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

Abstract

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.

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

“…Accumulating evidence suggests that relaxed structural constraints provide an advantage when accommodating multiple overlapping functions in coding regions (collectively referred to as synonymous constraint elements) (Castillo et al, 2014;Pancsa and Tompa, 2016). Additionally, recent studies have found a higher degree of positive selection on proteins with intrinsically disordered regions (Nillson et al, 2011;Afanasyeva et al, 2018).…”

Exploring Potential Signals of Selection for Disordered Residues in Naturally Occurring Prokaryotic and Eukaryotic Proteins

“…Thus terminal regions were considered as "evolutionary playgrounds" for the innovation of new functions [36]. This reduced efficacy of selection at the protein terminus, especially in eukaryotes because of their lower effective population size compared to prokaryotes [37] may have provided the permissive environment for the fixation of disordered promoting amino acids which are generally associated with high rates of insertions, deletions and substitutions [7,8,10]. It is possible that disordered residues in these regions tend to be less deleterious in eukaryotes than in prokaryotes facilitating their fixation.…”

Noncoding regions underpin avian bill shape diversification at macroevolutionary scales

“…We used genomes of 57 bird species with high quality annotations from NCBI RefSeq (O'Leary et al (Table S2). First, 12,013 orthologous protein coding genes were retrieved using RefSeq and HGNC gene identifiers, alongside reciprocal BLAST approaches based on three focal species, chicken, great tit and zebra finch -three of the best annotated high quality bird genomes available to date (Li et al 2003;Östlund et al 2009;Afanasyeva et al 2018). We then performed a first set of alignment runs using PRANK (Löytynoja and Goldman 2008).…”