Human disease-causing missense genetic variants are enriched in the evolutionarily ancient domains of the cytosolic aminoacyl-tRNA synthetase proteins

Abstract

All life depends on accurate and efficient protein synthesis. The aminoacyl-tRNA synthetases (aaRSs) are a family of proteins that play an essential role in protein translation, as they catalyze the esterification reaction that charges a transfer RNA (tRNA) with its cognate amino acid. However, new domains added to the aaRSs over the course of evolution in eukaryotes confer novel functions unrelated to protein translation. To date, damaging variants that affect aaRS-encoding genes have been linked to over 50 human diseases. In this study, we leverage the evolutionary history of the aaRS proteins to better understand the distribution of disease-causing missense variants in human cytosolic aaRSs. We hypothesized that disease-causing missense variants in human aaRSs were more likely to be located in the ancient domains of the aaRS, essential for the aminoacylation reaction, rather than in the evolutionarily more recent domains found in eukaryotes. We determined the locations of the modern and ancient domains in each aaRS protein found in humans. We then statistically assessed the positional conservation across each domain and examined the distribution of pathogenic and benign/unknown missense human genetic variants across these domains. We establish that pathogenic missense variants in the human aaRS proteins are enriched in the evolutionarily ancient domains while benign/unknown missense variants are enriched in the modern domains. In addition to defining the evolutionary history of human aaRS proteins through domain identification, we anticipate that this work will improve the ability to diagnose patients affected by damaging genetic variants in the aaRS protein family.

Keywords: aminoacyl‐tRNA synthetases; conservation; evolution; genetic diseases; human health; protein synthesis; rare disease.

FIGURE 1

Protein domain analysis for AsnRS and CysRS. The colored lines represent the percentage of the sequences belonging to each taxon that aligns to the corresponding human aminoacyl‐tRNA synthetase. The blue boxes under the graph correspond to the modern domains, note that these are the regions, larger than 15 residues long, where both the archaea and the bacteria curves are below 5%. Yellow boxes denote modern domains as defined by Guo et al. Secondary structures, determined running DSSP on the pdb file generated by AlphaFold, are shown in green (helices) and orange (sheets).

FIGURE 2

Comparison of the modern domains identified in this study to those identified by Guo et al. Each aminoacyl‐tRNA synthetase is represented by a box proportional to its length with X‐axis numbering denoting amino acid position. Areas in blue represent modern domains detected in the current study and areas in red represent the modern domains from Guo et al. To the right of each box is the percent agreement between both methods. Notable is the absence of modern domains in AlaRS, PheARS, and PheBRS. Since Guo et al. predicted a domain for PheRS, but did not specify in which subunit it is located, we removed it from the ensuing statistical analysis and didn't show it in the figure (*).