Evolvability of cancer-associated genes under APOBEC3A/B selection

Abstract

SummaryEvolvability is an emergent hallmark of cancer that depends on intra-tumor heterogeneity and, ultimately, genetic variation. Mutations generated by APOBEC3 cytidine deaminases can contribute to genetic variation and the consequences of APOBEC activation differ depending on the stage of cancer, with the most significant impact observed during the early stages. However, how APOBEC activity shapes evolutionary patterns of genes in the host genome and differential impacts on cancer-associated and non-cancer genes remain unclear. Analyzing over 40,000 human protein-coding transcripts, we identified distinct distribution patterns of APOBEC3A/B TC motifs between cancer-related genes and controls, suggesting unique associations with cancer. Studying a bat species with many more APOBEC3 genes, we found diverse motif patterns in orthologs of cancer genes compared to controls, similar to humans and suggesting APOBEC evolution to reduce impacts on the genome rather than the converse. Simulations confirmed that APOBEC-induced heterogeneity enhances cancer evolution, shaping clonal dynamics through bimodal introduction of mutations in certain classes of genes. Our results suggest that a major consequence of the bimodal distribution of APOBEC affects greater cancer heterogeneity.HighlightsUsing a measure of the extent which genes are affected by APOBEC activity, we found that many genes aremaximally robustin the human genome. Interestingly, the distribution in the genome of a bat that has many APOBEC genes was similar.In contrast, when analyzing the subset of cancer-associated genes the distribution is bimodal with many genes appearing to susceptible to APOBEC activity.Analysis of orthologs of human genes and other species showed a wide range in the extent to which APOBEC affects genes having the same function.The bimodal distribution of susceptibility to APOBEC drives greater heterogeneity in simulated clonal evolution of cancer.