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

TL;DR

This study uses a multiscale model to explore how pleiotropy and second order selection influence the rise and fall of mutators during bacterial stress adaptation, revealing stage-specific roles of these mechanisms.

Contribution

It introduces a microscopic model that couples molecular protein interactions with population genetics, avoiding assumptions of predefined fitness landscapes.

Findings

Both pleiotropy and second order selection are crucial at different adaptation stages.

Mutator rise is driven by destabilization of error correction complexes and protein level fluctuations.

Fixation of mutators occurs when beneficial mutations are sufficiently supplied.

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.