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Site-specific selection reveals selective constraints and functionality of tumor somatic mtDNA mutations.

ABSTRACT: 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.To test our hypothesis, we developed the largest collection of tumor mtDNA mutations to date and evaluated how natural selection shaped mtDNA mutation patterns.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 rate (mutation number in a region/region bp length) 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 rate of most codons and amino acids were consistent with the expectation under neutrality, several codons and amino acids had significantly different rates. Moreover, the mutations under selection were enriched for changes that are predicted to be deleterious, further supporting the evolutionary constraints on these regions.These results indicate the existence of site-specific selection and imply the important role of the mtDNA mutations at some specific sites in tumor development.

SUBMITTER: Li D

PROVIDER: S-EPMC5704541 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Site-specific selection reveals selective constraints and functionality of tumor somatic mtDNA mutations.

Li Deyang D Du Xiaohong X Guo Xu X Zhan Lei L Li Xin X Yin Chun C Chen Cheng C Li Mingkun M Li Bingshan B Yang Hushan H Xing Jinliang J

Journal of experimental & clinical cancer research : CR 20171128 1

<h4>Background</h4>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.<h4>Methods</h4>To test our hypothesis, we developed the largest collection of tumor mtDNA mutations to date and evaluated how natural selection shaped mtDNA mutation patterns. ...[more]

PMID: 29179728

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Project description:BackgroundMitochondrial DNA (mtDNA) codes for products necessary for electron transport and mitochondrial gene translation. mtDNA mutations can lead to human disease and influence organismal fitness. The PolG mutator mouse lacks mtDNA proofreading function and rapidly accumulates mtDNA mutations, making it a model for examining the causes and consequences of mitochondrial mutations. Premature aging in PolG mice and their physiology have been examined in depth, but the location, frequency, and diversity of their mtDNA mutations remain understudied. Identifying the locations and spectra of mtDNA mutations in PolG mice can shed light on how selection shapes mtDNA, both within and across organisms.ResultsHere, we characterized somatic and germline mtDNA mutations in brain and liver tissue of PolG mice to quantify mutation count (number of unique mutations) and frequency (mutation prevalence). Overall, mtDNA mutation count and frequency were the lowest in the D-loop, where an mtDNA origin of replication is located, but otherwise uniform across the mitochondrial genome. Somatic mtDNA mutations have a higher mutation count than germline mutations. However, germline mutations maintain a higher frequency and were also more likely to be silent. Cytosine to thymine mutations characteristic of replication errors were the plurality of basepair changes, and missense C to T mutations primarily resulted in increased protein hydrophobicity. Unlike wild type mice, PolG mice do not appear to show strand asymmetry in mtDNA mutations. Indel mutations had a lower count and frequency than point mutations and tended to be short, frameshift deletions.ConclusionsOur results provide strong evidence that purifying selection plays a major role in the mtDNA of PolG mice. Missense mutations were less likely to be passed down in the germline, and they were less likely to spread to high frequencies. The D-loop appears to have resistance to mutations, either through selection or as a by-product of replication processes. Missense mutations that decrease hydrophobicity also tend to be selected against, reflecting the membrane-bound nature of mtDNA-encoded proteins. The abundance of mutations from polymerase errors compared with reactive oxygen species (ROS) damage supports previous studies suggesting ROS plays a minimal role in exacerbating the PolG phenotype, but our findings on strand asymmetry provide discussion for the role of polymerase errors in wild type organisms. Our results provide further insight on how selection shapes mtDNA mutations and on the aging mechanisms in PolG mice.

Dataset Information

Site-specific selection reveals selective constraints and functionality of tumor somatic mtDNA mutations.

Publications

Site-specific selection reveals selective constraints and functionality of tumor somatic mtDNA mutations.

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