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A formal perturbation equation between genotype and phenotype determines the Evolutionary Action of protein-coding variations on fitness

The relationship between genotype mutations and phenotype variations determines health in the short term and evolution over the long term, and it hinges on the action of mutations on fitness. A fundamental difficulty in determining this action, however, is that it depends on the unique context of ea...

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Detalles Bibliográficos
Autores principales: Katsonis, Panagiotis, Lichtarge, Olivier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248321/
https://www.ncbi.nlm.nih.gov/pubmed/25217195
http://dx.doi.org/10.1101/gr.176214.114
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author Katsonis, Panagiotis
Lichtarge, Olivier
author_facet Katsonis, Panagiotis
Lichtarge, Olivier
author_sort Katsonis, Panagiotis
collection PubMed
description The relationship between genotype mutations and phenotype variations determines health in the short term and evolution over the long term, and it hinges on the action of mutations on fitness. A fundamental difficulty in determining this action, however, is that it depends on the unique context of each mutation, which is complex and often cryptic. As a result, the effect of most genome variations on molecular function and overall fitness remains unknown and stands apart from population genetics theories linking fitness effect to polymorphism frequency. Here, we hypothesize that evolution is a continuous and differentiable physical process coupling genotype to phenotype. This leads to a formal equation for the action of coding mutations on fitness that can be interpreted as a product of the evolutionary importance of the mutated site with the difference in amino acid similarity. Approximations for these terms are readily computable from phylogenetic sequence analysis, and we show mutational, clinical, and population genetic evidence that this action equation predicts the effect of point mutations in vivo and in vitro in diverse proteins, correlates disease-causing gene mutations with morbidity, and determines the frequency of human coding polymorphisms, respectively. Thus, elementary calculus and phylogenetics can be integrated into a perturbation analysis of the evolutionary relationship between genotype and phenotype that quantitatively links point mutations to function and fitness and that opens a new analytic framework for equations of biology. In practice, this work explicitly bridges molecular evolution with population genetics with applications from protein redesign to the clinical assessment of human genetic variations.
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spelling pubmed-42483212014-12-01 A formal perturbation equation between genotype and phenotype determines the Evolutionary Action of protein-coding variations on fitness Katsonis, Panagiotis Lichtarge, Olivier Genome Res Method The relationship between genotype mutations and phenotype variations determines health in the short term and evolution over the long term, and it hinges on the action of mutations on fitness. A fundamental difficulty in determining this action, however, is that it depends on the unique context of each mutation, which is complex and often cryptic. As a result, the effect of most genome variations on molecular function and overall fitness remains unknown and stands apart from population genetics theories linking fitness effect to polymorphism frequency. Here, we hypothesize that evolution is a continuous and differentiable physical process coupling genotype to phenotype. This leads to a formal equation for the action of coding mutations on fitness that can be interpreted as a product of the evolutionary importance of the mutated site with the difference in amino acid similarity. Approximations for these terms are readily computable from phylogenetic sequence analysis, and we show mutational, clinical, and population genetic evidence that this action equation predicts the effect of point mutations in vivo and in vitro in diverse proteins, correlates disease-causing gene mutations with morbidity, and determines the frequency of human coding polymorphisms, respectively. Thus, elementary calculus and phylogenetics can be integrated into a perturbation analysis of the evolutionary relationship between genotype and phenotype that quantitatively links point mutations to function and fitness and that opens a new analytic framework for equations of biology. In practice, this work explicitly bridges molecular evolution with population genetics with applications from protein redesign to the clinical assessment of human genetic variations. Cold Spring Harbor Laboratory Press 2014-12 /pmc/articles/PMC4248321/ /pubmed/25217195 http://dx.doi.org/10.1101/gr.176214.114 Text en © 2014 Katsonis and Lichtarge; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Method
Katsonis, Panagiotis
Lichtarge, Olivier
A formal perturbation equation between genotype and phenotype determines the Evolutionary Action of protein-coding variations on fitness
title A formal perturbation equation between genotype and phenotype determines the Evolutionary Action of protein-coding variations on fitness
title_full A formal perturbation equation between genotype and phenotype determines the Evolutionary Action of protein-coding variations on fitness
title_fullStr A formal perturbation equation between genotype and phenotype determines the Evolutionary Action of protein-coding variations on fitness
title_full_unstemmed A formal perturbation equation between genotype and phenotype determines the Evolutionary Action of protein-coding variations on fitness
title_short A formal perturbation equation between genotype and phenotype determines the Evolutionary Action of protein-coding variations on fitness
title_sort formal perturbation equation between genotype and phenotype determines the evolutionary action of protein-coding variations on fitness
topic Method
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248321/
https://www.ncbi.nlm.nih.gov/pubmed/25217195
http://dx.doi.org/10.1101/gr.176214.114
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