On the Decoupling of Evolutionary Changes in mRNA and Protein Levels

Variation in gene expression across lineages is thought to explain much of the observed phenotypic variation and adaptation. The protein is closer to the target of natural selection but gene expression is typically measured as the amount of mRNA. The broad assumption that mRNA levels are good proxies for protein levels has been undermined by a number of studies reporting moderate or weak correlations between the two measures across species. One biological explanation for this discrepancy is that there has been compensatory evolution between the mRNA level and regulation of translation. However, we do not understand the evolutionary conditions necessary for this to occur nor the expected strength of the correlation between mRNA and protein levels. Here, we develop a theoretical model for the coevolution of mRNA and protein levels and investigate the dynamics of the model over time. We find that compensatory evolution is widespread when there is stabilizing selection on the protein level; this observation held true across a variety of regulatory pathways. When the protein level is under directional selection, the mRNA level of a gene and the translation rate of the same gene were negatively correlated across lineages but positively correlated across genes. These findings help explain results from comparative studies of gene expression and potentially enable researchers to disentangle biological and statistical hypotheses for the mismatch between transcriptomic and proteomic data.

Automated summary

Variation in gene expression across lineages plays a crucial role in explaining phenotypic variation and adaptation. However, the assumption that mRNA levels can accurately represent protein levels has been challenged by studies showing weak correlations between the two measures across species. This discrepancy might be due to compensatory evolution between mRNA levels and translation regulation, but the conditions and strength of the correlation are still not well understood. A theoretical model of the coevolution of mRNA and protein levels reveals that compensatory evolution is common with stabilizing selection on protein levels, while under directional selection, mRNA levels and translation rates show negative correlations across lineages but positive correlations across genes. These findings offer insights into comparative studies of gene expression and provide a framework to distinguish biological and statistical hypotheses for the transcriptomic-proteomic mismatch.