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Key Questions

  1. What proportion of newly synthesized proteins fail to fold, and why?
  2. How do cells decide when a misfolded should be degraded rather than given another chance to fold?
  3. What is the cost of producing a protein that misfolds, compared to the cost if that protein folds properly?
  4. Why are misfolded proteins costly?
  5. How does inaccuracy in the translational apparatus (ribosomes, aa-tRNA synthetases, etc.) shape the evolution of coding sequences and proteins?

The fitness cost of protein misfolding

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Mistranslation-induced misfolding and gene evolution

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


  1. Drummond DA and Wilke CO. Mistranslation-induced protein misfolding as a dominant constraint on coding-sequence evolution. Cell. 2008 Jul 25;134(2):341-52. DOI:10.1016/j.cell.2008.05.042 | PubMed ID:18662548 | HubMed [Drummond-Cell-2008]

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Evolution and expression data

These tab-delimited files include gene and ortholog identifiers, dN, dS, ts/tv ratio, expression level, Fop, and (for the multicellular organisms) intronic guanine/cytosine (GC) content.

Coding sequence alignments

Alignments are in FASTA format, ZIP-compressed.