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Missense meanderings in sequence space: a biophysical view of protein evolution

Nature Reviews Genetics volume 6, pages 678–687 (2005)Cite this article

Key Points

  • In addition to functional properties, proteins have a wide range of biophysical characteristics, such as stability, propensity for aggregation and rate of degradation. These properties are at least as important as function for cellular and organismal fitness.

  • Proteins tolerate only narrow ranges of stability, aggregation propensity and degradation rate. Many individual missense mutations perturb these traits by amounts that are on the same order as the permissible range of values, and are consequently common causes of human genetic disease.

  • The narrow range of tolerance of deviations from optimum characteristics and the significant effects of mutations give rise to a substantial degree of epistasis for fitness. Moreover, mutations simultaneously affect function, stability, aggregation and degradation. For these reasons, mutations might be selectively beneficial on some genetic backgrounds and deleterious on others.

  • Mutations that change function often do so at the cost of protein stability and aggregation. Compensatory mutations therefore function by relieving the biophysical strain that is introduced by adaptive mutations.

  • We propose a new model of protein evolution that is reminiscent of a constrained 'random walk' through fitness space, which is based on the fitness consequences and distribution of mutational effects on function, stability, aggregation and degradation.

  • This model can account for both the micro-evolutionary events that are studied by biochemists and the long-term patterns of protein evolution that are observed by evolutionary biologists.

Abstract

Proteins are finicky molecules; they are barely stable and are prone to aggregate, but they must function in a crowded environment that is full of degradative enzymes bent on their destruction. It is no surprise that many common diseases are due to missense mutations that affect protein stability and aggregation. Here we review the literature on biophysics as it relates to molecular evolution, focusing on how protein stability and aggregation affect organismal fitness. We then advance a biophysical model of protein evolution that helps us to understand phenomena that range from the dynamics of molecular adaptation to the clock-like rate of protein evolution.

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Figure 1: The relationship between protein stability, organismal fitness and protein evolution.
Figure 2: Two models for the occurrence of compensatory pathogenic deviations.

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Acknowledgements

M.A.D. is a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation. D.M.W. and D.L.H. thank the National Science Foundation for support.

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  1. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, 02138, Massachusetts, USA

    Mark A. DePristo, Daniel M. Weinreich & Daniel L. Hartl

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  1. Mark A. DePristo
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DATABASES

OMIM

Alzheimer

Huntington

Glossary

FIXATION

A mutation that has achieved a frequency of 100% in a natural population.

ADAPTIVE EVOLUTION

A genetic change that results in increased fitness.

FITNESS

A measure of the capacity of an organism to survive and reproduce.

β SHEET

A secondary protein structure that has extensive, non-local hydrogen bonding.

CHAPERONES

A large class of cellular proteins that help other proteins to fold into their correct native conformation.

INCLUSION BODIES

Insoluble aggregates of misfolded proteins; inclusion bodies are common in prokaryotes.

UBIQUITIN–PROTEASOME PATHWAY

A eukaryotic degradation system in which ubiquitin molecules are attached to a target protein that is subsequently degraded by the proteasome complex.

EFFECTIVE CONCENTRATION

The concentration of functional molecules, as opposed to the total concentration of molecules.

NATIVELY UNFOLDED

Describes a class of proteins that are unfolded under physiological conditions.

POIKILOTHERMIC ORGANISM

An organism in which body temperature fluctuates with environmental temperature.

EXTREMOPHILE

An organism that thrives in environments that are inhospitable to most other organisms such as extreme heat (thermophiles), salinity (halophiles) and pressure (barophiles).

EPISTASIS

This occurs when the effect of a mutation varies with genetic background.

AMYLOIDOGENIC

Describes a protein that forms amyloid fibrils — a large, extended conformation that is adopted by many aggregated proteins. Amyloid fibrils are characteristic of several neurological disorders.

ORTHOLOGOUS PROTEINS

Proteins corresponding to genes that are related through speciation. By contrast, paralogous proteins are related by gene duplication.

GENETIC DRIFT

The stochastic variation in population frequency of a mutation that is due to the sampling process inherent in reproduction.

FITNESS VALLEY

The circumstance in which mutations individually reduce fitness while jointly increasing it, so that when fitness is represented graphically, these single mutants form a valley.

NON-MONOTONIC

A function in which the first derivative changes sign. Here this indicates that fitness decreases with departure from an optimal stability.

STABILIZING SELECTION

Selection that maintains a phenotype at some intermediate value.

LATTICE MODEL

An abstract model for protein folding in which a protein chain is constrained to occupy discrete points on a regular two- or three-dimensional lattice.

POPULATION DELOCALIZATION

A mechanism by which large populations can traverse fitness valleys without the fixation of deleterious mutational intermediates.

MOLECULAR CLOCK

The constant (clock-like) rate of missense fixation over evolutionary timescales.

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DePristo, M., Weinreich, D. & Hartl, D. Missense meanderings in sequence space: a biophysical view of protein evolution. Nat Rev Genet 6, 678–687 (2005). https://doi.org/10.1038/nrg1672

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