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.
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.
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D.S.T. is the incumbent of the Nella and 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.
The authors declare no competing financial interests.
- Protein mutations
Missense mutations that occur in encoded open reading frames.
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.
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.
The complete inactivation of a gene or protein by highly deleterious mutations.
The divergence of a duplicated gene or protein to execute a new function.
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.
Proteins that mediate the correct folding and assembly of other proteins.
Genes or proteins that exert one specific function with high proficiency.
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.
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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
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