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Interpreting the dependence of mutation rates on age and time
- Source :
- PLoS Biology, Vol 14, Iss 1, p e1002355 (2016), PLoS Biology
- Publication Year :
- 2015
- Publisher :
- arXiv, 2015.
-
Abstract
- Mutations can originate from the chance misincorporation of nucleotides during DNA replication or from DNA lesions that arise between replication cycles and are not repaired correctly. We introduce a model that relates the source of mutations to their accumulation with cell divisions, providing a framework for understanding how mutation rates depend on sex, age, and cell division rate. We show that the accrual of mutations should track cell divisions not only when mutations are replicative in origin but also when they are non-replicative and repaired efficiently. One implication is that observations from diverse fields that to date have been interpreted as pointing to a replicative origin of most mutations could instead reflect the accumulation of mutations arising from endogenous reactions or exogenous mutagens. We further find that only mutations that arise from inefficiently repaired lesions will accrue according to absolute time; thus, unless life history traits co-vary, the phylogenetic “molecular clock” should not be expected to run steadily across species.<br />Modeling how the source of mutations relates to their rate of accumulation with age, sex, and number of cell divisions helps to explain perplexing observations about germline and somatic mutations.<br />Author Summary We relate how mutations arise to how they accumulate in different sexes, with age and with cell division. This model provides a single framework within which to interpret emerging results from evolutionary biology, human genetics, and cancer genetics. We show that the accrual of mutations should track cell divisions not only when mutations originate during DNA replication but also when they arise through non-replicative mechanisms and are repaired efficiently. This realization means that previous observations of correlations between mutation and cell division rates actually provide little support to the commonly held belief that most germline and somatic mutations arise from replication errors. We further find that only mutations that arise from inefficiently repaired lesions will accrue according to absolute time; thus, without covariation in life history traits, the phylogenetic “molecular clock” should not be expected to run at constant rates across species.
- Subjects :
- 0301 basic medicine
DNA Replication
Mutation rate
Aging
Time Factors
Cell division
DNA repair
DNA damage
QH301-705.5
Biology
medicine.disease_cause
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Germline mutation
Mutation Rate
Genetics
medicine
Animals
Humans
Biology (General)
Quantitative Biology - Populations and Evolution
Molecular clock
Mutation
General Immunology and Microbiology
Models, Genetic
General Neuroscience
Cells--Growth--Mathematical models
DNA replication
Populations and Evolution (q-bio.PE)
Mutation (Biology)
030104 developmental biology
FOS: Biological sciences
Cytology
General Agricultural and Biological Sciences
Cell Division
Research Article
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- PLoS Biology, Vol 14, Iss 1, p e1002355 (2016), PLoS Biology
- Accession number :
- edsair.doi.dedup.....5399d455c216a787093296b84834a82c
- Full Text :
- https://doi.org/10.48550/arxiv.1507.06890