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Modular epistasis and the compensatory evolution of gene deletion mutants.

ABSTRACT: Screens for epistatic interactions have long been used to characterize functional relationships corresponding to protein complexes, metabolic pathways, and other functional modules. Although epistasis between adaptive mutations is also common in laboratory evolution experiments, the functional basis for these interactions is less well characterized. Here, we quantify the extent to which gene function (as determined by a genome-wide screen for epistasis among deletion mutants) influences the rate and genetic basis of compensatory adaptation in a set of 37 gene deletion mutants nested within 16 functional modules. We find that functional module has predictive power: mutants with deletions in the same module tend to adapt more similarly, on average, than those with deletions in different modules. At the same time, initial fitness also plays a role: independent of the specific functional modules involved, adaptive mutations tend to be systematically more beneficial in less-fit genetic backgrounds, consistent with a general pattern of diminishing returns epistasis. We measured epistatic interactions between initial gene deletion mutations and the mutations that accumulate during compensatory adaptation and found a general trend towards positive epistasis (i.e. mutations tend to be more beneficial in the background in which they arose). In two functional modules, epistatic interactions between the initial gene deletions and the mutations in their descendant lines caused evolutionary entrenchment, indicating an intimate functional relationship. Our results suggest that genotypes with similar epistatic interactions with gene deletion mutations will also have similar epistatic interactions with adaptive mutations, meaning that genome scale maps of epistasis between gene deletion mutations can be predictive of evolutionary dynamics.

SUBMITTER: Rojas Echenique JI

PROVIDER: S-EPMC6395002 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Modular epistasis and the compensatory evolution of gene deletion mutants.

Rojas Echenique José I JI Kryazhimskiy Sergey S Nguyen Ba Alex N AN Desai Michael M MM

PLoS genetics 20190215 2

Screens for epistatic interactions have long been used to characterize functional relationships corresponding to protein complexes, metabolic pathways, and other functional modules. Although epistasis between adaptive mutations is also common in laboratory evolution experiments, the functional basis for these interactions is less well characterized. Here, we quantify the extent to which gene function (as determined by a genome-wide screen for epistasis among deletion mutants) influences the rate ...[more]

PMID: 30768593

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Project description:BACKGROUND:Organisms, tissues and cells are genetically programmed to grow to a specific largely pre-set size and shape within the appropriate developmental timing. In the event of mutation, cell death, or tissue damage, the remaining cells may increase their rate of growth to compensate and generate an intact, potentially smaller, tissue or organism in order to achieve the desired size. A delay in the developmental timing could aid in this process. The insulin receptor signalling pathway with its central component, the Akt1 kinase, and endpoint regulator, the transcription factor foxo, plays a significant role in the control of growth. Drosophila melanogaster is an excellent model organism with a well-studied life cycle and a consistently developing compound eye that can undergo analysis to compare changes in the properties of adult ommatidia as an indicator of growth. FINDINGS:Imprecise excision of a PZ P-element inserted in the upstream region of Akt1 generated several novel hypomorphic alleles with internally deleted regions of the Pelement. These mutations lead to small, viable Drosophila that present with delays in development. Suppression of this phenotype by the directed expression of Akt1 (+) indicates that the phenotypes observed are Akt1 dependent. Somatic clones of the eyes, consisting of homozygous tissue in otherwise heterozygous organisms that develop within a standard timeframe, signify that more severe phenotypes are masked by an extension in the time of development of homozygous mutants. Generation of Drosophila having the hypomorphic Akt1 alleles and a null allele of the downstream target foxo result in a phenotype very similar to that of the foxo mutant and do not resemble the Akt1 mutants. CONCLUSION:The developmental delay of these novel Akt1 hypomorphs results in a latent phenotype uncovered by generation of somatic clones. The compensatory growth occurring during the extended time of development appears to be implemented through alteration of foxo activity. Production of clones is an effective and informative way to observe the effects of mutations that result in small, viable, developmentally delayed flies.

Dataset Information

Modular epistasis and the compensatory evolution of gene deletion mutants.

Publications

Modular epistasis and the compensatory evolution of gene deletion mutants.

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