Most cancers carry a substantial deleterious load due to Hill-Robertson interference
Cancer genomes exhibit surprisingly weak signatures of negative selection1,2. This may be because tumors evolve either under very weak selective pressures (weak selection) or under conditions that prevent the elimination of many deleterious passenger mutations (poor efficacy of selection). The weak selection model argues that the majority of genes are only important for multicellular function. The poor efficacy of selection model argues, in contrast, that genome-wide linkage in cancer prevents many deleterious mutations from being removed via Hill-Robertson interference3. Since these linkage effects weaken as mutation rates decrease, we predict that cancers with lower mutational burdens should exhibit stronger signals of negative selection. Furthermore, because linkage affects driver mutations as well, low mutational burden cancers should also show stronger evidence of positive selection in driver genes. Neither pattern - in drivers or passengers - is expected under the weak selection model. We leverage the 10,000-fold variation in mutational burden across cancer subtypes to stratify tumors by their genome-wide mutational burden and used a normalized ratio of nonsynonymous to synonymous substitutions (dN/dS) to quantify the extent that selection varies with mutation rate. We find that appreciable negative selection (dN/dS ~ 0.4) is present in tumors with a low mutational burden, while the remaining cancers (96%) exhibit dN/dS ratios approaching 1, suggesting that the majority of tumors do not remove deleterious passengers. A parallel pattern is seen in drivers, where positive selection attenuates as the mutational burden of cancers increases. Both trends persist across tumor-types, are not exclusive to essential or housekeeping genes, and are present in clonal and subclonal mutations. Two additional orthogonal lines of evidence support the weak efficacy model: passengers are less damaging in low mutational burden cancers, and patterns of attenuated selection also emerge in Copy Number Alterations. Finally, we find that an evolutionary model incorporating Hill-Robertson interference can reproduce both patterns of attenuated selection in drivers and passengers if the average fitness cost of passengers is 1.0% and the average fitness benefit of drivers is 19%. Collectively, our findings suggest that the lack of signals of negative selection in most tumors is not due to relaxed selective pressures, but rather the inability of selection to remove individual deleterious mutations in the presence of genome-wide linkage. As a result, despite the weak individual fitness effects of passengers, most cancers harbor a large mutational load (median ~40% total fitness cost) and succeed due to acquisition of additional strong drivers (~5 with an overall benefit of ~130%). Understanding how this deleterious load is overcome may help identify cancer vulnerabilities that may be targeted by new and existing therapies.