# Global genetic rewiring during compensatory evolution in the yeast polarity network

## TL;DR

The study shows how compensatory mutations in yeast can change genome-wide gene disruption tolerance, revealing how interconnected biological processes allow for functional recovery.

## Contribution

The study reveals that compensatory evolution in yeast rewires genome-wide disruption tolerance through interconnected cellular processes.

## Key findings

- Compensatory mutations in BEM3 and NRP1 alter transposon disruption tolerance for over 13% of the genome.
- Genes in the same cellular process show coordinated changes in disruption tolerance after compensation.
- Functional restoration is mediated by redundancies and interconnectivity in the polarity pathway.

## Abstract

Functional defects resulting from deleterious mutations can often be restored during evolution by compensatory mutations. Importantly, this process can generate the genetic diversity seen in networks regulating the same biological function in different species. How the options for compensatory evolution depend on the molecular interactions underlying these functions is currently unclear. We investigate how gene deletions compensating for a defect in the polarity pathway of Saccharomyces cerevisiae impact the fitness landscape. Using a transposon mutagenesis screen, we demonstrate that gene disruption tolerance has changed on a genome-wide scale in the compensated strain. An analysis of the functional associations between the affected genes reveals that compensation impacts cellular processes that have no clear connection to cell polarity. Moreover, genes belonging to the same process tend to show the same direction of tolerance change, indicating that compensation rewires the fitness contribution of cellular processes rather than of individual genes. In conclusion, our results strongly suggest that functional overlap between modules and the interconnectedness of the molecular interaction network play major roles in mediating compensatory evolution.

In Saccharomyces cerevisiae, loss of the polarity gene BEM1 can largely be compensated by loss-of-function mutations in BEM3 and NRP1, but these mutations alter the tolerance to transposon disruptions of more than 13% of the genes in the genome. The affected genes encode for components of several distinct cellular processes, indicating that pathway interconnectivity and functional overlap mediate the compensation through gene inactivation.

Compensatory evolution following the loss of the polarity gene BEM1 changes the transposon disruption tolerance of more than 13% of the genes in the genome.Functional association network analysis reveals that genes involved in the same cellular function typically exhibit disruption tolerance changes in the same direction, either increased or decreased.Functional restoration of polarity establishment is mediated by redundancies within the polarity pathway.

Compensatory evolution following the loss of the polarity gene BEM1 changes the transposon disruption tolerance of more than 13% of the genes in the genome.

Functional association network analysis reveals that genes involved in the same cellular function typically exhibit disruption tolerance changes in the same direction, either increased or decreased.

Functional restoration of polarity establishment is mediated by redundancies within the polarity pathway.

In Saccharomyces cerevisiae, loss of the polarity gene BEM1 can largely be compensated by loss-of-function mutations in BEM3 and NRP1, but these mutations alter the tolerance to transposon disruptions of more than 13% of the genes in the genome. The affected genes encode for components of several distinct cellular processes, indicating that pathway interconnectivity and functional overlap mediate the compensation through gene inactivation.