Evolutionary forces on different flavors of intrinsic disorder in the human proteome

Abstract

In this study, we perform a systematic analysis of evolutionary forces (i.e., mutational bias and natural selection) that shape the codon usage bias of human genes encoding for different structural and functional variants of proteins. Well-structured proteins are expected to be more under control by natural selection than intrinsically disordered proteins because one or few mutations (even synonymous) in the genes can result in a protein that no longer folds correctly. On the contrary, intrinsically disordered proteins are generally thought to evolve more rapidly than well-folded proteins, primarily attributed to relaxed purifying natural selection due to the lack of structural constraints. Using different genetic tools, we find compelling evidence that intrinsically disordered proteins are the variant of human proteins on which both mutational bias and natural selection act more effectively, corroborating their essential role for evolutionary adaptability and protein evolvability. We speculate that intrinsically disordered proteins have a high tolerance to mutations (both neutral and adaptive) but also a selective propensity to preserve their structural disorder, i.e., flexibility and conformational dynamics under physiological conditions. Additionally, we confirm not only that intrinsically disordered proteins are preferentially encoded by GC-rich genes, but also that they are characterized by the highest fraction of CpG-sites in the sequences, implying a higher susceptibility to methylation resulting in C-T transition mutations. Our results provide new insight about protein evolution and human genetic diseases identifying intrinsically disordered proteins as reservoirs for evolutionary innovations.

Variants of intrinsic disorder: structural characterization

“…In summary, our results corroborate our previous claim to consider IDPRs and IDPs as distinct protein variants [19,26]. At the same time, we identify IDPs as the true natively unfolded proteins, having peculiar functional and evolutionary features but also distinct physical-chemical and structural properties.…”

“…Furthermore, performing systematic analyses of these variants in terms of evolutionary forces acting on them, we have recently shown that IDPRs on the one side are subject to different patterns of evolutionary pressures with respect to IDPs and ORDPs on the other one [26]. protein segments with transient residual structure), inducible foldons (i.e., segments that are able to fold at interaction with specific binding partners), nonfoldons (i.e., protein segments with functions depending on their intrinsically disordered nature), and unfoldons (i.e., segments that are able to unfold under specific conditions, becoming functional) [9,44].…”

“…With this study, we emphasize this result by performing a systematic analysis of their amino acid compositions, their physical-chemical properties, and their structural aspects (both predicted and directly calculated on the structures in the Protein Data Bank). We concluded that IDPRs and IDPs are different, not only in terms of functional properties, roles in diseases, and evolutionary forces acting on them [19,26], but also as regards basic physical-chemical and structural properties.…”

“…Many studies aiming at a general classification of functional roles of protein intrinsic disorder were based on the required presence of long disordered regions in the sequence, thus considering IDPRs and IDPs as a single entity [10][11][12][22][23][24][25]. The main result of the study by Deiana et al is that IDPs and IDPRs have different functional roles in the cell, and they deserve to be treated as distinct categories of proteins [19,26].…”

Bioinformatic analysis and functional predictions of selected regeneration-associated transcripts expressed by zebrafish microglia

“…As noted above, P4 is predicted to be a disordered protein (Supplemental Figure 2). Many intrinsically disordered proteins evolve rapidly [75][76][77][78], and therefore, predicting a function for P4 is difficult based on amino acid sequence. Accordingly, analyses based on sequence similarity were overall minimally informative.…”