Mistranslation-Induced Protein Misfolding as a Dominant Constraint on Coding-Sequence Evolution

摘要: Strikingly consistent correlations between rates of coding-sequence evolution and gene expression levels are apparent across taxa, but the biological causes behind selective pressures on remain controversial. Here, we demonstrate conserved patterns simple covariation sequence evolution, codon usage, mRNA level in E. coli, yeast, worm, fly, mouse, human that suggest all observed trends stem largely from a unified underlying pressure. In metazoans, these strongest tissues composed neurons, whose structure lifetime confer extreme sensitivity to protein misfolding. We propose, using molecular-level evolutionary simulation, selection against toxicity misfolded proteins generated by ribosome errors suffices create covariation. The mechanistic model molecular emerges yields testable biochemical predictions, calls into question use nonsynonymous-to-synonymous substitution ratios (Ka/Ks) detect functional selection, suggests how mistranslation may contribute neurodegenerative disease.