Polymorphism Analysis Reveals Reduced Negative Selection and Elevated Rate of Insertions and Deletions in Intrinsically Disordered Protein Regions.
Bottom Line: We also confirm previous findings that nonframeshifting indels are much more abundant in disordered regions relative to structured regions.We find that the rate of nonframeshifting indel polymorphism in intrinsically disordered regions resembles that of noncoding DNA and pseudogenes, and that large indels segregate in disordered regions in the human population.Our survey of polymorphism confirms patterns of evolution in disordered regions inferred based on longer evolutionary comparisons.
Affiliation: Department of Cell & Systems Biology, University of Toronto, Ontario, Canada.Show MeSH
Mentions: One of the strongest predictors of protein evolutionary rate is the expression levelof the protein, due in part to stronger natural selection to reduce the negativeconsequences of protein misfolding in highly expressed proteins (Drummond et al. 2005). Hence, we sought torule out the possibility that the differences observed were due to differences inexpression levels between the different types of proteins regions by determiningPa/Ps ratios as a functionof protein expression levels (fig.2A). This analysis revealed consistent differences inPa/Ps values betweendisordered regions, Pfam domains, and other ordered regions at all expression levels.Interestingly, a clear negative correlation (R2 =0.73, P = 0.002) was observed for disordered regions.Although disordered regions might not be expected to show a correlation between therate of evolution and expression level under the model of selection against proteinmisfolding (Drummond et al. 2005),there are several reasons why this might be expected, such as spuriousprotein–protein interactions (Yang etal. 2012), amyloid formation (Knowles et al. 2014), and folding upon target binding (Love et al. 1995; Bowers et al. 1999; Young et al. 2000). As above, to get an idea of the variability in thesevalues, we averaged the per genePa/Ps ratios and plottedthe mean and three times the standard error (fig. 2B). Once again, we found that disordered regionshave higher Pa/Ps ratiosacross the whole range of expression levels. Taken together, these results indicatethat reduced constraints in disordered regions are not likely to be due to overallexpression differences between ordered and disordered protein regions. Fig. 3.
Affiliation: Department of Cell & Systems Biology, University of Toronto, Ontario, Canada.