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

Author:

Tilk Susanne1ORCID,Tkachenko Svyatoslav2,Curtis Christina345ORCID,Petrov Dmitri A1ORCID,McFarland Christopher D2

Affiliation:

1. Department of Biology, Stanford University

2. Department of Genetics and Genome Sciences, Case Western Reserve University

3. Department of Medicine, Division of Oncology, Stanford University School of Medicine

4. Department of Genetics, Stanford University School of Medicine

5. Stanford Cancer Institute, Stanford University School of Medicine

Abstract

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.

Funder

National Human Genome Research Institute

National Institutes of Health

National Cancer Institute

National Institute of General Medical Sciences

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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