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

Abstract

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

The Unpluggable in Pursuit of the Undruggable: Tackling the Dark Matter of the Cancer Therapeutics Universe

“…For this reason alone, cancer treatment strategies focused solely on “driver” pathway inhibition seem likely to fail – for no sooner is the proverbial plug extracted from the driver pathway than the underlying apoptotic gene defect permits selection for heterologous pathway upregulation and/or additional oncogenic events, manifesting as a rapidly proliferative (high Ki67) tumor outgrowth reflecting the suppressor gene mutation burden (9). This problem is made even worse by coexisting caretaker defects that speed selection and cell adaptation – a useful coping mechanism for germline (species) evolution (10), but yet another therapeutic hurdle for restoring phenotypic stability to growing neoplasms.…”

Unexpected functional similarities between gatekeeper tumour suppressor genes and proto-oncogenes revealed by systems biology

“…69 Indeed, increasing evidence supports the importance of such epistatic processes for mammalian cancer development 24,[70][71][72][73] and, perhaps, also for transgenerational carcinogenesis. 6,74 The central finding of the present study is the unanticipated insight that the structural and functional attributes of GKs and POs-when compared with control subgroups of CT cancer suppressor genes and functionally unrelated but developmentally important HD genes-are strikingly similar, as indicated by congruences of evolutionary rate, expression level and breadth, gene length and methylation-dependent mutation confirmed by logistic regression and C-statistics. These data imply that GKs have undergone epigenetic evolution trajectories similar to those of POs, suggesting an explanation for the otherwise puzzling observation that wild-type GK (but not CT) expression is often selectively increased in tumors.…”

“…Framedependent dinucleotide alignment and evolutionary analysis have shown that CpG sites in GKs and POs fix missense mutations more often than do those in CTs, and that similar trends apply to wholegenome comparison of apoptosis vs repair genes. 6 As the minimum sequence motif is a dinucleotide, we hypothesized that nonrandom alterations in dinucleotide patterns-including asymmetries due to transcription-coupled repair-may be selected from transgenerational variations, the frequency of which varies with germline gene methylation. 58 With this in mind, directional analyses of methylation- Similarity of tumor suppressors and oncogenes Y Zhao and RJ Epstein dependent dinucleotides in the target gene sets reveal an asymmetry: not only are GKs and POs characterized by a higher CpG content than CTs but also by a selectively lower CpA-but not TpG-content, suggesting greater transcription-coupled repair of methylation-dependent mutation in GKs and POs than in CTs.…”

“…In contrast, we have shown in earlier work that CT dysfunction, which could be subtle, polymorphic and/or multiallelic 5 -is better tolerated in the germline than GK dysfunction is, implicating environmental selection for germline CT gene methylation as a mechanism that may contribute both to maintenance of genome plasticity for the species, and also to heritable but non-familial cancer predisposition. 6 Frequent occurrence in sporadic tumors of TSG protein overexpression without gene mutation-as has been reported for TP53, 7 CDKN2A, 8 RB1, 9 SMAD4 10 and CDH1, 11 among others-with tumor-promoting effects is less understood. 12,13 As confirmed by literature data mining, 14 such overexpression is more strongly associated with GKs rather than with CTs (Po0.001; Supplementary Table S1); this suggests that GKs express a selectable phenotype, which is lacking in CTs.…”

The origins and evolution of genetic disease risk in modern humans

“…Evidence for a trade‐off between male fertility and cancer risk comes from studies the Y‐linked TSPY1 gene, which exhibits positive correlations of gene copy number with human male sperm count, 286 and aberrant high expression of the gene associated with a range of cancers 287 . More generally, mouse knockouts of tumor‐suppressor genes that are not lethal exhibit a striking preponderance of differential phenotypic effects on fertility, especially in males 288 …”