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      Expression attenuation as a mechanism of robustness against gene duplication

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          Significance

          Many studies have focused on the mechanisms of long-term retention of gene duplicates, such as the gain of functions or reciprocal losses. However, such changes are more likely to occur if the duplicates are maintained for a long period. This time span will be short if duplication is immediately deleterious. We measured the distribution of fitness effects of gene duplication for 899 genes in budding yeast. We find that gene duplication is more likely to be deleterious than beneficial. However, contrary to previous models, in general, gene duplication does not affect fitness by altering the organization of protein complexes. We show that expression attenuation may protect complexes from the effects of gene duplication.

          Abstract

          Gene duplication is ubiquitous and a major driver of phenotypic diversity across the tree of life, but its immediate consequences are not fully understood. Deleterious effects would decrease the probability of retention of duplicates and prevent their contribution to long-term evolution. One possible detrimental effect of duplication is the perturbation of the stoichiometry of protein complexes. Here, we measured the fitness effects of the duplication of 899 essential genes in the budding yeast using high-resolution competition assays. At least 10% of genes caused a fitness disadvantage when duplicated. Intriguingly, the duplication of most protein complex subunits had small to nondetectable effects on fitness, with few exceptions. We selected four complexes with subunits that had an impact on fitness when duplicated and measured the impact of individual gene duplications on their protein–protein interactions. We found that very few duplications affect both fitness and interactions. Furthermore, large complexes such as the 26S proteasome are protected from gene duplication by attenuation of protein abundance. Regulatory mechanisms that maintain the stoichiometric balance of protein complexes may protect from the immediate effects of gene duplication. Our results show that a better understanding of protein regulation and assembly in complexes is required for the refinement of current models of gene duplication.

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          Most cited references70

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          Evolution by gene duplication: an update

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            The probability of duplicate gene preservation by subfunctionalization.

            It has often been argued that gene-duplication events are most commonly followed by a mutational event that silences one member of the pair, while on rare occasions both members of the pair are preserved as one acquires a mutation with a beneficial function and the other retains the original function. However, empirical evidence from genome duplication events suggests that gene duplicates are preserved in genomes far more commonly and for periods far in excess of the expectations under this model, and whereas some gene duplicates clearly evolve new functions, there is little evidence that this is the most common mechanism of duplicate-gene preservation. An alternative hypothesis is that gene duplicates are frequently preserved by subfunctionalization, whereby both members of a pair experience degenerative mutations that reduce their joint levels and patterns of activity to that of the single ancestral gene. We consider the ways in which the probability of duplicate-gene preservation by such complementary mutations is modified by aspects of gene structure, degree of linkage, mutation rates and effects, and population size. Even if most mutations cause complete loss-of-subfunction, the probability of duplicate-gene preservation can be appreciable if the long-term effective population size is on the order of 10(5) or smaller, especially if there are more than two independently mutable subfunctions per locus. Even a moderate incidence of partial loss-of-function mutations greatly elevates the probability of preservation. The model proposed herein leads to quantitative predictions that are consistent with observations on the frequency of long-term duplicate gene preservation and with observations that indicate that a common fate of the members of duplicate-gene pairs is the partitioning of tissue-specific patterns of expression of the ancestral gene.
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              Dosage sensitivity and the evolution of gene families in yeast.

              According to what we term the balance hypothesis, an imbalance in the concentration of the subcomponents of a protein-protein complex can be deleterious. If so, there are two consequences: first, both underexpression and overexpression of protein complex subunits should lower fitness, and second, the accuracy of transcriptional co-regulation of subunits should reflect the deleterious consequences of imbalance. Here we show that all these predictions are upheld in yeast (Saccharomyces cerevisiae). This supports the hypothesis that dominance is a by-product of physiology and metabolism rather than the result of selection to mask the deleterious effects of mutations. Beyond this, single-gene duplication of protein subunits is expected to be harmful, as this, too, leads to imbalance. As then expected, we find that members of large gene families are rarely involved in complexes. The balance hypothesis therefore provides a single theoretical framework for understanding components both of dominance and of gene family size.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc Natl Acad Sci U S A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                09 February 2021
                01 February 2021
                01 February 2021
                : 118
                : 6
                : e2014345118
                Affiliations
                [1] aRegroupement Québécois de Recherche sur la Fonction, l’Ingénierie et les Applications des Protéines , Québec, QC G1V 0A6, Canada;
                [2] bInstitut de Biologie Intégrative et des Systèmes, Université Laval , Québec, QC G1V 0A6, Canada;
                [3] cCentre de Recherche en Données Massives de l’Université Laval, Université Laval , Québec, QC G1V 0A6, Canada;
                [4] dDépartement de Biochimie, de Microbiologie et de Bio-informatique, Université Laval , Québec, QC G1V 0A6, Canada;
                [5] eDépartement de Biologie, Université Laval , Québec, QC G1V 0A6, Canada;
                [6] fUnidad de Genómica Avanzada (Langebio), Centro de Investigación y de Estudios Avanzados , 36824 Irapuato, Guanajuato, Mexico
                Author notes
                2To whom correspondence may be addressed. Email: christian.landry@ 123456bio.ulaval.ca .

                Edited by Michael Lynch, Arizona State University, Tempe, AZ, and approved December 24, 2020 (received for review July 10, 2020)

                Author contributions: D.A., G.D., A.D., and C.R.L. designed research; D.A., G.D., I.G.-A., and A.K.D. performed research; A.D. contributed new reagents/analytic tools; D.A., G.D., and I.G.-A. analyzed data; and D.A. and C.R.L. wrote the paper.

                1Present address: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.

                Author information
                https://orcid.org/0000-0003-4808-1244
                https://orcid.org/0000-0001-9153-4523
                https://orcid.org/0000-0003-2661-1929
                https://orcid.org/0000-0001-8718-9894
                https://orcid.org/0000-0002-9236-2804
                https://orcid.org/0000-0003-3028-6866
                Article
                202014345
                10.1073/pnas.2014345118
                7970654
                33526669
                8b7f154d-aefc-445f-a497-0413ca3d583b
                Copyright © 2021 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                History
                Page count
                Pages: 10
                Funding
                Funded by: Gouvernement du Canada | Canadian Institutes of Health Research (CIHR) 501100000024
                Award ID: 387697
                Award Recipient : Diana Ascencio Award Recipient : Isabelle Gagnon-Arsenault Award Recipient : Alexandre K Dube Award Recipient : Christian R Landry
                Categories
                418
                Biological Sciences
                Evolution
                Custom metadata
                March 17, 2021

                gene duplication,gene expression,protein interaction,dosage balance hypothesis,fitness effects

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