Article ; Online: The mtDNA mutation spectrum in the PolG mutator mouse reveals germline and somatic selection.
BMC genomic data
2021 Volume 22, Issue 1, Page(s) 52
Abstract: Background: Mitochondrial 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 ... ...
| Abstract | Background: Mitochondrial 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. Results: Here, 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. Conclusions: Our 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. |
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| MeSH term(s) | Aging, Premature/genetics ; Animals ; DNA Mutational Analysis ; DNA Polymerase gamma/genetics ; DNA, Mitochondrial/genetics ; Germ Cells/metabolism ; Male ; Mice ; Mutation ; Reactive Oxygen Species/metabolism |
| Chemical Substances | DNA, Mitochondrial ; Reactive Oxygen Species ; DNA Polymerase gamma (EC 2.7.7.7) ; Polg protein, mouse (EC 2.7.7.7) |
| Language | English |
| Publishing date | 2021-11-26 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ISSN | 2730-6844 |
| ISSN (online) | 2730-6844 |
| DOI | 10.1186/s12863-021-01005-x |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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