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  • Review Article
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Causes of molecular convergence and parallelism in protein evolution

Nature Reviews Genetics volume 17, pages 239–250 (2016)Cite this article

Subjects

Key Points

  • An important question in evolutionary genetics concerns the extent to which adaptive convergence in protein function is caused by convergent or parallel changes at the amino acid level. Even when there is a many-to-one mapping of genotype to phenotype, particular mutations may be preferentially fixed (substitution bias) owing to among-site variation in the rate of mutation to function-altering alleles and/or variation among mutations in their probability of fixation once they arise.

  • Within the set of mutations that have functionally equivalent effects on a selected phenotype, those that incur a lower magnitude of deleterious pleiotropy will generally have higher fixation probabilities. Mutational pleiotropy may therefore represent an important source of substitution bias.

  • A key finding is that the fitness effects of amino acid mutations are often conditional on the genetic background in which they occur. This context dependence (epistasis) reduces the probability of molecular convergence and parallelism because it reduces the number of possible mutations that have unconditionally acceptable effects in divergent genetic backgrounds.

  • Context-dependent mutational effects often stem from pleiotropic trade-offs, as evidenced by cases where the fitness impact of a given mutation is determined by compensatory (conditionally beneficial) mutations at other sites in the same protein.

  • Even if mutations have identical functional effects on a selected phenotype, they can have different fitness effects owing to a nonlinear mapping of phenotype to fitness. Thus, probabilities of convergence and parallelism are reduced by species differences in the genotype-phenotype map and by differences in the phenotype-fitness map.

  • Although computational analyses of sequence variation play a key part in suggesting hypotheses about the causes of convergent and parallel substitutions and their possible adaptive significance, experimental analyses of specific mutations are necessary to test such hypotheses.

Abstract

To what extent is the convergent evolution of protein function attributable to convergent or parallel changes at the amino acid level? The mutations that contribute to adaptive protein evolution may represent a biased subset of all possible beneficial mutations owing to mutation bias and/or variation in the magnitude of deleterious pleiotropy. A key finding is that the fitness effects of amino acid mutations are often conditional on genetic background. This context dependence (epistasis) can reduce the probability of convergence and parallelism because it reduces the number of possible mutations that are unconditionally acceptable in divergent genetic backgrounds. Here, I review factors that influence the probability of replicated evolution at the molecular level.

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Figure 1: Convergent and parallel substitutions: phylogenetically replicated changes that involve different mutational paths.
Figure 2: Phylogenetic patterns of parallel and unique substitutions in ATPα1 that are associated with resistance to toxic cardenolides in herbivorous insects.
Figure 3: Schematic depiction of how single-position fitness landscapes change through time.
Figure 4: Mutations with additive effects on phenotype can have epistatic effects on fitness.

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Acknowledgements

The author thanks M. W. Hahn, M. J. Harms, D. McCandlish, M. D. Rausher, A. Stoltzfus and anonymous reviewers for helpful suggestions. This work was supported by grants from the US National Institutes of Health (HL087216) and the US National Science Foundation (MCB-1517636 and IOS-0949931).

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    Jay F. Storz

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Glossary

Orthologous

A form of homologous relationship between genes from different species, indicating that they trace their common ancestry back to speciation events (represented by internal nodes of the species tree) rather than gene duplication events.

Fixation

The process by which the frequency of a mutant allele increases to 100% in a population, thereby supplanting the ancestral allele.

Identical-by-state

The identity of allelic gene copies that is attributable to independent mutational changes to a shared character state. The alleles in question have independent mutational origins.

Cardenolides

Plant-derived steroidal toxins that have an important role in defence against insect herbivores by inhibiting the Na+/K+-ATPase enzyme.

Identical-by-descent

The identity of allelic gene copies that is attributable to direct descent from a single-copy ancestral allele. The alleles in question have a single mutational origin.

Incomplete lineage sorting

The retention of ancestral polymorphism from one population-splitting event to the next, followed by stochastic sorting of allelic lineages among descendant species. A common cause of genealogical discordance between gene trees and species trees.

Introgressive hybridization

The incorporation of allelic variants from one species into the gene pool of another species via hybridization and repeated backcrossing.

Genealogical discordance

Topological discrepancies among the allelic genealogies (gene trees) of different loci in the same organismal phylogeny.

Homoplasy

Sharing of character states between species that is attributable to convergence, parallelism, or evolutionary reversal rather than direct inheritance from a common ancestor.

Pleiotropy

The phenomenon where the same mutation (or genetic locus) affects multiple phenotypes.

Selection coefficients

Measures of the relative fitnesses of particular genotypes in comparison with a reference genotype in a defined environment.

Transition:transversion bias

The commonly observed excess of transition mutations (exchanges between purine DNA bases [A↔G] or between pyrimidine bases [C↔T]) relative to transversion mutations (exchanges between purines and pyrimidines).

CpG bias

If the DNA nucleotide cytosine (C) is immediately 5′ to guanine (G) on the same coding strand (a so-called 'CpG' dinucleotide), and if the C is methylated to form 5′-methylcytosine, then C→T and G→A transition mutations occur at an elevated rate relative to mutations at non-CpG sites.

Adaptive walks

Adaptive evolution that occurs via the sequential fixation of beneficial mutations. The process can be conceptualized as the movement of a population through genotype space via discrete mutational steps, following a trajectory of progressively increasing fitness.

Nonsynonymous mutation

A point mutation in coding sequence that causes an amino acid replacement in the encoded protein.

Standing variation

Allelic variation that is currently segregating in a population, as opposed to allelic variants produced by de novo mutation.

Epistasis

Non-additive interactions between alleles at two or more loci, such that the phenotypic effect of the different alleles in combination cannot be predicted by the sum of the individual effects of each allele by itself.

Stabilizing selection

Selection on phenotypic variation that favours intermediate trait values.

Purifying selection

Selection that removes deleterious allelic variants.

Equilibrium frequencies

Expected frequencies of amino acids in a given sequence or at each site within a sequence. In most models of amino acid sequence evolution, the frequencies are assumed to remain constant over the time period under consideration.

Markov process

A 'memoryless' process of stochastic change with the property that future states depend only on the present state, not on the sequence of antecedent states.

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Storz, J. Causes of molecular convergence and parallelism in protein evolution. Nat Rev Genet 17, 239–250 (2016). https://doi.org/10.1038/nrg.2016.11

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