Dataset Information

Multi-environment fitness landscapes of a tRNA gene.

ABSTRACT: A fitness landscape (FL) describes the genotype-fitness relationship in a given environment. To explain and predict evolution, it is imperative to measure the FL in multiple environments because the natural environment changes frequently. Using a high-throughput method that combines precise gene replacement with next-generation sequencing, we determine the in vivo FL of a yeast tRNA gene comprising over 23,000 genotypes in four environments. Although genotype-by-environment interaction is abundantly detected, its pattern is so simple that we can transform an existing FL to that in a new environment with fitness measures of only a few genotypes in the new environment. Under each environment, we observe prevalent, negatively biased epistasis between mutations. Epistasis-by-environment interaction is also prevalent, but trends in epistasis difference between environments are predictable. Our study thus reveals simple rules underlying seemingly complex FLs, opening the door to understanding and predicting FLs in general.

SUBMITTER: Li C

PROVIDER: S-EPMC5966336 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Multi-environment fitness landscapes of a tRNA gene.

Li Chuan C Zhang Jianzhi J

Nature ecology & evolution 20180423 6

A fitness landscape (FL) describes the genotype-fitness relationship in a given environment. To explain and predict evolution, it is imperative to measure the FL in multiple environments because the natural environment changes frequently. Using a high-throughput method that combines precise gene replacement with next-generation sequencing, we determine the in vivo FL of a yeast tRNA gene comprising over 23,000 genotypes in four environments. Although genotype-by-environment interaction is abunda ...[more]

PMID: 29686238

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Project description:BACKGROUND: Tumorigenesis requires multiple genetic changes. Mutator mutations are mutations that increase genomic instability, and according to the mutator hypothesis, accelerate tumorigenesis by facilitating oncogenic mutations. Alternatively, repeated lineage selection and expansion without increased mutation frequency may explain observed cancer incidence. Mutator lineages also risk increased deleterious mutations, leading to extinction, thus providing another counterargument to the mutator hypothesis. Both selection and extinction involve changes in lineage fitness, which may be represented as "trajectories" through a "fitness landscape" defined by genetics and environment. METHODOLOGY/PRINCIPAL FINDINGS: Here I systematically analyze the relative efficiency of tumorigenesis with and without mutator mutations by evaluating archetypal fitness trajectories using deterministic and stochastic mathematical models. I hypothesize that tumorigenic mechanisms occur clinically in proportion to their relative efficiency. This work quantifies the relative importance of mutator pathways as a function of experimentally measurable parameters, demonstrating that mutator pathways generally enhance efficiency of tumorigenesis. An optimal mutation rate for tumor evolution is derived, and shown to differ from that for species evolution. CONCLUSIONS/SIGNIFICANCE: The models address the major counterarguments to the mutator hypothesis, confirming that mutator mechanisms are generally more efficient routes to tumorigenesis than non-mutator mechanisms. Mutator mutations are more likely to occur early, and to occur when more oncogenic mutations are required to create a tumor. Mutator mutations likely occur in a minority of premalignant lesions, but these mutator premalignant lesions are disproportionately likely to develop into malignant tumors. Tumor heterogeneity due to mutator mutations may contribute to therapeutic resistance, and the degree of heterogeneity of tumors may need to be considered when therapeutic strategies are devised. The model explains and predicts important biological observations in bacterial and mouse systems, as well as clinical observations.

Dataset Information

Multi-environment fitness landscapes of a tRNA gene.

Publications

Multi-environment fitness landscapes of a tRNA gene.

Similar Datasets

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