Secreted Proteins Defy the Expression Level-Evolutionary Rate Anticorrelation

Area of Science:

• Evolutionary biology
• Molecular biology
• Genomics

Background:

• Protein expression levels strongly correlate with evolutionary rates across organisms, known as the expression-rate (E-R) anticorrelation.
• This anticorrelation is often attributed to fitness costs associated with protein misfolding and non-specific interactions, which increase with protein abundance.
• Secreted proteins undergo specialized folding in the endoplasmic reticulum and function extracellularly, potentially altering these fitness costs.

Purpose of the Study:

• To investigate whether the secretory pathway and extracellular location mitigate the E-R anticorrelation.
• To determine if secreted proteins exhibit different evolutionary rate patterns compared to intracellular proteins.

Main Methods:

• Analysis of protein abundance and evolutionary rates in human proteomes.
• Examination of protein abundance data across multiple human tissues.
• Comparative analysis of mRNA abundance and E-R correlation in various model organisms (C. elegans, E. coli, D. melanogaster, S. cerevisiae, A. thaliana).

Main Results:

• Human secreted proteins show no correlation between evolutionary rates and protein abundance.
• This finding remains robust after controlling for confounding factors and across different human tissues.
• The E-R correlation is consistently weaker (less negative or nonsignificant) in secreted proteins across multiple species.

Conclusions:

• The specialized environment of the secretory pathway and extracellular space reduces the fitness consequences of protein misfolding and interactions.
• These factors weaken or abolish the typical E-R anticorrelation observed for intracellular proteins.
• Understanding these mechanisms provides insights into the drivers of protein evolution.