DNA asymmetric strand bias affects the amino acid composition of mitochondrial proteins

Variations in CC content between genomes have been extensively documented. Genomes with comparable CC contents can, however, still differ in the apportionment of the C and C nucleotides between the two DNA strands. This asymmetric strand bias is known as CC skew. Here, we have investigated the impact of differences in nucleotide skew on the amino acid composition of the encoded proteins. We compared orthologous genes between animal mitochondrial genomes that show large differences in CC and AT skews. Specifically, we compared the mitochondrial genomes of mammals, which are characterized by a negative GC skew and a positive AT skew, to those of flatworms, which show the opposite skews for both GC and AT base pairs. We found that the mammalian proteins are highly enriched in amino acids encoded by CA-rich codons (as predicted by their negative CC and positive AT skews), whereas their flatworm orthologs were enriched in amino acids encoded by GT-rich codons (also as predicted from their skews). We found that these differences in mitochondrial strand asymmetry (measured as CC and AT skews) can have very large, predictable effects on the composition of the encoded proteins.