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Mechanistic approaches to the study of evolution: the functional synthesis

Key Points

  • By combining evolutionary sequence analyses and manipulative molecular experiments, the functional synthesis of molecular evolution provides a powerful framework to elucidate the mechanisms by which historical mutations have altered biochemical processes and produced novel phenotypes. By using this approach, inferred ancestral sequences can be resurrected and their phenotypes and fitness effects assessed experimentally.

  • The functional synthesis of molecular evolution provides independent corroboration of statistical inferences that have been drawn from sequence analyses.

  • The functional synthesis of molecular evolution explicitly connects genotype with phenotype to allow mechanistic insights into the causes of adaptive change and evolutionary constraint.

  • The functional synthesis of molecular evolution provides decisive tests of recent adaptations where genetic variation still segregates in present-day species, and of ancient adaptations where genetic variation is fixed in present-day species.

  • The functional synthesis of molecular evolution can resolve long-standing questions about evolutionary processes and important evolutionary questions about metabolic, cellular, developmental and behavioural systems.

  • The functional synthesis of molecular evolution can be used to characterize adaptive landscapes and explore the evolution of complexity.

  • The functional synthesis of molecular evolution is poised to move beyond studies of single genes to allow the analysis of the evolution of pathways and networks that are made up of multiple genes.

  • The functional synthesis of molecular evolution should become routine in studies of molecular evolution.

Abstract

An emerging synthesis of evolutionary biology and experimental molecular biology is providing much stronger and deeper inferences about the dynamics and mechanisms of evolution than were possible in the past. The new approach combines statistical analyses of gene sequences with manipulative molecular experiments to reveal how ancient mutations altered biochemical processes and produced novel phenotypes. This functional synthesis has set the stage for major advances in our understanding of fundamental questions in evolutionary biology. Here we describe this emerging approach, highlight important new insights that it has made possible, and suggest future directions for the field.

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Figure 1: Evolution of insecticide resistance by a single amino-acid change.
Figure 2: Evolution of spectral sensitivity in vertebrate opsins.
Figure 3: Uphill adaptive walks among amino-acid replacements in the adaptive landscape of TEM β-lactamase.
Figure 4: Constraint and opportunity in the evolution of coenzyme use by paralogous dehydrogenases.
Figure 5: Evolution of corticosteroid-receptor specificity.

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Acknowledgements

We thank M. Borello, M. Travisano, P. Phillips, B. Cresko, P. Rainey, A. Kondrashov, S. Yokoyama, R. Newcomb, D.Weinreich, B. Hall, an anonymous referee and members of the Thornton and Dean laboratories for comments. Supported by the US National Science Foundation (NSF IOB-0546906), the US National Institutes of Health (NIH R01-GM081592), and a Sloan Foundation Fellowship to J.W.T. and NIH R01-GM060,611 to A.M.D.

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Glossary

Evo–devo synthesis

The study of the origin and evolution of development, originally restricted to comparative methods, but increasingly using experimental approaches.

Coalescent theory

A mathematical framework, based on the genealogy of alleles, for estimating population genetic alleles.

Strong selection–weak mutation model

A population genetic model in which beneficial mutations are fixed sequentially in the population through a series of selective sweeps, and in which neutral and deleterious mutations can be ignored as having low probabilities of fixation.

Chemostat competition assay

A precise assay of the relative growth rates (fitnesses) of competing strains can be obtained in the chemostat, a continuous culture device that is used to impose starvation for a specific resource in a constant environment.

Directed evolution

A library of random mutants that have been generated by PCR amplification of a gene is ligated into a plasmid, transformed into a strain and screened for a desired function.

Michaelis complex

A complex of substrate bound to enzyme just before catalysis.

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Dean, A., Thornton, J. Mechanistic approaches to the study of evolution: the functional synthesis. Nat Rev Genet 8, 675–688 (2007). https://doi.org/10.1038/nrg2160

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