Almost all mutations are recessive. Over the last 70 years, many explanations of this striking pattern have been offered. The debate over which of these theories, if any, is correct became one of the longest and fiercest controversies in the history of evolutionary biology.
Perhaps the most famous-and contested-of these theories was offered by Fisher (1). Fisher argued that the dominance of wild-type alleles results from natural selection against recurrent mutations: although most mutations were originally semidominant, selection against their deleterious heterozygous effects gradually reduced their expression among heterozygotes until these mutations became nearly completely recessive. Fisher claimed that this decrease in dominance resulted from the accumulation of modifier alleles at other loci. Although Wright (2, 3) severely criticized this theory, showing that the selection pressure on dominance modification would only be of the order of the mutation rate, Fisher (4) maintained that extremely small selection coefficients were adequate if selection were exerted over a very long time.
Wright (2, 3), on the other hand, argued that dominance follows from the physiology ofgene action. Wright suggested that there were simple metabolic reasons to expect a curve of diminishing returns relating phenotype to genotype. If most wild-type alleles have very high enzyme activities, then having one allele will increase flux through some metabolic pathway from zero to a substantial level, while adding a second allele will cause a negligible increase in flux. Obviously, then, organisms will enjoy a margin of safety against loss-of-activity mutations: flux through mutant heterozygoteswill roughly equal that through wild-type homozygotes.
As a result, most mutations will appear recessive. Regardless of whether the high activity of wild-type enzymes results from selection to withstand environmental fluctuations, as Wright, Plunkett (5), and Muller (6) suggested, or is simply an inevitable consequence of metabolism, as Kacser and Burns (7) have suggested, this physiological theory of dominance differs profoundly from Fisher’s: it does not invoke modification of heterozygotes by natural selection.
Few tests of these theories have been performed. Indeed, the strongest evidence against Fisher’s theory is a statistical pattern noted by Charlesworth (8): although Fisher’s theory predicts no correlation between the homozygous effect of a mutation on fitness (s) and its dominance coefficient (h), s and h show a strong inverse correlation. Here I perform a direct test of Fisher’s theory of dominance by examining the dominance of mutations in a normally haploid eukaryote, the unicellular alga Chlamydomonas reinhardtii. The results falsify the notion that dominance results from modification of heterozygotes by natural selection.