The Nuanced Interplay of Intrinsic Disorder and Other Structural Properties Driving Protein Evolution

Ahrens, Joseph B.; Santos, Helena; Siltberg-Liberles, Jessica

doi:10.1093/molbev/msw092

Cited by 22 publications

(32 citation statements)

References 37 publications

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“…The lack of three-dimensional constraint may explain the fast evolution of these protein regions. However, it has been shown that there are amino acid residues that maintain the intrinsic disorder and that these residues are under stronger evolutionary constraint than in ordered regions (Ahrens et al 2016). It is therefore important to note that the vast majority of IDP regions experienced substantial purifying selection during their evolution (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, parts exposed to the solvent protein surface evolve much faster (Franzosa and Xia 2009). IDPs generally tend to evolve more rapidly, largely attributed to relaxed purifying selection due to the lack of structural constraint (Brown et al 2011), although Ahrens et al (2016) found that sites that were predicted to be disordered and to have secondary structure were evolving at a lower rate than sites that were predicted to be ordered and to have secondary structure. Other important evolutionary determinants of the rate at which disordered regions evolve are synonymous constraint elements (Macossay-Castillo et al 2014) and gene age, as evolutionarily young proteins tend to be enriched in disordered regions (Wilson et al 2017).…”

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Human long intrinsically disordered protein regions are frequent targets of positive selection

et al. 2018

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Intrinsically disordered regions occur frequently in proteins and are characterized by a lack of a well-defined three-dimensional structure. Although these regions do not show a higher order of structural organization, they are known to be functionally important. Disordered regions are rapidly evolving, largely attributed to relaxed purifying selection and an increased role of genetic drift. It has also been suggested that positive selection might contribute to their rapid diversification. However, for our own species, it is currently unknown whether positive selection has played a role during the evolution of these protein regions. Here, we address this question by investigating the evolutionary pattern of more than 6600 human proteins with intrinsically disordered regions and their ordered counterparts. Our comparative approach with data from more than 90 mammalian genomes uses a priori knowledge of disordered protein regions, and we show that this increases the power to detect positive selection by an order of magnitude. We can confirm that human intrinsically disordered regions evolve more rapidly, not only within humans but also across the entire mammalian phylogeny. They have, however, experienced substantial evolutionary constraint, hinting at their fundamental functional importance. We find compelling evidence that disordered protein regions are frequent targets of positive selection and estimate that the relative rate of adaptive substitutions differs fourfold between disordered and ordered protein regions in humans. Our results suggest that disordered protein regions are important targets of genetic innovation and that the contribution of positive selection in these regions is more pronounced than in other protein parts.

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Section: Discussionmentioning

confidence: 99%

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Human long intrinsically disordered protein regions are frequent targets of positive selection

et al. 2018

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“…The selective forces governing this process have been studied by examining the properties of orphan proteins. Intrinsic disorder, low complexity, subtelomeric location, high β -sheet preference as well as other features have been associated with orphan proteins [16, 17]. It has also been proposed that with age proteins (i) accumulate interactions, (ii) become more often essential and (iii) obtain lower β -strand content and higher stability [18].…”

Section: Introductionmentioning

confidence: 99%

High GC content causes orphan proteins to be intrinsically disordered

et al. 2017

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De novo creation of protein coding genes involves the formation of short ORFs from noncoding regions; some of these ORFs might then become fixed in the population. These orphan proteins need to, at the bare minimum, not cause serious harm to the organism, meaning that they should for instance not aggregate. Therefore, although the creation of short ORFs could be truly random, the fixation should be subjected to some selective pressure. The selective forces acting on orphan proteins have been elusive, and contradictory results have been reported. In Drosophila young proteins are more disordered than ancient ones, while the opposite trend is present in yeast. To the best of our knowledge no valid explanation for this difference has been proposed. To solve this riddle we studied structural properties and age of proteins in 187 eukaryotic organisms. We find that, with the exception of length, there are only small differences in the properties between proteins of different ages. However, when we take the GC content into account we noted that it could explain the opposite trends observed for orphans in yeast (low GC) and Drosophila (high GC). GC content is correlated with codons coding for disorder promoting amino acids. This leads us to propose that intrinsic disorder is not a strong determining factor for fixation of orphan proteins. Instead these proteins largely resemble random proteins given a particular GC level. During evolution the properties of a protein change faster than the GC level causing the relationship between disorder and GC to gradually weaken.

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“…It has later been shown that some of 14 these proteins are not de novo created but rather assigned as orphans as a result of 15 limited phylogenetic coverage in earlier studies [9]. 16 Today supported by the vast amount of complete genome sequences available and 17 improved search methods [10], many of the initially identified orphans have been shown 18 to have distant homologs in other genomes. Still, at least in yeast, a large set of genes 19 appears to have been created through recent de novo formation [11,12].…”

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“…The selective forces governing this 30 process have been studied by examining the properties of orphan proteins. Intrinsic 31 disorder, low complexity, subtelomeric location, high β-sheet preference as well as other 32 features have been associated with orphan proteins [16,17]. It has also been proposed 33 that with age proteins (i) accumulate interactions, (ii) become more often essential and 34 (iii) obtain lower β-strand content and higher stability [18].…”

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High GC Content Causes Orphan Proteins to be Intrinsically Disordered

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et al. 2017

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De novo creation of protein coding genes involves the formation of short ORFs from noncoding regions; some of these ORFs might then become fixed in the populationThese orphan proteins need to, at the bare minimum, not cause serious harm to the organism, meaning that they should for instance not aggregate. Therefore, although the creation of short ORFs could be truly random, the fixation should be subjected to some selective pressure. The selective forces acting on orphan proteins have been elusive, and contradictory results have been reported. In Drosophila young proteins are more disordered than ancient ones, while the opposite trend is present in yeast. To the best of our knowledge no valid explanation for this difference has been proposed.To solve this riddle we studied structural properties and age of proteins in 187 eukaryotic organisms. We find that, with the exception of length, there are only small differences in the properties between proteins of different ages. However, when we take the GC content into account we noted that it could explain the opposite trends observed for orphans in yeast (low GC) and Drosophila (high GC). GC content is correlated with codons coding for disorder promoting amino acids. This leads us to propose that intrinsic disorder is not a strong determining factor for fixation of orphan proteins. Instead these proteins largely resemble random proteins given a particular GC level. During evolution the properties of a protein change faster than the GC level causing the relationship between disorder and GC to gradually weaken. Author SummaryWe show that the GC content of a genome is of great importance for the properties of an orphan protein. GC content affects the frequency of the codons and this affects the probability for each amino acid to be included in a de novo created protein. The codons encoding for Ala, Pro and Gly contain 80% GC, while codons for Lys, Phe, Asn, Tyr and Ile contain 20% or less. The three high GC amino acids are all disorder promoting, while Phe, Tyr and Ile are order promoting. Therefore, random protein sequences at a high GC will be more disordered than the ones created at a low GC. The structural properties of the youngest proteins match to a large degree the properties of random PLOS

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The Nuanced Interplay of Intrinsic Disorder and Other Structural Properties Driving Protein Evolution

Cited by 22 publications

References 37 publications

Human long intrinsically disordered protein regions are frequent targets of positive selection

Human long intrinsically disordered protein regions are frequent targets of positive selection

High GC content causes orphan proteins to be intrinsically disordered

High GC Content Causes Orphan Proteins to be Intrinsically Disordered

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