Protein Evolution with Dependence Among Codons Due to Tertiary Structure

Robinson, Douglas; Jones, David T.; Kishino, Hirohisa; Goldman, Nick; Thorne, Jeffrey L.

doi:10.1093/molbev/msg184

Cited by 185 publications

(240 citation statements)

References 36 publications

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“…In addition to having mild effects on stability and fitness, substitutions are distributed nonrandomly in the protein structure. We find more substitutions at sites with greater solvent-accessible surface area (Pearson's correlation ρ = 0.54, P <10 −15 ; see SI Appendix) as well as at residues occupying small volumes in the protein (Pearson's correlation ρ = −0.22, P =0.0008; see SI Appendix), consistent with biophysical expectations (46,(81)(82)(83).…”

Section: Resultssupporting

confidence: 81%

“…In reality, however, it is likely that the strength of selection on stability varies within a protein-so that the protein core experiences stronger purifying selection than the periphery (46,(81)(82)(83). Incorporating local stability requirements would certainly improve our understanding of selective constraints, but it seems unlikely to qualitatively change our results on the dominant sources of epistasis that modulate substitutions.…”

Section: Discussionmentioning

confidence: 98%

“…Indeed, although some more sophisticated models have been proposed (e.g., refs. [45][46][47][48][49][50], all commonly used phylogenetic models of long-term protein evolution assume that epistasis is absent so that sites evolve independently (51)(52)(53)(54)(55)(56).…”

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confidence: 99%

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Contingency and entrenchment in protein evolution under purifying selection

Shah

McCandlish

Plotkin

2015

Proc. Natl. Acad. Sci. U.S.A.

183

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The phenotypic effect of an allele at one genetic site may depend on alleles at other sites, a phenomenon known as epistasis. Epistasis can profoundly influence the process of evolution in populations and shape the patterns of protein divergence across species. Whereas epistasis between adaptive substitutions has been studied extensively, relatively little is known about epistasis under purifying selection. Here we use computational models of thermodynamic stability in a ligand-binding protein to explore the structure of epistasis in simulations of protein sequence evolution. Even though the predicted effects on stability of random mutations are almost completely additive, the mutations that fix under purifying selection are enriched for epistasis. In particular, the mutations that fix are contingent on previous substitutions: Although nearly neutral at their time of fixation, these mutations would be deleterious in the absence of preceding substitutions. Conversely, substitutions under purifying selection are subsequently entrenched by epistasis with later substitutions: They become increasingly deleterious to revert over time. Our results imply that, even under purifying selection, protein sequence evolution is often contingent on history and so it cannot be predicted by the phenotypic effects of mutations assayed in the ancestral background.intragenic epistasis | coevolution | near neutrality | protein stability W hether a heritable mutation is advantageous or deleterious to an organism often depends on the evolutionary history of the population. A mutation that is beneficial at the time of its introduction may confer its beneficial effect only in the presence of other potentiating or permissive mutations (1-9). Thus, the fate of a mutation arising in a population may be contingent on previous mutations (10-13). Conversely, once a mutation has fixed in a population, the mutation becomes part of the genetic background onto which subsequent modifications are introduced. Because the beneficial effects of the subsequent modifications may depend on the focal mutation, as time passes reversion of the focal mutation may become increasingly deleterious, leading to a type of evolutionary conservatism, or entrenchment (14-18).In the context of protein evolution, the effects of contingency and entrenchment are most easily studied by considering a sequence of single amino acid changes (19) that extends both forward and backward in time from some focal substitution. To assess the roles of contingency and entrenchment we can study the degree to which each focal substitution was facilitated by previous substitutions, and the degree to which the focal substitution influences the subsequent course of evolution (Fig. 1A).Dependencies within a sequence of substitutions are closely connected to the concept of epistasis-that is, the idea that the phenotypic effect of a mutation at a particular genetic site may depend on the genetic background in which it arises (20-24). In the absence of epistasis, a mutation has the same effect ...

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Section: Resultssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 98%

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Contingency and entrenchment in protein evolution under purifying selection

Shah

McCandlish

Plotkin

2015

Proc. Natl. Acad. Sci. U.S.A.

183

236

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“…Research in this area is ongoing, with the most recently developed models relaxing the assumption of independence among sites by taking into account the occurrence of context-dependent 127 , multiple-nucleotide 128 and structurally constrained 129,130 substitutions. Likelihood models that relax the assumptions of homogeneity and stationarity have also been designed to handle sequences with heterogeneous composition 131,132 .…”

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confidence: 99%

Phylogenomics and the reconstruction of the tree of life

2005

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Correspondence to H.P. email: herve.philippe@umontreal.ca -2 - PrefaceAs more complete genomes are sequenced, phylogenetic analysis is entering a new era -that of phylogenomics. One branch of this expanding field aims to reconstruct the evolutionary history of organisms based on the analysis of their genomes. Recent studies have demonstrated the power of this approach, which has the potential to provide answers to a number of fundamental evolutionary questions. However, challenges for the future have also been revealed. The very nature of the evolutionary history of organisms and the limitations of current phylogenetic reconstruction methods mean that part of the tree of life may prove difficult, if not impossible, to resolve with confidence. Introductory paragraphUnderstanding phylogenetic relationships between organisms is a prerequisite of almost any evolutionary study, as contemporary species all share a common history through their ancestry. The notion of phylogeny follows directly from the theory of evolution presented by Charles Darwin in "The Origin of Species" 1 : the only illustration in his famous book is the first representation of evolutionary relationships among species, in the form of a phylogenetic tree. The subsequent enthusiasm of biologists for the phylogenetic concept is illustrated by the publication of Ernst Haeckel's famous "trees" as early as 1866 2 .Today, phylogenetics -the reconstruction of evolutionary history -relies on using mathematical methods to infer the past from features of contemporary species, with only the fossil record to provide a window on the evolutionary past of life on our planet. This reconstruction involves the identification of HOMOLOGOUS CHARACTERS that are shared among different organisms, and the inference of phylogenetic trees from the comparison of these characters using reconstruction methods (BOX 1). The accuracy of -3 -the inference is therefore heavily dependent upon the quality of models for the evolution of such characters. Because the underlying mechanisms are not yet well understood, reconstructing the evolutionary history of life on Earth based solely on the information provided by living organisms has turned out to be difficult.Until the 1970s, which brought the dawn of molecular techniques for sequencing proteins and DNA, phylogenetic reconstruction was essentially based on the analysis of morphological or ultrastructural characters. The comparative anatomy of fossils and extant species has proved powerful in some respects; for example, the main groups of animals and plants have been delineated fairly easily using these methods. However, this approach is hampered by the limited number of reliable homologous characters available; these are almost non-existent in micro-organisms 3 and are rare even in complex organisms.The introduction of the use of molecular data in phylogenetics 4 led to a revolution.In the late 1980s, access to DNA sequences increased the number of homologous characters that could be compared from less than 100 to more than 1,000, ...

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“…This has been done for proteins (Robinson et al [32], Rodrigue et al [33]) and RNAs (Yu and Thorne [34], Thorne et al [35]). It is assumed that fitness depends on energy: mutations that lower the energy are treated as advantageous and those that increase the energy are treated as deleterious.…”

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confidence: 99%

Linking population genetics to phylogenetics

Higgs

2008

Stochastic Models in Biological Sciences

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Abstract. Population geneticists study the variability of gene sequences within a species, whereas phylogeneticists compare gene sequences between species and usually have only one representative sequence per species. Stochastic models in population genetics are used to determine probability distributions for gene frequencies and to predict the probability that a new mutation will become fixed in a population. Stochastic models in phylogenetics describe the substitution process in the single sequence that represents a species. These latter models are of great practical use in inferring evolutionary trees, but they ignore population genetics. Here, we consider the way that the two fields are linked. In a finite population with a low mutation rate, most sites in a gene are monomorphic; therefore it is a reasonable approximation to represent a species by a single sequence and to ignore within population variability. We show that population genetics theory can be used to predict the substitution rates that will be seen in phylogenetic models. However, a substitution in the phylogenetic sense is really the fixation of a new mutation in the population genetics sense. Substitution rates are dependent on mutation, selection and random drift, not just on mutation. An appreciation of the relationship with population genetics is important when designing new empirical models for phylogenetics, for example, paired-site models for RNA sequences with secondary structure and codon-based models for protein-coding regions of DNA.

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Protein Evolution with Dependence Among Codons Due to Tertiary Structure

Cited by 185 publications

References 36 publications

Contingency and entrenchment in protein evolution under purifying selection

Contingency and entrenchment in protein evolution under purifying selection

Phylogenomics and the reconstruction of the tree of life

Linking population genetics to phylogenetics

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