Cargando…

Population Heterogeneity in Mutation Rate Increases the Frequency of Higher-Order Mutants and Reduces Long-Term Mutational Load

Mutation rate is a crucial evolutionary parameter that has typically been treated as a constant in population genetic analyses. However, the propensity to mutate is likely to vary among co-existing individuals within a population, due to genetic polymorphisms, heterogeneous environmental influences,...

Descripción completa

Detalles Bibliográficos
Autores principales: Alexander, Helen K., Mayer, Stephanie I., Bonhoeffer, Sebastian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850754/
https://www.ncbi.nlm.nih.gov/pubmed/27836985
http://dx.doi.org/10.1093/molbev/msw244
_version_ 1783306278851837952
author Alexander, Helen K.
Mayer, Stephanie I.
Bonhoeffer, Sebastian
author_facet Alexander, Helen K.
Mayer, Stephanie I.
Bonhoeffer, Sebastian
author_sort Alexander, Helen K.
collection PubMed
description Mutation rate is a crucial evolutionary parameter that has typically been treated as a constant in population genetic analyses. However, the propensity to mutate is likely to vary among co-existing individuals within a population, due to genetic polymorphisms, heterogeneous environmental influences, and random physiological fluctuations. We review the evidence for mutation rate heterogeneity and explore its consequences by extending classic population genetic models to allow an arbitrary distribution of mutation rate among individuals, either with or without inheritance. With this general new framework, we rigorously establish the effects of heterogeneity at various evolutionary timescales. In a single generation, variation of mutation rate about the mean increases the probability of producing zero or many simultaneous mutations on a genome. Over multiple generations of mutation and selection, heterogeneity accelerates the appearance of both deleterious and beneficial multi-point mutants. At mutation-selection balance, higher-order mutant frequencies are likewise boosted, while lower-order mutants exhibit subtler effects; nonetheless, population mean fitness is always enhanced. We quantify the dependencies on moments of the mutation rate distribution and selection coefficients, and clarify the role of mutation rate inheritance. While typical methods of estimating mutation rate will recover only the population mean, analyses assuming mutation rate is fixed to this mean could underestimate the potential for multi-locus adaptation, including medically relevant evolution in pathogenic and cancerous populations. We discuss the potential to empirically parameterize mutation rate distributions, which have to date hardly been quantified.
format Online
Article
Text
id pubmed-5850754
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-58507542018-03-23 Population Heterogeneity in Mutation Rate Increases the Frequency of Higher-Order Mutants and Reduces Long-Term Mutational Load Alexander, Helen K. Mayer, Stephanie I. Bonhoeffer, Sebastian Mol Biol Evol Discoveries Mutation rate is a crucial evolutionary parameter that has typically been treated as a constant in population genetic analyses. However, the propensity to mutate is likely to vary among co-existing individuals within a population, due to genetic polymorphisms, heterogeneous environmental influences, and random physiological fluctuations. We review the evidence for mutation rate heterogeneity and explore its consequences by extending classic population genetic models to allow an arbitrary distribution of mutation rate among individuals, either with or without inheritance. With this general new framework, we rigorously establish the effects of heterogeneity at various evolutionary timescales. In a single generation, variation of mutation rate about the mean increases the probability of producing zero or many simultaneous mutations on a genome. Over multiple generations of mutation and selection, heterogeneity accelerates the appearance of both deleterious and beneficial multi-point mutants. At mutation-selection balance, higher-order mutant frequencies are likewise boosted, while lower-order mutants exhibit subtler effects; nonetheless, population mean fitness is always enhanced. We quantify the dependencies on moments of the mutation rate distribution and selection coefficients, and clarify the role of mutation rate inheritance. While typical methods of estimating mutation rate will recover only the population mean, analyses assuming mutation rate is fixed to this mean could underestimate the potential for multi-locus adaptation, including medically relevant evolution in pathogenic and cancerous populations. We discuss the potential to empirically parameterize mutation rate distributions, which have to date hardly been quantified. Oxford University Press 2017-02 2016-11-11 /pmc/articles/PMC5850754/ /pubmed/27836985 http://dx.doi.org/10.1093/molbev/msw244 Text en © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Discoveries
Alexander, Helen K.
Mayer, Stephanie I.
Bonhoeffer, Sebastian
Population Heterogeneity in Mutation Rate Increases the Frequency of Higher-Order Mutants and Reduces Long-Term Mutational Load
title Population Heterogeneity in Mutation Rate Increases the Frequency of Higher-Order Mutants and Reduces Long-Term Mutational Load
title_full Population Heterogeneity in Mutation Rate Increases the Frequency of Higher-Order Mutants and Reduces Long-Term Mutational Load
title_fullStr Population Heterogeneity in Mutation Rate Increases the Frequency of Higher-Order Mutants and Reduces Long-Term Mutational Load
title_full_unstemmed Population Heterogeneity in Mutation Rate Increases the Frequency of Higher-Order Mutants and Reduces Long-Term Mutational Load
title_short Population Heterogeneity in Mutation Rate Increases the Frequency of Higher-Order Mutants and Reduces Long-Term Mutational Load
title_sort population heterogeneity in mutation rate increases the frequency of higher-order mutants and reduces long-term mutational load
topic Discoveries
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850754/
https://www.ncbi.nlm.nih.gov/pubmed/27836985
http://dx.doi.org/10.1093/molbev/msw244
work_keys_str_mv AT alexanderhelenk populationheterogeneityinmutationrateincreasesthefrequencyofhigherordermutantsandreduceslongtermmutationalload
AT mayerstephaniei populationheterogeneityinmutationrateincreasesthefrequencyofhigherordermutantsandreduceslongtermmutationalload
AT bonhoeffersebastian populationheterogeneityinmutationrateincreasesthefrequencyofhigherordermutantsandreduceslongtermmutationalload