Programmed genetic instability revealed by adaptive evolution of caretaker tumor suppressor genes

Abstract

Human tumor suppressor genes (TSGs) can be subclassified either as caretaker genes (CTs) that maintain genetic stability or else as gatekeeper genes (GKs) that regulate programmed cell death. Cancer risk is increased by dysfunction of either CTs or GKs, but the evolutionary significance of these respective TSG subgroups is less clear. Here we show that germline loss of gene function is better tolerated for CTs than for GKs, and that methylation-dependent CT mutation and/or gene silencing is likely to contribute to such functional germline losses. These conclusions are supported by data mining of familial and sporadic human tumor mutations. Ortholog and single nucleotide polymorphism analyses confirm accelerated evolution of CTs compared to GKs, indicating positive selection due to an adaptive advantage for CT transcriptional repression and/or mutation. We propose that age-dependent CT methylation represents a selectable mechanism for programmed genetic instability (PGI) in the germline, and that somatic cell PGI likewise contributes to the age-dependent incidence of human cancer.