Academic journal article Genetics

Widespread Correlations between Dominance and Homozygous Effects of Mutations: Implications for Theories of Dominance

Academic journal article Genetics

Widespread Correlations between Dominance and Homozygous Effects of Mutations: Implications for Theories of Dominance

Article excerpt

ABSTRACT

The dominance of deleterious mutations has important consequences for phenomena such as inbreeding depression, the evolution of diploidy, and levels of natural genetic variation. Kacser and Burns' metabolic theory provides a paradigmatic explanation for why most large-effect mutations are recessive. According to the metabolic theory, the recessivity of large-effect mutations is a consequence of a diminishing-returns relationship between flux through a metabolic pathway and enzymatic activity at any step in the pathway, which in turn is an inevitable consequence of long metabolic pathways. A major line of support for this theory was the demonstration of a negative correlation between homozygous effects and dominance of mutations in Drosophila, consistent with a central prediction of the metabolic theory. Using data on gene deletions in yeast, we show that a negative correlation between homozygous effects and dominance of mutations exists for all major categories of genes analyzed, not just those encoding enzymes. The relationship between dominance and homozygous effects is similar for duplicated and single-copy genes and for genes whose products are members of protein complexes and those that are not. A complete explanation of dominance therefore requires either a generalization of Kacser and Burns' theory to nonenzyme genes or a new theory.

MOST major-effect mutations are recessive; i.e., the wild-type allele is almost always the dominant allele (FISHER 1928; WRIGHT 1934; SIMMONS and CROW 1977; ORR 1991; NANJUNDIAH 1993; WILKIE 1994). This is central to several important evolutionary phenomena. Recessive deleterious mutations are a major cause for the phenomenon of inbreeding depression (CHARLESWORTH and CHARLESWORTH 1999), and diploidy may have evolved to mask the effects of recessive deleterious mutations (KONDRASHOV and CROW 1991). A necessary condition for some genetic load theories of the evolution of sex is that most deleterious mutations should be recessive (KONDRASHOV 1982; CHASNOV 2000). The dominance of deleterious mutations thus represents an important parameter in evolutionary biology.

The rediscovery of Mendel's laws and with it dominance attracted a great deal of attention, including that of the major architects of the modern evolutionary theory. FISHER (1928) made an early attempt to explain the ubiquity of genetic dominance. According to him, new mutations have additive effects when they first occur but gradually become recessive through the accumulation of dominance modifiers, which reflect natural selection against the deleterious heterozygous effects of recurrent mutations. Wright and Haldane criticized Fisher's theory, arguing that unrealistically high selection pressures acting over long periods of time were required for the evolution of dominance modifiers (WRIGHT 1929,1934; HALDANE 1930). Haldanepointed out that the frequency of hétérozygotes in a population would be high during the course of fixation of a beneficial allele and that dominance modification was more likely under such circumstances (HALDANE 1956). WRIGHT (1934), on the other hand, proposed a physiological theory of dominance, according to which the relationship between a phenotype and gene activity could be described as a hyperbolic curve of diminishing returns. Haldane and Muller agreed with Wright's model and suggested that wild-type alleles with high levels of gene activity are selected to provide a factor of safety against genetic and environmental fluctuations (HALDANE 1930, 1939; MULLER 1932). KACSER and BURNS (1981), using metabolic control analysis (MCA), developed a theoretical model for dominance along the lines of Wright's physiological theory. Kacser and Burns hypothesized-on mathematical grounds and citing abundant empirical data-that the relationship between flux through a long metabolic pathway and enzyme activity at any single step in the pathway is a curve of diminishing returns. They also showed that the wild-type levels of enzyme activity are usually at or near the plateau of the curve. …

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