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

Abstract
Data availability
Article and author information
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Abstract

Cancer genomes exhibit surprisingly weak signatures of negative selection^1,2. 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 ~ 0.56) 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.

Data availability

Exonic, open-access SNV calls (WES) of 10,486 cancer patients in (The Cancer Genome Atlas) TCGA were downloaded from the Multi-Center Mutation Calling in Multiple Cancers (MC3) project. This repository uses a consensus of seven mutation-calling algorithms. Expression data of SNVs were downloaded from the Genotype-Tissue Expression (GTEx) project (v7 release). All CNAs were downloaded from the COSMIC database on June 20151.Gene expression data compared to CNAs was downloaded from the COSMIC database on 14 September 2019.

The following previously published data sets were used

1. Ellrott et al
(2018) TCGA - MC3 mutation calls
Genomic Data Commons, MC3 Public MAF.

https://gdc.cancer.gov/about-data/publications/mc3-2017
1. Tate et al
(2018) COSMIC - copy number calls
COSMIC, CosmicCompleteCNA.tsv.gz.

https://cancer.sanger.ac.uk/cosmic/download
1. Tate et al
(2018) COSMIC - gene expression data
COSMIC, CosmicCompleteGeneExpression.tsv.gz.

https://cancer.sanger.ac.uk/cosmic/download
1. GTEX Consortium
(2020) GTEX - expression data
GTEX, GTEx_Analysis_2016-01-15_v7_RNASeQCv1.1.8_gene_median_tpm.gct.gz.

https://www.gtexportal.org/home/datasets

Article and author information

Author details

Susanne Tilk

Department of Biology, Stanford University, Stanford, United States

For correspondence
tilk@stanford.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9156-9360
Svyatoslav Tkachenko

Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.
Christina Curtis

Department of Genetics, Stanford University, Stanford, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0166-3802
Dmitri A Petrov

Department of Biology, Stanford University, Stanford, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3664-9130
Christopher D McFarland

Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, United States

For correspondence
cdm113@case.edu

Competing interests
The authors declare that no competing interests exist.

Funding

National Human Genome Research Institute (T32-HG000044-21)

Christopher D McFarland

National Institutes of Health (E25-CA180993)

Christopher D McFarland

National Institutes of Health (DP1-CA238296)

Christina Curtis

National Cancer Institute (R01-CA207133)

Dmitri A Petrov

National Institute of General Medical Sciences (R35-GM118165)

Dmitri A Petrov

National Institutes of Health (R01-CA231253)

Dmitri A Petrov

National Cancer Institute (K99-CA226506)

Christopher D McFarland

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.