Genetic instability and the quasispecies model.
Genetic instability is a defining characteristic of cancers. Microsatellite instability (MIN) leads to by elevated point mutation rates, whereas chromosomal instability (CIN) refers to increased rates of losing or gaining whole chromosomes or parts of chromosomes during cell division. CIN and MIN are, in general, mutually exclusive. The quasispecies model is a very successful theoretical framework for the study of evolution at high mutation rates. It predicts the existence of an experimentally verified error catastrophe. This catastrophe occurs when the mutation rates exceed a threshold value, the error threshold, above which replicative infidelity is incompatible with cell survival. We analyse the semiconservative quasispecies model of both MIN and CIN tumors. We consider the role of post-methylation DNA repair in tumor cells and demonstrate that DNA repair is fundamental to the nature of the error catastrophe in both types of tumors. We find that CIN introduces a plateau in the maximum viable mutation rate for a repair-free model, which does not exist in the case of MIN. This provides a plausible explanation for the mutual exclusivity of CIN and MIN.
Brumer
Yisroel
Y
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. brumer@post.harvard.edu
Michor
Franziska
F
Shakhnovich
Eugene I
EI
D043171:Chromosomal Instability; D019175:DNA Methylation; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D016678:Genome; D006801:Humans; D053842:Microsatellite Instability; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*
D004273:DNA, Neoplasm