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Most cancers carry a substantial deleterious load due to Hill-Robertson interference
Cancer genomes exhibit surprisingly weak signatures of negative selection (Martincorena et al., 2017; Weghorn, 2017). This may be because selective pressures are relaxed or because genome-wide linkage prevents deleterious mutations from being removed (Hill-Robertson interference; Hill and Robertson,...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499534/ https://www.ncbi.nlm.nih.gov/pubmed/36047771 http://dx.doi.org/10.7554/eLife.67790 |
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author | Tilk, Susanne Tkachenko, Svyatoslav Curtis, Christina Petrov, Dmitri A McFarland, Christopher D |
author_facet | Tilk, Susanne Tkachenko, Svyatoslav Curtis, Christina Petrov, Dmitri A McFarland, Christopher D |
author_sort | Tilk, Susanne |
collection | PubMed |
description | Cancer genomes exhibit surprisingly weak signatures of negative selection (Martincorena et al., 2017; Weghorn, 2017). This may be because selective pressures are relaxed or because genome-wide linkage prevents deleterious mutations from being removed (Hill-Robertson interference; Hill and Robertson, 1966). By stratifying tumors by their genome-wide mutational burden, we observe negative selection (dN/dS ~ 0.56) in low mutational burden tumors, while remaining cancers exhibit dN/dS ratios ~1. This suggests that most tumors do not remove deleterious passengers. To buffer against deleterious passengers, tumors upregulate heat shock pathways as their mutational burden increases. Finally, evolutionary modeling finds that Hill-Robertson interference alone can reproduce patterns of attenuated selection and estimates the total fitness cost of passengers to be 46% per cell on average. Collectively, our findings suggest that the lack of observed negative selection in most tumors is not due to relaxed selective pressures, but rather the inability of selection to remove deleterious mutations in the presence of genome-wide linkage. |
format | Online Article Text |
id | pubmed-9499534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-94995342022-09-23 Most cancers carry a substantial deleterious load due to Hill-Robertson interference Tilk, Susanne Tkachenko, Svyatoslav Curtis, Christina Petrov, Dmitri A McFarland, Christopher D eLife Evolutionary Biology Cancer genomes exhibit surprisingly weak signatures of negative selection (Martincorena et al., 2017; Weghorn, 2017). This may be because selective pressures are relaxed or because genome-wide linkage prevents deleterious mutations from being removed (Hill-Robertson interference; Hill and Robertson, 1966). By stratifying tumors by their genome-wide mutational burden, we observe negative selection (dN/dS ~ 0.56) in low mutational burden tumors, while remaining cancers exhibit dN/dS ratios ~1. This suggests that most tumors do not remove deleterious passengers. To buffer against deleterious passengers, tumors upregulate heat shock pathways as their mutational burden increases. Finally, evolutionary modeling finds that Hill-Robertson interference alone can reproduce patterns of attenuated selection and estimates the total fitness cost of passengers to be 46% per cell on average. Collectively, our findings suggest that the lack of observed negative selection in most tumors is not due to relaxed selective pressures, but rather the inability of selection to remove deleterious mutations in the presence of genome-wide linkage. eLife Sciences Publications, Ltd 2022-09-01 /pmc/articles/PMC9499534/ /pubmed/36047771 http://dx.doi.org/10.7554/eLife.67790 Text en © 2022, Tilk et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Evolutionary Biology Tilk, Susanne Tkachenko, Svyatoslav Curtis, Christina Petrov, Dmitri A McFarland, Christopher D Most cancers carry a substantial deleterious load due to Hill-Robertson interference |
title | Most cancers carry a substantial deleterious load due to Hill-Robertson interference |
title_full | Most cancers carry a substantial deleterious load due to Hill-Robertson interference |
title_fullStr | Most cancers carry a substantial deleterious load due to Hill-Robertson interference |
title_full_unstemmed | Most cancers carry a substantial deleterious load due to Hill-Robertson interference |
title_short | Most cancers carry a substantial deleterious load due to Hill-Robertson interference |
title_sort | most cancers carry a substantial deleterious load due to hill-robertson interference |
topic | Evolutionary Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499534/ https://www.ncbi.nlm.nih.gov/pubmed/36047771 http://dx.doi.org/10.7554/eLife.67790 |
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