The response of amino acid frequencies to directional mutation pressure in mitochondrial genome sequences is related to the physical properties of the amino acids and to the structure of the genetic code.

The frequencies of A, C, G, and T in mitochondrial DNA vary among species due to unequal rates of mutation between the bases. The frequencies of bases at fourfold degenerate sites respond directly to mutation pressure. At first and second positions, selection reduces the degree of frequency variation. Using a simple evolutionary model, we show that first position sites are less constrained by selection than second position sites and, therefore, that the frequencies of bases at first position are more responsive to mutation pressure than those at second position. We define a measure of distance between amino acids that is dependent on eight measured physical properties and a similarity measure that is the inverse of this distance. Columns 1, 2, 3, and 4 of the genetic code correspond to codons with U, C, A, and G in their second position, respectively. The similarity of amino acids in the four columns decreases systematically from column 1 to column 2 to column 3 to column 4. We then show that the responsiveness of first position bases to mutation pressure is dependent on the second position base and follows the same decreasing trend through the four columns. Again, this shows the correlation between physical properties and responsiveness. We determine a proximity measure for each amino acid, which is the average similarity between an amino acid and all others that are accessible via single point mutations in the mitochondrial genetic code structure. We also define a responsiveness for each amino acid, which measures how rapidly an amino acid frequency changes as a result of mutation pressure acting on the base frequencies. We show that there is a strong correlation between responsiveness and proximity, and that both these quantities are also correlated with the mutability of amino acids estimated from the mtREV substitution rate matrix. We also consider the variation of base frequencies between strands and between genes on a strand. These trends are consistent with the patterns expected from analysis of the variation among genomes.