The universal trend of amino acid gain-loss is caused by CpG hypermutability.

Understanding the cause of the changes in the amino acid composition of proteins is essential for understanding the evolution of protein functions. Since the early 1970s, it has been known that the frequency of some amino acids in protein sequences is increasing and that of others is decreasing. Recently, it was found that the trends of amino acid changes were similar in 15 taxa representing Bacteria, Archaea, and Eukaryota. However, the cause of this similarity in the trend of the gains and losses of amino acids continued to be debated. Here, we show that this trend of the gain and loss of amino acids can be simply explained by CpG hypermutability. We found that the frequency of amino acids coded by codons with TpG dinucleotides and those with CpA dinucleotides is increasing, while that of amino acids coded by codons with CpG dinucleotides is decreasing. We also found that organisms that lack DNA methyltransferase show different trends of the gain and loss of amino acids. DNA methyltransferase methylates CpG dinucleotides and induces CpG hypermutability. The incorporation of CpG hypermutability into models of protein evolution will improve studies on protein evolution in different organisms.