The effectiveness of selection in a species affects the direction of amino acid frequency evolution.

According to the nearly neutral theory of molecular evolution, selection is less able to distinguish between similar alleles in species with lower population size. We identify which amino acids are subject to such weak preferences - these tend to be smaller, to be less costly to make, to promote structural disorder of proteins, and to be enriched in thermophiles relative to mesophiles. The latter agrees with theories of marginal protein stability under mutation-selection-drift balance.