Secreted Proteins Defy the Expression Level-Evolutionary Rate Anticorrelation

Abstract

The rates of evolution of the proteins of any organism vary across orders of magnitude. A primary factor influencing rates of protein evolution is expression. A strong negative correlation between expression levels and evolutionary rates (the so-called E-R anticorrelation) has been observed in virtually all studied organisms. This effect is currently attributed to the abundance-dependent fitness costs of misfolding and unspecific protein-protein interactions, among other factors. Secreted proteins are folded in the endoplasmic reticulum, a compartment where chaperones, folding catalysts, and stringent quality control mechanisms promote their correct folding and may reduce the fitness costs of misfolding. In addition, confinement of secreted proteins to the extracellular space may reduce misinteractions and their deleterious effects. We hypothesize that each of these factors (the secretory pathway quality control and extracellular location) may reduce the strength of the E-R anticorrelation. Indeed, here we show that among human proteins that are secreted to the extracellular space, rates of evolution do not correlate with protein abundances. This trend is robust to controlling for several potentially confounding factors and is also observed when analyzing protein abundance data for 6 human tissues. In addition, analysis of mRNA abundance data for 32 human tissues shows that the E-R correlation is always less negative, and sometimes nonsignificant, in secreted proteins. Similar observations were made in Caenorhabditis elegans and in Escherichia coli, and to a lesser extent in Drosophila melanogaster, Saccharomyces cerevisiae and Arabidopsis thaliana. Our observations contribute to understand the causes of the E-R anticorrelation.

Keywords: E–R anticorrelation; dN/dS; expression levels; rates of evolution; secreted proteins..

Fig. 1.

Correlation between rates of protein evolution (ω) and protein abundance for human secreted and nonsecreted proteins. The E–R anticorrelation is only significant for nonsecreted proteins (indicated by an asterisk). ρ, Spearman’s rank correlation coefficient; ppm, parts per million.

Fig. 2.

Correlation between ω and protein abundance for secreted and nonsecreted proteins expressed at different human organs/tissues. Although nonsecreted proteins show a strong negative correlation, secreted proteins exhibit weaker correlations. Significant Spearman correlation coefficients are marked with an asterisk. ρ, Spearman’s rank correlation coefficient; ppm, parts per million.

Fig. 3.

Spearman correlation coefficients between ω and mRNA abundance in 32 human tissues/organs. Tissues are sorted according to the Spearman correlation for nonsecreted proteins, with testis having the highest (ρ = −0.140) and cerebral cortex having the lowest (ρ = −0.3235) correlations (supplementary table S3, Supplementary Material online). In all tissues, the E–R correlations are higher (less negative) for secreted proteins.

Fig. 4.

Correlation between rates of protein evolution and protein abundance for secreted and nonsecreted proteins in C. elegans, D. melanogaster, S. cerevisiae, A. thaliana, and E. coli. Significant correlation coefficients are marked with an asterisk. ρ, Spearman’s rank correlation coefficient; ppm, parts per million.

Fig. 5.

Correlation between rates of protein evolution and mRNA abundance for secreted and nonsecreted proteins in C. elegans, D. melanogaster, S. cerevisiae, A. thaliana, and E. coli. For C. elegans and D. melanogaster, expression datasets corresponding to the whole adult body were used. For A. thaliana, a dataset corresponding to the whole plant (entry ATGE 23) was used. Significant correlation coefficients are marked with an asterisk. ρ, Spearman’s rank correlation coefficient.