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A common root for coevolution and substitution rate variability in protein sequence evolution.

ABSTRACT: We introduce a simple model that describes the average occurrence of point variations in a generic protein sequence. This model is based on the idea that mutations are more likely to be fixed at sites in contact with others that have mutated in the recent past. Therefore, we extend the usual assumptions made in protein coevolution by introducing a time dumping on the effect of a substitution on its surrounding and makes correlated substitutions happen in avalanches localized in space and time. The model correctly predicts the average correlation of substitutions as a function of their distance along the sequence. At the same time, it predicts an among-site distribution of the number of substitutions per site highly compatible with a negative binomial, consistently with experimental data. The promising outcomes achieved with this model encourage the application of the same ideas in the field of pairwise and multiple sequence alignment.

SUBMITTER: Rizzato F

PROVIDER: S-EPMC6888882 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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A common root for coevolution and substitution rate variability in protein sequence evolution.

Rizzato Francesca F Zamuner Stefano S Pagnani Andrea A Laio Alessandro A

Scientific reports 20191202 1

We introduce a simple model that describes the average occurrence of point variations in a generic protein sequence. This model is based on the idea that mutations are more likely to be fixed at sites in contact with others that have mutated in the recent past. Therefore, we extend the usual assumptions made in protein coevolution by introducing a time dumping on the effect of a substitution on its surrounding and makes correlated substitutions happen in avalanches localized in space and time. T ...[more]

PMID: 31792239

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Project description:Since the inception of the molecular clock model for sequence evolution, the investigation of protein divergence has revolved around the question of a more or less constant change of amino acid sequences, with specific overall rates for each family. Although anomalies in clock-like divergence are well known, the assumption of a constant decay rate for a given protein family is usually taken as the null model for protein evolution. However, systematic tests of this null model at a genome-wide scale have lagged behind, despite the databases' enormous growth. We focus here on divergence rate comparisons between very closely related lineages since this allows clear orthology assignments by synteny and reliable alignments, which are crucial for determining substitution rate changes. We generated a high-confidence dataset of syntenic orthologs from four ape species, including humans. We find that despite the appearance of an overall clock-like substitution pattern, several hundred protein families show lineage-specific acceleration and deceleration in divergence rates, or combinations of both in different lineages. Hence, our analysis uncovers a rather dynamic history of substitution rate changes, even between these closely related lineages, implying that one should expect that a large fraction of proteins will have had a history of episodic rate changes in deeper phylogenies. Furthermore, each of the lineages has a separate set of particularly fast diverging proteins. The genes with the highest percentage of branch-specific substitutions are ADCYAP1 in the human lineage (9.7%), CALU in chimpanzees (7.1%), SLC39A14 in the internal branch leading to humans and chimpanzees (4.1%), RNF128 in gorillas (9%), and S100Z in gibbons (15.2%). The mutational pattern in ADCYAP1 suggests a biased mutation process, possibly through asymmetric gene conversion effects. We conclude that a null model of constant change can be problematic for predicting the evolutionary trajectories of individual proteins.

Project description:The number of amino acids that occupy a given protein site during evolution reflects the selective constraints operating on the site. This evolutionary variability is strongly influenced by the structural properties of the site in the native structure, and it is quantified either through sequence entropy or through substitution rates. However, while the sequence entropy only depends on the equilibrium frequencies of the amino acids, the substitution rate also depends on the exchangeability matrix that describes mutations in the mathematical model of the substitution process. Here we apply two variants of a mathematical model of protein evolution with selection for protein stability, both against unfolding and against misfolding. Exploiting the approximation of independent sites, these models allow computing site-specific substitution processes that satisfy global constraints on folding stability. We find that site-specific substitution rates do not depend only on the selective constraints acting on the site, quantified through its sequence entropy. In fact, polar sites evolve faster than hydrophobic sites even for equal sequence entropy, as a consequence of the fact that polar amino acids are characterized by higher mutational exchangeability than hydrophobic ones. Accordingly, the model predicts that more polar proteins tend to evolve faster. Nevertheless, these results change if we compare proteins that evolve under different mutation biases, such as orthologous proteins in different bacterial genomes. In this case, the substitution rates are faster in genomes that evolve under mutational bias that favor hydrophobic amino acids by preferentially incorporating the nucleotide Thymine that is more frequent in hydrophobic codons. This appearingly contradictory result arises because buried sites occupied by hydrophobic amino acids are characterized by larger selective factors that largely amplify the substitution rate between hydrophobic amino acids, while the selective factors of exposed sites have a weaker effect. Thus, changes in the mutational bias produce deep effects on the biophysical properties of the protein (hydrophobicity) and on its evolutionary properties (sequence entropy and substitution rate) at the same time. The program Prot_evol that implements the two site-specific substitution processes is freely available at https://ub.cbm.uam.es/prot_fold_evol/prot_fold_evol_soft_main.php#Prot_Evol.

Dataset Information

A common root for coevolution and substitution rate variability in protein sequence evolution.

Publications

A common root for coevolution and substitution rate variability in protein sequence evolution.

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