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.
-
TCGA - MC3 mutation callsGenomic Data Commons, MC3 Public MAF.
-
COSMIC - copy number callsCOSMIC, CosmicCompleteCNA.tsv.gz.
-
COSMIC - gene expression dataCOSMIC, CosmicCompleteGeneExpression.tsv.gz.
-
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.
Metrics
-
- 2,464
- views
-
- 392
- downloads
-
- 17
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Most cancers carry a substantial deleterious load due to Hill-Robertson interference
eLife 11:e67790.
https://doi.org/10.7554/eLife.67790
Further reading
-
- Cell Biology
- Evolutionary Biology
Maintenance of rod-shape in bacterial cells depends on the actin-like protein MreB. Deletion of mreB from Pseudomonas fluorescens SBW25 results in viable spherical cells of variable volume and reduced fitness. Using a combination of time-resolved microscopy and biochemical assay of peptidoglycan synthesis, we show that reduced fitness is a consequence of perturbed cell size homeostasis that arises primarily from differential growth of daughter cells. A 1000-generation selection experiment resulted in rapid restoration of fitness with derived cells retaining spherical shape. Mutations in the peptidoglycan synthesis protein Pbp1A were identified as the main route for evolutionary rescue with genetic reconstructions demonstrating causality. Compensatory pbp1A mutations that targeted transpeptidase activity enhanced homogeneity of cell wall synthesis on lateral surfaces and restored cell size homeostasis. Mechanistic explanations require enhanced understanding of why deletion of mreB causes heterogeneity in cell wall synthesis. We conclude by presenting two testable hypotheses, one of which posits that heterogeneity stems from non-functional cell wall synthesis machinery, while the second posits that the machinery is functional, albeit stalled. Overall, our data provide support for the second hypothesis and draw attention to the importance of balance between transpeptidase and glycosyltransferase functions of peptidoglycan building enzymes for cell shape determination.
-
- Evolutionary Biology
Life-history theory, central to our understanding of diversity in morphology, behaviour, and senescence, describes how traits evolve through the optimisation of trade-offs in investment. Despite considerable study, there is only minimal support for trade-offs within species between the two traits most closely linked to fitness – reproductive effort and survival – questioning the theory’s general validity. We used a meta-analysis to separate the effects of individual quality (positive survival/reproduction correlation) from the costs of reproduction (negative survival/reproduction correlation) using studies of reproductive effort and parental survival in birds. Experimental enlargement of brood size caused reduced parental survival. However, the effect size of brood size manipulation was small and opposite to the effect of phenotypic quality, as we found that individuals that naturally produced larger clutches also survived better. The opposite effects on parental survival in experimental and observational studies of reproductive effort provide the first meta-analytic evidence for theory suggesting that quality differences mask trade-offs. Fitness projections using the overall effect size revealed that reproduction presented negligible costs, except when reproductive effort was forced beyond the maximum level observed within species, to that seen between species. We conclude that there is little support for the most fundamental life-history trade-off, between reproductive effort and survival, operating within a population. We suggest that within species the fitness landscape of the reproduction–survival trade-off is flat until it reaches the boundaries of the between-species fast–slow life-history continuum. Our results provide a quantitative explanation as to why the costs of reproduction are not apparent and why variation in reproductive effort persists within species.
