Interplay between pleiotropy and secondary selection determines rise and fall of mutators in stress response

📝 Abstract

Dramatic rise of mutators has been found to accompany adaptation of bacteria in response to many kinds of stress. Two views on the evolutionary origin of this phenomenon emerged: the pleiotropic hypothesis positing that it is a byproduct of environmental stress or other specific stress response mechanisms and the second order selection which states that mutators hitchhike to fixation with unrelated beneficial alleles. Conventional population genetics models could not fully resolve this controversy because they are based on certain assumptions about fitness landscape. Here we address this problem using a microscopic multiscale model, which couples physically realistic molecular descriptions of proteins and their interactions with population genetics of carrier organisms without assuming any a priori fitness landscape. We found that both pleiotropy and second order selection play a crucial role at different stages of adaptation: the supply of mutators is provided through destabilization of error correction complexes or fluctuations of production levels of prototypic mismatch repair proteins (pleiotropic effects), while rise and fixation of mutators occur when there is a sufficient supply of beneficial mutations in replication-controlling genes. This general mechanism assures a robust and reliable adaptation of organisms to unforeseen challenges. This study highlights physical principles underlying physical biological mechanisms of stress response and adaptation.

💡 Analysis

Dramatic rise of mutators has been found to accompany adaptation of bacteria in response to many kinds of stress. Two views on the evolutionary origin of this phenomenon emerged: the pleiotropic hypothesis positing that it is a byproduct of environmental stress or other specific stress response mechanisms and the second order selection which states that mutators hitchhike to fixation with unrelated beneficial alleles. Conventional population genetics models could not fully resolve this controversy because they are based on certain assumptions about fitness landscape. Here we address this problem using a microscopic multiscale model, which couples physically realistic molecular descriptions of proteins and their interactions with population genetics of carrier organisms without assuming any a priori fitness landscape. We found that both pleiotropy and second order selection play a crucial role at different stages of adaptation: the supply of mutators is provided through destabilization of error correction complexes or fluctuations of production levels of prototypic mismatch repair proteins (pleiotropic effects), while rise and fixation of mutators occur when there is a sufficient supply of beneficial mutations in replication-controlling genes. This general mechanism assures a robust and reliable adaptation of organisms to unforeseen challenges. This study highlights physical principles underlying physical biological mechanisms of stress response and adaptation.

📄 Content

1 Interplay between pleiotropy and secondary selection determines rise and fall of mutators in stress response.

Muyoung Heo and Eugene I. Shakhnovich

Department of Chemistry and Chemical Biology, Harvard University,
12 Oxford St, Cambridge, MA

Corresponding author: Eugene Shakhnovich; Email: eugene@belok.harvard.edu 2 Abstract

The role of mutator clones, whose mutation rate is about two to three order of magnitude higher than the rate of wild-type clones, in adaptive evolution of asexual populations has been controversial. Here we address this problem by using an ab initio microscopic model of living cells, which combines population genetics with physically realistic presentation of protein stability and protein-protein interactions. The genome of model organisms encodes replication controlling genes (RCGs) and genes modeling the mismatch repair (MMR) complexes. The genotype-phenotype relationship posits that replication rate of an organism is proportional to protein copy numbers of RCGs in their functional form and there is a production cost penalty for protein overexpression. The mutation rate depends linearly on the concentration of homodimers of MMR proteins. By simulating multiple runs of evolution of populations under various environmental stresses – stationary phase, starvation or temperature-jump – we find that adaptation most often occurs through transient fixation of a mutator phenotype, regardless of the nature of stress, but the fixation mechanism depends on the nature of stress. In temperature jump stress, mutators take over the population due to loss of stability of MMR complexes. In contrast, in starvation and stationary phase stresses, mutators are supplied in small fraction of the population via epigenetic stochastic noise in production of MMR proteins (a pleiotropic effect), and their net supply is higher in populations of low fitness due to reduced genetic drift. Subsequently, mutators in stationary phase or starvation hitchhike to fixation with a beneficial mutation in the RCGs, (second order selection) and finally a mutation stabilizing the MMR complex arrives, returning the population to a non-mutator phenotype. Our results provide microscopic insights into the rise and fall of mutators in adapting finite asexual populations. 3 Author Summary Dramatic rise of mutators has been found to accompany adaptation of bacteria in response to many kinds of stress. Two views on the evolutionary origin of this phenomenon emerged: the pleiotropic hypothesis positing that it is a byproduct of environmental stress or other specific stress response mechanisms and the second order selection which states that mutators hitchhike to fixation with unrelated beneficial alleles. Conventional population genetics models could not fully resolve this controversy because they are based on certain assumptions about fitness landscape. Here we address this problem using a microscopic multiscale model, which couples physically realistic molecular descriptions of proteins and their interactions with population genetics of carrier organisms without assuming any a priori fitness landscape. We found that both pleiotropy and second order selection play a crucial role at different stages of adaptation: the supply of mutators is provided through destabilization of error correction complexes or fluctuations of production levels of prototypic mismatch repair proteins (pleiotropic effects), while rise and fixation of mutators occur when there is a sufficient supply of beneficial mutations in replication-controlling genes. This general mechanism assures a robust and reliable adaptation of organisms to unforeseen challenges. This study highlights physical principles underlying physical biological mechanisms of stress response and adaptation.
4 Introduction Bacterial populations often respond to various stresses by inducing mutagenesis whereby mutator clones rise to fixation, at least transiently, during adaptation to stressful environments [1,2,3,4,5]. The rise of mutator clones has been observed as a universal response regardless of the nature of stress, despite the diversity of detailed molecular mechanisms associated with such responses (reviewed in [1,5]). (See, however, [6] where this interpretation is questioned for a particular experimental system.) The evolutionary significance of this observation has been controversial as two views emerged in the literature [3,7]. The pleiotropic hypothesis posits that high mutation rate is a by-product of genetic mechanisms invoked in response to stress or other physical mechanisms unrelated to adaptation [8]. The key aspect of the pleiotropic hypothesis is that high level of error correction and maintenance may be energetically costly so that bacteria would not fully activate them in stable environments [3]. Consistent with that view is the observation that natural populations exhibit a broad range of mutator

This content is AI-processed based on ArXiv data.