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

Area of Science:

• Cancer Biology
• Evolutionary Genetics
• Genomics

Background:

• Cancer genomes show weak negative selection signatures, potentially due to relaxed selective pressures or Hill-Robertson interference.
• Hill-Robertson interference describes how genome-wide linkage hinders the removal of deleterious mutations.

Purpose of the Study:

• Investigate the reasons behind the weak negative selection observed in cancer genomes.
• Determine the role of Hill-Robertson interference in the inability of tumors to remove deleterious mutations.

Main Methods:

• Stratified tumors based on genome-wide mutational burden to analyze selection signatures (dN/dS ratios).
• Observed heat shock pathway upregulation in response to increasing mutational burden.
• Employed evolutionary modeling to assess the impact of Hill-Robertson interference.

Main Results:

• Negative selection (dN/dS ~ 0.56) was evident in low mutational burden tumors, while high burden tumors showed dN/dS ratios near 1.
• Tumors with higher mutational burden do not effectively remove deleterious passenger mutations.
• Heat shock pathways are upregulated to counteract deleterious passengers as mutational burden increases.
• Evolutionary models indicate Hill-Robertson interference alone can explain attenuated selection patterns.

Conclusions:

• The lack of observed negative selection in most cancers stems from the inability to remove deleterious mutations due to genome-wide linkage (Hill-Robertson interference).
• Selective pressures are not necessarily relaxed; rather, the efficiency of selection is compromised.
• The estimated average fitness cost of passenger mutations is 46% per cell.