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Power law fitness landscapes and their ability to predict fitness.

ABSTRACT: Whether or not evolution by natural selection is predictable depends on the existence of general patterns shaping the way mutations interact with the genetic background. This interaction, also known as epistasis, has been observed during adaptation (macroscopic epistasis) and in individual mutations (microscopic epistasis). Interestingly, a consistent negative correlation between the fitness effect of beneficial mutations and background fitness (known as diminishing returns epistasis) has been observed across different species and conditions. We tested whether the adaptation pattern of an additional species, Schizosaccharomyces pombe, followed the same trend. We used strains that differed by the presence of large karyotype differences and observed the same pattern of fitness convergence. Using these data along with published datasets, we measured the ability of different models to describe adaptation rates. We found that a phenotype-fitness landscape shaped like a power law is able to correctly predict adaptation dynamics in a variety of species and conditions. Furthermore we show that this model can provide a link between the observed macroscopic and microscopic epistasis. It may be very useful in the development of algorithms able to predict the adaptation of microorganisms from measures of the current phenotypes. Overall, our results suggest that even though adaptation quickly slows down, populations adapting to lab conditions may be quite far from a fitness peak.

SUBMITTER: Passagem-Santos D

PROVIDER: S-EPMC6180038 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Power law fitness landscapes and their ability to predict fitness.

Passagem-Santos Diogo D Zacarias Simone S Perfeito Lilia L

Heredity 20180906 5

Whether or not evolution by natural selection is predictable depends on the existence of general patterns shaping the way mutations interact with the genetic background. This interaction, also known as epistasis, has been observed during adaptation (macroscopic epistasis) and in individual mutations (microscopic epistasis). Interestingly, a consistent negative correlation between the fitness effect of beneficial mutations and background fitness (known as diminishing returns epistasis) has been o ...[more]

PMID: 30190560

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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

Power law fitness landscapes and their ability to predict fitness.

Publications

Power law fitness landscapes and their ability to predict fitness.

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