Theses Doctoral

Evolutionary rate determinants and functional optimization of proteins

Usmanova, Dinara R.

A fundamental phenomenon in molecular evolution is the accumulation of mutations in proteins at an approximately constant rate, known as the molecular clock. Remarkably, although this rate remains constant across lineages, it varies by several orders of magnitude across different proteins. The nature of the molecular clock and its variability across proteins is a foundational question in molecular evolution. In addition, understanding the essence of evolutionary constraints provides insights into the principles of biological systems optimization.The primary determinants of the molecular clock have been actively investigated and debated for several decades. It has been established that the strongest predictor of the rate of protein evolution is protein expression. However, the underlying basis for the widely observed anti-correlation between Expression and evolutionary Rate (ER) remains poorly understood.

The main goal of this study is to unravel the basic mechanisms of the molecular clock variability across proteins and in particular the nature of ER anti-correlation. We begin by investigating the molecular basis of the ER phenomenon. In this regard, we first addressed the validity of the misfolding avoidance hypothesis, which has dominated related evolutionary discussions for more than a decade. We analyzed multiple recent genome-wide datasets describing protein stability and aggregation propensities – properties predicted to constrain the evolution of highly expressed proteins to avoid toxicity caused by misfolding. We rigorously tested the predictions of the hypothesis, and our results suggest that misfolding avoidance is unlikely to play any substantial role in explaining the variability of the molecular clock across proteins. Thus, other mechanisms should be explored.

We focused on the functional hypothesis, which proposes that variability in evolutionary constraints is due to different levels of functional optimization across proteins. We collected data on catalytic efficiency across multiple enzymes in several species to serve as a proxy for protein functional optimality. Notably, we demonstrated that the optimization of protein molecular function substantially constrains the rate of protein evolution. Moreover, up to half of the correlation between protein expression and evolutionary rate can be explained by the level of protein functional efficiency. These findings support to the functional theory of protein evolution.

We further investigated the cellular mechanisms behind the ER correlation. To this end, we analyzed how protein expression levels in different tissues of multicellular species or in strains of unicellular species living in different environmental conditions jointly affect protein optimization and evolution. Using tissue- and condition-specific expression data from various animal, plant, and bacterial species, we demonstrated that the protein clock rate and the degree of protein functional optimality are primarily affected by expression in several distinct cell types. Furthermore, the strength of the association between protein expression and evolutionary rate is correlated with the upregulation of specific cellular processes, namely functions related to synaptic transmission in animals and active cellular growth in plants and bacteria. We hypothesize that these cellular properties result in particularly high cost of protein expression, leading to a more pronounced optimization of highly abundant proteins and consequently slowing down the molecular clock.

Overall, the study reveals how various constraints from the molecular, cellular, and species’ levels of biological organization jointly affect protein evolution and the level of protein optimization and adaptation.

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More About This Work

Academic Units
Cellular, Molecular and Biomedical Studies
Thesis Advisors
Vitkup, Dennis
Degree
Ph.D., Columbia University
Published Here
August 23, 2023