Compensatory mutations potentiate constructive neutral evolution by gene duplication

Després, Philippe C; Dubé, Alexandre K; Grenier, Jordan; Picard, Marie-Ève; Shi, Rong; Landry, Christian R

doi:10.1101/2024.02.12.579783

Cited by 3 publications

References 63 publications

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Mutational biases favor complexity increases in protein interaction networks after gene duplication

Cisneros,

Nielly-Thibault,

Mallik

et al. 2024

Mol Syst Biol

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Biological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At the molecular level, one example is heteromeric complexes replacing homomeric ones following gene duplication. Here, we build a biophysical model and simulate the evolution of homodimers and heterodimers following gene duplication using distributions of mutational effects inferred from available protein structures. We keep the specific activity of each dimer identical, so their concentrations drift neutrally without new functions. We show that for more than 60% of tested dimer structures, the relative concentration of the heteromer increases over time due to mutational biases that favor the heterodimer. However, allowing mutational effects on synthesis rates and differences in the specific activity of homo- and heterodimers can limit or reverse the observed bias toward heterodimers. Our results show that the accumulation of more complex protein quaternary structures is likely under neutral evolution, and that natural selection would be needed to reverse this tendency.

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Mutational biases favor complexity increases in protein interaction networks after gene duplication

Cisneros,

Nielly-Thibault,

Mallik

et al. 2024

Mol Syst Biol

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Variations and predictability of epistasis on an intragenic fitness landscape

Baheti,

Raj,

Saini

2024

Preprint

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How epistasis hinders or facilitates movement on fitness landscapes has been a longstanding question of interest. Several high throughput experiments have demonstrated that despite its idiosyncrasy, epistatic effects exhibit global statistical patterns. Recently, Papkou et. al. constructed a fitness landscape for a 9-base region in the folA gene, which encodes for dihydrofolate reductase (DHFR), in E. coli, and demonstrated that despite being highly rugged, the landscape is highly navigable. In this work, using the folA landscape, we ask two questions: (1) How does the nature of epistatic interactions change as a function of the genomic background? (2) How predictable is epistasis within a gene? Our results show that epistasis is 'fluid' - the nature of epistasis exhibited by a pair of mutations is strongly contingent on the genetic background. Mutations exhibit one of two binary 'states': a small fraction of mutations exhibit extremely strong patterns of global epistasis, while most do not. Despite these observations, we observe that the distribution of fitness effects (DFE) of a genotype is highly predictable based on its fitness. These results offer a new perspective on how epistasis operates within a gene, and how it can be predicted.

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Compensatory mutations potentiate constructive neutral evolution by gene duplication

Després,

Dubé,

Picard

et al. 2024

Science

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The functions of proteins generally depend on their assembly into complexes. During evolution, some complexes have transitioned from homomers encoded by a single gene to heteromers encoded by duplicate genes. This transition could occur without adaptive evolution through intermolecular compensatory mutations. Here, we experimentally duplicated and evolved a homodimeric enzyme to determine whether and how this could happen. We identified hundreds of deleterious mutations that inactivate individual homodimers but produce functional enzymes when coexpressed as duplicated proteins that heterodimerize. The structure of one such heteromer reveals how both losses of function are buffered through the introduction of asymmetry in the complex that allows them to subfunctionalize. Constructive neutral evolution can thus occur by gene duplication followed by only one deleterious mutation per duplicate.

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Compensatory mutations potentiate constructive neutral evolution by gene duplication

Cited by 3 publications

References 63 publications

Mutational biases favor complexity increases in protein interaction networks after gene duplication

Mutational biases favor complexity increases in protein interaction networks after gene duplication

Variations and predictability of epistasis on an intragenic fitness landscape

Compensatory mutations potentiate constructive neutral evolution by gene duplication

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