Glutamine Codon Usage and polyQ Evolution in Primates Depend on the Q Stretch Length

Abstract

Amino acid usage in a proteome depends mostly on its taxonomy, as it does the codon usage in transcriptomes. Here, we explore the level of variation in the codon usage of a specific amino acid, glutamine, in relation to the number of consecutive glutamine residues. We show that CAG triplets are consistently more abundant in short glutamine homorepeats (polyQ, four to eight residues) than in shorter glutamine stretches (one to three residues), leading to the evolutionary growth of the repeat region in a CAG-dependent manner. The length of orthologous polyQ regions is mostly stable in primates, particularly the short ones. Interestingly, given a short polyQ the CAG usage is higher in unstable-in-length orthologous polyQ regions. This indicates that CAG triplets produce the necessary instability for a glutamine stretch to grow. Proteins related to polyQ-associated diseases behave in a more extreme way, with longer glutamine stretches in human and evolutionarily closer nonhuman primates, and an overall higher CAG usage. In the light of our results, we suggest an evolutionary model to explain the glutamine codon usage in polyQ regions.

Fig. 1.

—Characterization of glutamine stretches in complete proteomes. (a) Number of glutamine stretches per number of proteins per proteome, depending on the stretch length. (b) Percentage of CAG triplets in glutamine stretches per proteome, depending on the stretch length. (c) Percentage of CAG triplets in glutamine stretches of lengths 4–8 compared with lengths 1–3; the result for each proteome is colored depending on the pairwise divergence time with human. The discontinuous line represents x = y values. (d) Overall CAG percentages in primates in glutamine stretches of varying lengths.

Fig. 2.

—Length differences of glutamine stretches between primates. Length differences from the reference glutamine stretch to the rest of the orthologous glutamine stretches, when the length of the reference stretch is (a) 0–3, (b) 4–8, and (c) >8.

Fig. 3.

—Codon purity of glutamine stretches in primates. Percentage of glutamine stretches per length encoded by (a) only CAG codons, (b) a mix of CAG and CAA codons, (c) a mix of CAG, CAA, and other interrupting codons, and (d) only CAA codons. Considering only glutamine stretches encoded by more than one different triplet, maximum number of consecutive (e) CAG, and (f) CAA per length.

Fig. 4.

—Length-stability of glutamine stretches. Percentage of orthologous glutamine stretch regions with a stable length in at least half of the orthologs.

Fig. 5.

—Glutamine codon usage in stable- versus unstable-in-length polyQ. Codon usage calculated in stable-in-length (S) and unstable-in-length (U), short (4–8 Q), and long (>8 Q) polyQ stretches, in 12 primates.

Fig. 6.

—PolyQ lengths and glutamine codon usage in proteins related to polyQ-expansion diseases. Divergence time for each organism and human is measured in million years (Myr). The tree on top relates the species based on their NCBI taxonomy. Each protein is appended with its related disease. The overall Q lengths (in blue) and CAG percentage prevalence (in red) plots take into account the results per species of the nine proteins shown above.