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Most cancers carry a substantial deleterious load due to Hill-Robertson interference

View ORCID ProfileSusanne Tilk, View ORCID ProfileChristina Curtis, View ORCID ProfileDmitri A Petrov, View ORCID ProfileChristopher D McFarland
doi: https://doi.org/10.1101/764340
Susanne Tilk
1Department of Biology, Stanford University, Stanford CA 94305
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Christina Curtis
2Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA
3Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
4Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
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Dmitri A Petrov
1Department of Biology, Stanford University, Stanford CA 94305
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Christopher D McFarland
1Department of Biology, Stanford University, Stanford CA 94305
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  • For correspondence: cmcfarl2@stanford.edu
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Abstract

Cancer genomes exhibit surprisingly weak signatures of negative selection1,2. This may be because selective pressures are relaxed or because genome-wide linkage prevents deleterious mutations from being removed (Hill-Robertson interference)3. By stratifying tumors by their genome-wide mutational burden, we observe negative selection (dN/dS ~ 0.47) 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 40% 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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* dpetrov{at}stanford.edu

  • Additional negative controls for the use of our dN/dS statistic are included. Abstract is shorted. Common misconceptions in the field are better addressed.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 24, 2021.
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Most cancers carry a substantial deleterious load due to Hill-Robertson interference
Susanne Tilk, Christina Curtis, Dmitri A Petrov, Christopher D McFarland
bioRxiv 764340; doi: https://doi.org/10.1101/764340
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Most cancers carry a substantial deleterious load due to Hill-Robertson interference
Susanne Tilk, Christina Curtis, Dmitri A Petrov, Christopher D McFarland
bioRxiv 764340; doi: https://doi.org/10.1101/764340

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