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MBE Advance Access published online on June 4, 2008
Molecular Biology and Evolution, doi:10.1093/molbev/msn126
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© 2008 The Authors.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Research Article

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 germline

Yongzhong Zhao and Richard J. Epstein*

Laboratory of Computational Oncology, 8/F Laboratory Block, Faculty of Medicine, University of Hong Kong, Sassoon Rd, Pokfulam, Hong Kong

* For proofs and correspondence: Department of Medicine, Faculty of Medicine, Sassoon Rd, Pokfulam, Hong Kong Email: repstein{at}hku.hk Tel: (852) 2855 3994 Fax: (852) 2816 286

Received for publication January 11, 2008. Revision received May 19, 2008. Accepted for publication May 26, 2008.

Tumor suppressor genes are classified by their somatic behavior either as caretakers (CTs) that maintain DNA fidelity or as gatekeepers (GKs) that regulate cell survival, but the germline 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 germline CT/repair gene function is relatively dispensable for survival, and imply that milder (e.g., epimutational) male pre-zygotic 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 germline lineages.

Key Words: molecular evolution • adaptive evolution • carcinogenesis • DNA repair

Current address: NE20, Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH, 44195, E-mail: zhaoy{at}ccf.org Tel: 1-216-4443840 Fax: 1-216-4440512


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