title: Stress-induced hypermutation as a physical property of life, a force of natural selection and its role in four thought experiments.
abstract: The independence of genetic mutation rate from selection is central to neo-Darwinian evolutionary theory. However, it has been continuously challenged for more than 30 years by experimental evidence of genetic mutation rate transiently increasing in response to stress (stress-induced hypermutation, SIH). The prominent concept of evolved evolvability (EE) explains that natural selection for strategies more competitive at evolutionary adaptation itself gives rise to mechanisms dynamically adjusting mutation rates to environmental stress. Here, we theoretically investigate the alternative (not mutually exclusive) hypothesis that SIH is an inherent physical property of all genetically reproducing life. We define stress as any condition lowering the capability of utilizing metabolic resources for genome storage and replication. This thermodynamical analysis indicates stress-induced increases in the genetic mutation rate in genome storage and in genome replication as inherent physical properties of genetically reproducing life. Further integrating SIH into an overall organismic thermodynamic budget identifies SIH as a force of natural selection, alongside death rate, replication rate and constitutive mutation rate differences. We execute four thought experiments with a non-recombinant lesion mutant strain to predict experimental observations due to SIH in response to different stresses and stress combinations. We find (1) acceleration of adaptation over models without SIH, (2) possibility of adaptation at high stresses which are not explicable by mutation in genome replication alone and (3) different adaptive potential under high growth-inhibiting versus high lethal stresses. The predictions are directly comparable to culture experiments (colony size time courses, antibacterial resistance assay and occurrence of lesion-reversion mutant colonies) and genome sequence analysis. Considering suggestions of drug-mediated disruption of SIH and attempts to target mutation-associated sites with chemotherapeutic agents to prevent resistance, our findings seem to be relevant knowledge for resistance-averse drug development and administration.
authors: Department of Physiology, Centre for Applied Mathematics in Bioscience and Medicine, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada. lennart.hilbert@mail.mcgill.ca
authors: Lennart
authors: L
authors: Hilbert
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D005075:Biological Evolution; D003198:Computer Simulation; D016678:Genome; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D059645:Mutation Rate; D012641:Selection, Genetic; D013312:Stress, Physiological; D013816:Thermodynamics