Adaptive Landscapes in the Age of Synthetic Biology

Xiao, Yi; Dean, Anthony M.

doi:10.1093/molbev/msz004

Cited by 30 publications

(35 citation statements)

References 179 publications

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“…The advent of deep sequencing technology has enabled large-scale, systematic measurements of the DFE in experiments called Deep Mutational Scanning (DMS) (13,14). However, most DMS studies use phenotypes or protein properties as a proxy for fitness (often outside the protein's native context) with limited relevance for organismal fitness landscapes and protein evolution (15)(16)(17)(18). Studies that present organismal fitness effects of random mutations in proteins (e.g.…”

mentioning

confidence: 99%

Collateral fitness effects of mutations

Mehlhoff

Stearns

Rohm

et al. 2019

Preprint

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AbstractThe distribution of fitness effects (DFE) of mutation plays a central role in constraining protein evolution. The underlying mechanisms by which mutations lead to fitness effects are typically attributed to changes in protein specific activity or abundance. Here, we reveal the importance of a mutation’s collateral fitness effects, which we define as effects that do not derive from changes in the protein’s ability to perform its physiological function. We comprehensively measured the collateral fitness effects of missense mutations in the E. coli TEM-1 β-lactamase antibiotic resistance gene using growth competition experiments in the absence of antibiotic. At least 42% of missense mutations in TEM-1 were deleterious, indicating that for some proteins, collateral fitness effects occur as frequently as effects on protein activity and abundance. Deleterious mutations caused improper post-translational processing, incorrect disulfide-bond formation, protein aggregation, changes in gene expression, and pleiotropic effects on cell phenotype. Deleterious collateral fitness effects occurred more frequently in TEM-1 than deleterious effects on antibiotic resistance in environments with low concentrations of the antibiotic. The surprising prevalence of deleterious collateral fitness effects suggests they may play a role in constraining protein evolution, particularly for highly-expressed proteins, for proteins under intermittent selection for their physiological function, and for proteins whose contribution to fitness is buffered against mutations with deleterious effects on protein activity and protein abundance.Significance StatementMutations provide the source of genetic variability upon which evolution acts. Deleterious protein mutations are commonly thought of in terms of how they compromise the protein’s ability to perform its physiological function. However, mutations might also be deleterious if they cause negative effects on one of the countless other cellular processes. The frequency and magnitude of such collateral fitness effects is unknown. Our systematic study of mutations in a bacterial protein finds widespread collateral fitness effects that were associated with protein aggregation, improper protein processing, incomplete protein transport across membranes, incorrect disulfide-bond formation, induction of stress-response pathways, and unexpected changes in cell properties. Our results suggest that deleterious collateral fitness effects may be an important constraint on protein evolution.

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mentioning

confidence: 99%

Collateral fitness effects of mutations

Mehlhoff

Stearns

Rohm

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The effects of the mutations are quantified by deep sequencing the alleles before and after selection. Many DMS studies use phenotypes or protein properties as a proxy for fitness (often outside the protein's native context) with limited relevance for organismal fitness landscapes and protein evolution (17)(18)(19)(20). DMS studies using growth competition as the selective pressure have measured organismal fitness effects (e.g., refs.…”

Section: Significancementioning

confidence: 99%

Collateral fitness effects of mutations

Mehlhoff

Stearns

Rohm

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The distribution of fitness effects of mutation plays a central role in constraining protein evolution. The underlying mechanisms by which mutations lead to fitness effects are typically attributed to changes in protein specific activity or abundance. Here, we reveal the importance of a mutation’s collateral fitness effects, which we define as effects that do not derive from changes in the protein’s ability to perform its physiological function. We comprehensively measured the collateral fitness effects of missense mutations in theEscherichia coli TEM-1β-lactamase antibiotic resistance gene using growth competition experiments in the absence of antibiotic. At least 42% of missense mutations inTEM-1were deleterious, indicating that for some proteins collateral fitness effects occur as frequently as effects on protein activity and abundance. Deleterious mutations caused improper posttranslational processing, incorrect disulfide-bond formation, protein aggregation, changes in gene expression, and pleiotropic effects on cell phenotype. Deleterious collateral fitness effects occurred more frequently inTEM-1than deleterious effects on antibiotic resistance in environments with low concentrations of the antibiotic. The surprising prevalence of deleterious collateral fitness effects suggests they may play a role in constraining protein evolution, particularly for highly expressed proteins, for proteins under intermittent selection for their physiological function, and for proteins whose contribution to fitness is buffered against deleterious effects on protein activity and protein abundance.

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“…We believe that some of these challenges offer unique learning opportunities that could expand our understanding of basic and intriguing aspects of cell biology and genetics. Apart from the physical limitations of yeast cell size when hosting large amounts of additional (exogenous) genomic material (see the work by Peris et al 14 to get an idea of the effect of genome size on yeast cell volume), different emergent properties—from pleiotropies to epistasis and the derived metabolic trade-offs 15 – 17 —may arise with the introduction of each new synthetic pathway. However, all these potential pitfalls should serve to stimulate the study of basic biological aspects regarding the existence of genomic and functional incompatibilities in yeast cells, the fitness cost and dynamics of adaptation when incorporating exogenous genes or functions (from phylogenetically close or distant species), or even the limits of hoarding of ecosystem functions that might compromise the fitness, and the ecological and evolutionary stability of the yeasts.…”

Section: Untangling Yeast Communities With Synthetic Metagenomicsmentioning

confidence: 99%