Programmed Genetic Instability: A Tumor-Permissive Mechanism for Maintaining the Evolvability of Higher Species through Methylation-Dependent Mutation of DNA Repair Genes in the Male Germ Line

摘要: Tumor suppressor genes are classified by their somatic behavior either as caretakers (CTs) that maintain DNA integrity or gatekeepers (GKs) regulate cell survival, but the germ line role of these disease-related gene subgroups may differ. To test this hypothesis, we have used genomic data mining to compare features human CTs (n = 38), GKs 36), repair 165), apoptosis 622), and orthologs. This analysis reveals numerically less common than in genomes multicellular organisms (P < 0.01), whereas CT orthologs commoner GK unicellular 0.05). Gene targeting show essential for survival 0.0005) knockouts often permit offspring viability at cost male sterility. Patterns familial oncogenic mutations confirm isolated loss is 0.00001). In sexually reproducing species, appear subject efficient purifying selection (i.e., higher Ka/Ks) 0.000003); faster evolution seems likely be mediated methylation reduced transcription-coupled repair, based on differences dinucleotide patterns 0.001). These suggest CT/repair function relatively dispensable imply milder (e.g., epimutational) prezygotic defects could enhance sperm variation—and hence environmental adaptation speciation—while sparing fertility. We submit general targets epigenetically initiated adaptive evolution, propose a model which cancers arise part an evolutionarily programmed side effect age- damage-inducible genetic instability affecting both lineages.