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Genetics.Org/ Gote Would Have fitness on Average Equal to 1 – Hs Times Cgi/Content/Full/Genetics.110.124560/DC1 Copyright Ó 2011 by the Genetics Society of America DOI: 10.1534/genetics.110.124560 Inferences About the Distribution of Dominance Drawn From Yeast Gene Knockout Data Aneil F. Agrawal*,1 and Michael C. Whitlock† *Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, Ontario M5S 3B2, Canada and †Department of Zoology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada Manuscript received October 25, 2010 Accepted for publication November 10, 2010 ABSTRACT Data from several thousand knockout mutations in yeast (Saccharomyces cerevisiae) were used to estimate the distribution of dominance coefficients. We propose a new unbiased likelihood approach to measuring dominance coefficients. On average, deleterious mutations are partially recessive, with a mean dominance coefficient 0.2. Alleles with large homozygous effects are more likely to be more recessive than are alleles of weaker effect. Our approach allows us to quantify, for the first time, the substantial variance and skew in the distribution of dominance coefficients. This heterogeneity is so great that many population genetic processes analyses based on the mean dominance coefficient alone will be in substantial error. These results are applied to the debate about various mechanisms for the evolution of dominance, and we conclude that they are most consistent with models that depend on indirect selection on homeostatic gene expression or on the ability to perform well under periods of high demand for a protein. S Mendel observed, the effects of an allele in a strongly on the dominance coefficient (Charlesworth A homozygous state may be difficult to predict from and Charlesworth 1987). In a medical genetic con- its effects in heterozygous individuals. Such genetic text, the degree of dominance of deleterious mutations dominance is a common phenomenon, and dominance affects the impact of each new mutation on human affects many important evolutionary processes in diploid health. organisms. Dominance may predict the fate of beneficial In spite of the importance of dominance for fitness, alleles, through a process called Haldane’s sieve, because we have remarkably little reliable information about the recessive beneficial mutations are less likely to fix when magnitude of such dominance. Most of our information started from a low frequency than beneficial alleles about dominance comes from a small number of species (Haldane 1927), but this difference may disappear (Drosophila melanogaster, Caenorhabditis elegans, Arabidop- depending on the starting conditions in the population sis thaliana, and yeast), and many of the estimates of (Orr and Betancourt 2001). More importantly, if dominance are mutually inconsistent (see Table 1). deleterious alleles are maintained in populations mainly Moreover, we have very little information about the due to the balance between selection removing them variation in dominance among genes, and what exists and recurrent mutation to the deleterious state, then is biased in a number of ways (Caballero et al. 1997; the frequency of such alleles should be inversely pro- Garcı´a-Dorado and Caballero 2000; Fry and portional to their dominance coefficient when paired Nuzhdin 2003; Fry 2004). with a fully functional allele (Haldane 1937). While In this article we adopt the usual population genetic dominance does not affect the mean fitness in panmictic conventions of describing dominance and fitness. populations except for completely recessive alleles When discussing deleterious alleles, the selection co- (Muller 1950), dominance is a key determinant of efficient s is the proportional decline in fitness of an mutation load in populations with some nonrandom individual homozygous for a mutant allele, relative to mating, either because of inbreeding (Morton 1971) individuals that are homozygous for the wild-type allele. or because of population structure (Whitlock 2002). Thus, the homozygote mutant individual will on average Moreover, the amount of inbreeding depression associ- have fitness that is 1 À s as great as that of an average ated with segregating deleterious alleles depends quite wild-type homozygote. We use h to indicate the domi- nance coefficient of the allele, the proportion of fitness effect expressed in the homozygote. Thus, a heterozy- Supporting information is available online at http://www.genetics.org/ gote would have fitness on average equal to 1 – hs times cgi/content/full/genetics.110.124560/DC1. the fitness of the wild-type homozygote. If h ¼ 0, the 1Corresponding author: Department of Ecology and Evolutionary Biology, University of Toronto, 25 Willcocks St., Toronto, Ontario M5S 3B2, heterozygote has fitness equal to that of the wild-type Canada. E-mail: [email protected] heterozygote, while if h ¼ 1, then the heterozygote has Genetics 187: 553–566 (February 2011) 554 A. F. Agrawal and M. C. Whitlock TABLE 1 cient (e.g.,Caballero and Keightley 1994); the ac- Previous dominance estimates for new mutations affecting curacy of these models may depend on the accuracy of fitness components their assumptions about this relationship. Variation in h is interesting for another reason, for it Method of points to the potential variety of mechanisms for, and the Species mutationa h Source evolution of, dominance. A deleterious allele may be recessive because a single copy of a functioning allele C. elegans EMS 0.1 Peters et al. (2003) C. elegans MA 0.55 Vassilieva et al. may be sufficient to meet the needs of the organism, or it (2000) may be partially recessive or dominant if two functional D. melanogaster MA À0.22b Mukai et al. (1964) alleles are required for full function. In some cases, a D. melanogaster MA 0.09b Mukai et al. (1965) mutated allele can directly cause problems for the 0.13b organism, over and above a loss of function. We discuss b ukai amazaki D. melanogaster MA 0.34 M and Y these mechanisms in greater depth later in the discus- (1968) sion. Many researchers have hypothesized that some 0.35b À0.32b types of proteins—such as structural proteins—may be D. melanogaster MA À0.09b Mukai (1969) more likely to have dominant deleterious mutations, À0.15b while others, for example enzymes, are more likely to À0.09b have recessive deleterious mutations (Bourguet et al. D. melanogaster MA 0.49b Ohnishi (1977a,b) 1997; Veitia 2005). Some empirical work has supported b 0.40 such variation by functional type (Kondrashov and D. melanogaster P elements 0.01 Mackay et al. (1992) Koonin 2004; Phadnis and Fry 2005). D. melanogaster MA 0.12 Houle et al. (1997) D. melanogaster MA 0.3 Chavarrias et al. The distribution of dominance coefficients—and its (2001) possible relationship with correlates such as functional D. melanogaster MA 0.17 Fry and Nuzhdin type and selection coefficient—may inform the search (2003) for the mechanism for evolution of dominance, a long- D. melanogaster Transposable 0.5 Fry and Nuzhdin standing question in evolutionary biology. Some models elements (2003) of dominance suggest that it is purely a by-product of S. cerevisiae EMS 0.2 Szafraniec et al. (2003) protein function and not subject to effective selection. This is essentially the perspective of Sewall Wright who a MA, mutation accumulation; EMS, ethyl methanesulfo- argued for a physiological basis of dominance. In con- nate mutagenesis. trast, some models suggest that dominance often evolves b Serious concerns have been raised about these estimates; see Garcia-Dorado and Caballero (2000) and Fry (2004). due to selection on heterozygous individuals; this was championed by R. A. Fisher in his famous conflict with Wright over dominance that drove the two seminal pop- fitness equal to that of the mutant homozygote. In ulation geneticists apart (Provine 1986). Many other practice h can be negative (indicating overdominance if models of the evolution of dominance have appeared in the mutant allele is deleterious), between 0 and 1 as the years since, and these models sometimes make discussed above or even .1 with underdominance. different predictions about the relationship between s To model evolution with new mutations, it is essential and h or between h and functional types. For example, to know not only what the average dominance coeffi- Charlesworth (1979) pointed out that a pattern of cient of new mutations might be, but also the variation negative correlation between s and h is not predicted among loci in this average and whether the dominance under Fisher’s hypothesis. However, the widespread view coefficient h is correlated in any way with the strength of that there is an inverse relationship between dominance selection against deleterious alleles s. If alleles of large coefficient and the selection coefficient is based on effect are recessive but alleles of small effect are additive, largely two studies, one a review article by Simmons and then inbreeding depression will largely be caused by Crow (1977) and the other an analysis of yeast deletion alleles of large effect. In this case, purging through data by Phadnis and Fry (2005). In the discussion,we repeated inbreeding may strongly affect the inbreeding return to various models of the evolution of dominance, depression of a population. If, on the other hand, there to compare them in the light of the results of our in- are a large number of deleterious recessive alleles of vestigation of dominance coefficients for growth rate in small effect, purging will be less effective, and inbreed- yeast deletion mutations. ing depression cannot evolve as easily (Lande and Simmons and Crow (1977) summarized the Drosoph- Schemske 1985; Charlesworth and Charlesworth ila studies of the 1960s and 1970s and concluded that the 1987; Charlesworth et al. 1990; Hedrick 1994). More dominance coefficient of mildly deleterious mutations generally, many simulation models of evolution assume averaged something close to 0.3, while the mean h for a relationship between dominance and the strength of alleles of large homozygous effect was closer to 0.02. selection or of the variation in the dominance coeffi- However, experimental protocols, including most types The Distribution of Dominance 555 of mutation accumulation experiments and mutagenesis zygous or homozygous states.
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