PT  - JOURNAL ARTICLE
AU  - Susanne Tilk
AU  - Christina Curtis
AU  - Dmitri A Petrov
AU  - Christopher D McFarland
TI  - Most cancers carry a substantial deleterious load due to Hill-Robertson interference
AID  - 10.1101/764340
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 764340
4099  - http://biorxiv.org/content/early/2021/02/24/764340.short
4100  - http://biorxiv.org/content/early/2021/02/24/764340.full
AB  - 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 StatementThe authors have declared no competing interest.