Mutational effects and the evolution of new protein functions

KEY POINTS * The divergence of new genes and proteins occurs through mutations that modulate protein function. The effects of these mutations are pleiotropic, thus imposing trade-offs

between selection pressures for the existing function and the newly evolving one and among the protein's activity, stability and dosage. * Various compensatory and buffering mechanisms,

such as gene duplication, upregulation of expression, stabilizing mutations and chaperone folding assistance, can alleviate these trade-offs and so facilitate functional divergence. *

Despite buffering effects, the fitness distribution of mutations at the protein level, and for whole organisms, is such that most of the mutations are either neutral or deleterious. This

results in the rapid and irreversible non-functionalization of proteins that accumulate mutations under no selection. * The distribution of fitness effects of mutations for whole organisms

is comparable, and possibly even more deleterious, than that of protein mutations. * Duplication underlies the divergence of new genes and proteins. Duplication is almost as frequent as

point mutations and is a common mechanism for resolving the trade-off conflicts that arise owing to parallel selection pressures. These pressures may regard the existing and the new function

and maintenance of the protein's structural stability. * Duplication, and the emergence of new genes and proteins, may occur at different stages of the divergence process. The

selection pressures that act on the gene and its duplicate may differ, giving rise to different mechanisms of divergence. These mechanisms are described under three schematic models —

Ohno's model, the 'divergence before duplication' (DPD) model and the sub-functionalization model. * In Ohno's model of divergence, duplication is a neutral event. The

duplicated copy of the protein drifts under no selection until a new function becomes under selection. The downside of this model is that under no selection, non-functionalization of the

drifting protein is inevitable. Its advantage is that divergence is independent of trade-offs between the new and existing functions. * The DPD model is based on a 'generalist'

intermediate that confers a selectable degree of both the new and existing functions. Duplication occurs after the acquisition of a new function, and occurs under positive selection to

increase protein dosage and/or alleviate trade-offs that make the acquisition of new function depend on loss of the existing one. * The sub-functionalization model combines elements of the

DPD model and Ohno's model. Duplication is initially a neutral event, but once mutations that partially reduce protein activity or dosage appear, both copies must remain functional.

Duplication therefore enables a larger genetic variability to accumulate, thereby facilitating the emergence of new functions. * The DPD and sub-functionalization models are both based on

mutations with adaptive potential initially accumulating as neutral. As such, they are related to the notions of hidden or apparently neutral variation and of neutral networks. ABSTRACT The

divergence of new genes and proteins occurs through mutations that modulate protein function. However, mutations are pleiotropic and can have different effects on organismal fitness

depending on the environment, as well as opposite effects on protein function and dosage. We review the pleiotropic effects of mutations. We discuss how they affect the evolution of gene and

protein function, and how these complex mutational effects dictate the likelihood and mechanism of gene duplication and divergence. We propose several factors that can affect the divergence

of new protein functions, including mutational trade-offs and hidden, or apparently neutral, variation. Access through your institution Buy or subscribe This is a preview of subscription

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ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS FUNCTIONAL SYNONYMOUS MUTATIONS AND THEIR

EVOLUTIONARY CONSEQUENCES Article 20 May 2025 THE POPULATION GENOMICS OF ADAPTIVE LOSS OF FUNCTION Article Open access 11 February 2021 CHANGES IN THE DISTRIBUTION OF FITNESS EFFECTS AND

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Leon Benoziyo Professorial Chair. Financial support from the Meil de Botton Aynsley and the EU network BioModularH2 are gratefully acknowledged. We are very grateful to S. Bershtein, N.

Tokuriki, F. Kondrashov and J. G. Zhang for their insightful comments regarding this manuscript and to A. Eyre-Walker for providing the data for the figure in Box 1. AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS * Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel Misha Soskine & Dan S. Tawfik Authors * Misha Soskine View author

publications You can also search for this author inPubMed Google Scholar * Dan S. Tawfik View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING

AUTHOR Correspondence to Dan S. Tawfik. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. GLOSSARY * Protein mutations Missense mutations that

occur in encoded open reading frames. * Trade-offs Gains of a new activity or property at the expense of other activities or properties. * Protein stability The capacity of a protein to

adopt its native, functional structure. Stability also correlates with cellular protein levels. * Sub-functionalization Degenerate mutations that result in a gene and its duplicated copy

sharing the burden of one function. * Negative epistasis The combined effect of mutations being more deleterious than expected from their individual effects. * Protein fitness Levels of

physiological function exerted by a given protein variant under a certain selection pressure. * Non-functionalization The complete inactivation of a gene or protein by highly deleterious

mutations. * Neo-functionalization The divergence of a duplicated gene or protein to execute a new function. * ΔΔG The stability difference for a protein variant versus its wild-type

reference (ΔΔG > 0 indicates lower stability). * Disordered domains Protein domains with a high degree of random coil and loop regions and a low degree of highly ordered secondary

structure. * Apparently neutral mutations Mutations that have no significant or observable fitness effect under a given environment. * New-function mutations Mutations that mediate changes

in protein activity, typically by increasing a weak, latent promiscuous function. * New–existing function trade-offs The acquisition of a new function through mutations that undermine the

existing function. * Chaperones Proteins that mediate the correct folding and assembly of other proteins. * Specialists Genes or proteins that exert one specific function with high

proficiency. * Generalist A gene or protein that exerts multiple functions, typically one primary function and additional secondary or promiscuous functions. * New-function–stability

trade-offs Mutations that increase the new, evolving function but reduce protein stability and protein dosage. * Productive variation Genetic variation that does not compromise fitness in

the dwelling environment but holds the potential for adaptation to new environments. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Soskine, M., Tawfik,

D. Mutational effects and the evolution of new protein functions. _Nat Rev Genet_ 11, 572–582 (2010). https://doi.org/10.1038/nrg2808 Download citation * Issue Date: August 2010 * DOI:

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