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Site-Specific Selection Reveals Evolutional Constraints and Functionality of Tumor Somatic mtdna mutations

Site-Specific Selection Reveals Evolutional Constraints and ...

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2017年中国肿瘤标志物学术大会暨第十一届肿瘤标志物青...

作者： Deyang Li Xu guo Chun Yin Jinliang Xing State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine Fourth Military Medical University

Background: Previous studies have indicated that tumor mitochondrial DNA（mtdna） mutations are primarily shaped by relaxed negative selection, which is contradictory to the critical roles of mtdna mutations in tumorigenesis. Therefore, we hypothesized that site-specific selection may influence tumor mtdna mutations. Methods: To test our hypothesis, we developed the largest collection of tumor mtdna mutations to date and evaluated how natural selection shaped mtdna mutation patterns. Results: Our data demonstrated that both positive and negative selections acted on specific positions or functional units of tumor mtdnas, although the landscape of these mutations was consistent with the relaxation of negative selection. In particular, mutation frequencies in complex V and tRNA coding regions, especially in ATP8 within complex V and in loop and variable regions within tRNA, were significantly lower than those in other regions. While the mutation frequencies of most codons and amino acids were consistent with the expectation under neutrality, several codons and amino acids had significantly different frequencies. Moreover, the mutations under selection were enriched for changes that are predicted to be deleterious, further supporting the evolutionary constraints on these regions. Conclusions: In conclusion, these results indicate the existence of site-specific selection and imply the important role of mtdna mutations in tumor development.

关键词： mtdna mutation tumorigenesis site-specific selection

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