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Originally published as Genetics Published Articles Ahead of Print on June 21, 2005.
Genetics, Vol. 171, 385-392, September 2005, Copyright © 2005
doi:10.1534/genetics.104.039016
Widespread Correlations Between Dominance and Homozygous Effects of Mutations: Implications for Theories of Dominance
Nitin Phadnis1 and James D. Fry
Department of Biology, University of Rochester, Rochester, New York 14627-0211
1 Corresponding author: Department of Biology, 313 Hutchinson Hall, University of Rochester, Rochester, NY 14627-0211.
E-mail: pdns{at}mail.rochester.edu
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.
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