Mutation signatures in germline mitochondrial genome provide insights into human mitochondrial evolution and disease

  • Xiwen GuEmail author
  • Xinyun Kang
  • Jiankang LiuEmail author
Original investigation


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).

Author contributions

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.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of StomatologyXi’an Jiaotong UniversityXi’anChina
  2. 2.Center for Mitochondrial Biology and Medicine & Douglas C. Wallace Institute for Mitochondrial and Epigenetic Information Sciences, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anChina

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