 to JL).
XG conceived the idea, designed the research, performed the analysis, analyzed data, and wrote the paper; XK analyzed the data, JL analyzed the data and co-wrote the paper. All authors reviewed the manuscript.
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Conflict of interest
The authors declare no competing financial interests.
- Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjord JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jager N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, Lopez-Otin C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdes-Mas R, van Buuren MM, van Veer L, Vincent-Salomon A, Waddell N, Yates LR, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR (2013) Signatures of mutational processes in human cancer. Nature 500:415–421. https://doi.org/10.1038/nature12477 CrossRefGoogle Scholar
- Faith JJ, Pollock DD (2003) Likelihood analysis of asymmetrical mutation bias gradients in vertebrate mitochondrial genomes. Genetics 165:735–745Google Scholar
- Floros VI, Pyle A, Dietmann S, Wei W, Tang WCW, Irie N, Payne B, Capalbo A, Noli L, Coxhead J, Hudson G, Crosier M, Strahl H, Khalaf Y, Saitou M, Ilic D, Surani MA, Chinnery PF (2018) Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos. Nat Cell Biol 20:144–151. https://doi.org/10.1038/s41556-017-0017-8 CrossRefGoogle Scholar
- Ju YS, Alexandrov LB, Gerstung M, Martincorena I, Nik-Zainal S, Ramakrishna M, Davies HR, Papaemmanuil E, Gundem G, Shlien A, Bolli N, Behjati S, Tarpey PS, Nangalia J, Massie CE, Butler AP, Teague JW, Vassiliou GS, Green AR, Du MQ, Unnikrishnan A, Pimanda JE, Teh BT, Munshi N, Greaves M, Vyas P, El-Naggar AK, Santarius T, Collins VP, Grundy R, Taylor JA, Hayes DN, Malkin D, Foster CS, Warren AY, Whitaker HC, Brewer D, Eeles R, Cooper C, Neal D, Visakorpi T, Isaacs WB, Bova GS, Flanagan AM, Futreal PA, Lynch AG, Chinnery PF, McDermott U, Stratton MR, Campbell PJ (2014) Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. Elife. https://doi.org/10.7554/elife.02935 Google Scholar
- Kivisild T, Shen P, Wall DP, Do B, Sung R, Davis K, Passarino G, Underhill PA, Scharfe C, Torroni A, Scozzari R, Modiano D, Coppa A, de Knijff P, Feldman M, Cavalli-Sforza LL, Oefner PJ (2006) The role of selection in the evolution of human mitochondrial genomes. Genetics 172:373–387. https://doi.org/10.1534/genetics.105.043901 CrossRefGoogle Scholar
- Rebolledo-Jaramillo B, Su MS, Stoler N, McElhoe JA, Dickins B, Blankenberg D, Korneliussen TS, Chiaromonte F, Nielsen R, Holland MM, Paul IM, Nekrutenko A, Makova KD (2014) Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. Proc Natl Acad Sci USA 111:15474–15479. https://doi.org/10.1073/pnas.1409328111 CrossRefGoogle Scholar
- Reyes A, Gissi C, Pesole G, Saccone C (1998) Asymmetrical directional mutation pressure in the mitochondrial genome of mammals. Mol Biol Evol 15:957–966. https://doi.org/10.1093/oxfordjournals.molbev.a026011 CrossRefGoogle Scholar