![]() ![]() The two sets of codons encoding serine cannot be connected through a single point mutation 1. However, serine is unique among the 20 amino acids in that it is encoded by two disjoint sets of codons that require a tandem substitution of two nucleotides to switch between the two sets, one comprised of the codons TCT, TCC, TCA and TCG (TCN, denoted set S′) and the other set includes only two codons - AGT and AGC (AGY, denoted set S′′) 1. In most cases the codons encoding for a specific amino acid differ only by a single nucleotide (typically the third one). Combined, our results, that cover evolutionary signals at different temporal scales, demonstrate that through its encoding by two codon sets, serine allows for the existence of alternating substitution patterns within positions of functional maintenance versus sites of rapid diversification.ĭue to the redundancy of the genetic code most amino acids are encoded by more than one codon. Finally, we analyzed the substitutions across 60,000 individual human exomes to show that, when serine has a specific functional constraint of phosphorylation capability, S′ codons are 32-folds less prone than S″ to substitutions to Threonine or Tyrosine that could potentially retain the phosphorylation site capacity. In both instances, we identified an opposite abundance of two groups of serine substitutions, with enrichment of S′PA in the conserved positions, and GS″N in the hypervariable regions. These fast evolving proteins both have hypervariable positions, which are under diversifying selection, closely adjacent to highly conserved structural regions. We tested this phenomenon in the HIV envelope glycoprotein (gp120), and the V-gene that encodes B-cell receptors/antibodies. In contrast, the less conserved positions are enriched for serine encoded with AGY codons (denoted S″), glycine and asparagine, (GS″N). We found that in humans, positions that are conserved among ~100 vertebrates, and thus subjected to purifying selection, are enriched for substitutions involving serine (TCN, denoted S′), proline, and alanine, (S′PA). We show that these codon sets underlie distinct substitution patterns at positions subject to purifying and diversifying selections. Serine is the only amino acid that is encoded by two disjoint codon sets (TCN & AGY) so that a tandem substitution of two nucleotides is required to switch between the two sets.
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