Most cancers carry a substantial deleterious load due to Hill-Robertson interference
- Stanford University, United States
- Case Western Reserve University, United States
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 ~ 0.56) 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.
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TCGA - MC3 mutation callsGenomic Data Commons, MC3 Public MAF.
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COSMIC - copy number callsCOSMIC, CosmicCompleteCNA.tsv.gz.
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COSMIC - gene expression dataCOSMIC, CosmicCompleteGeneExpression.tsv.gz.
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GTEX - expression dataGTEX, GTEx_Analysis_2016-01-15_v7_RNASeQCv1.1.8_gene_median_tpm.gct.gz.
Article and author information
Author details
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
© 2022, Tilk et al.
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.
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Most cancers carry a substantial deleterious load due to Hill-Robertson interference
eLife 11:e67790.
https://doi.org/10.7554/eLife.67790
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