Heterozygote advantage as a natural consequence of adaptation in diploids

Abstract

Molecular adaptation is typically assumed to proceed by sequential fixation of beneficial mutations. In diploids, this picture presupposes that for most adaptive mutations, the homozygotes have a higher fitness than the heterozygotes. Here, we show that contrary to this expectation, a substantial proportion of adaptive mutations should display heterozygote advantage. This feature of adaptation in diploids emerges naturally from the primary importance of the fitness of heterozygotes for the invasion of new adaptive mutations. We formalize this result in the framework of Fisher's influential geometric model of adaptation. We find that in diploids, adaptation should often proceed through a succession of short-lived balanced states that maintain substantially higher levels of phenotypic and fitness variation in the population compared with classic adaptive walks. In fast-changing environments, this variation produces a diversity advantage that allows diploids to remain better adapted compared with haploids despite the disadvantage associated with the presence of unfit homozygotes. The short-lived balanced states arising during adaptive walks should be mostly invisible to current scans for long-term balancing selection. Instead, they should leave signatures of incomplete selective sweeps, which do appear to be common in many species. Our results also raise the possibility that balancing selection, as a natural consequence of frequent adaptation, might play a more prominent role among the forces maintaining genetic variation than is commonly recognized.A daptation by natural selection is the key process responsible for the fit between organisms and their environments. The invasion of new adaptive mutations is an essential component of this process that fundamentally differs between haploid and diploid populations. In diploids, while a new mutation is still rare, natural selection acts primarily on the mutant heterozygote (1). As a result, only those adaptive mutations that confer a fitness advantage as heterozygotes have an appreciable chance of invading the population ("Haldane's sieve"). However, if the heterozygote of an invading adaptive mutation is fitter than the mutant homozygote, the mutation will not be driven to fixation but, instead, maintained at an intermediate, balanced frequency.We argue that heterozygote advantage should be very common during adaptation in diploids if selection is stabilizing and at least some mutations are large enough to overshoot the optimum. Consider, for example, adaptation through changes in gene expression (Fig. 1A), which is an important, if not the dominant, mechanism of adaptation (2). Here, mutations of small effect (Fig. 1B) will be adaptive when they modify expression in the adaptive direction whether the organism is haploid or diploid. However, mutations of large effect (Fig. 1C) can be nonadaptive in haploids, because they overshoot the optimum, yet be adaptive in diploids, because their phenotypic effect is moderated when heterozygous. These mutations will have heterozy...

Balancing Selection in Species with Separate Sexes: Insights from Fisher’s Geometric Model

“…Sellis et al (2011) showed that, among loci contributing to adaptive evolutionary change, the probability of heterozygote advantage tends to increase with the "standardized size" (Orr 1998) of adaptive mutations. Under Fisher's original scaling, mutation size is given by x ¼ r ffiffiffi n p =ð2zÞ; where r is the absolute phenotypic effect size of the mutation, n is the number of traits, and z represents the displacement of the population from a fitness optimum within phenotypic space (see Fisher 1930, pp.…”

“…However, most theory cannot predict the probability of balancing selection because it does not incorporate details of the fitness effect distribution among random alleles and genotypes in a population. Such details ultimately determine the relative likelihood of different forms of selection at individual loci.A recent study by Sellis et al (2011) provides new insight into the probability of balancing selection by modeling the (Fisher 1930; Orr 2005a,b)-an influential theoretical framework for the fitness effect distribution of random mutations. Sellis et al (2011) showed that, among loci contributing to adaptive evolutionary change, the probability of heterozygote advantage tends to increase with the "standardized size" (Orr 1998) of adaptive mutations.…”

“…Population genetics models are often used to evaluate the plausibility of sexual antagonism as a common mechanism for balancing selection (Kidwell et al 1977;Pamilo 1979;Curtsinger 1980 . On the other hand, fitness landscape topography biases the range of fitness effect values that beneficial alleles are likely to take (Orr 2005a(Orr ,b, 2010Manna et al 2011;Sellis et al 2011), with mutations that are subject to fitness trade-offs (including sexually antagonistic alleles) preferentially occupying portions of the conceivable parameter space that are the most amenable to balancing selection (Gillespie 1978;Fry 2010).Our analysis of the dioecious Fisher's geometric model, coupled with the recent monoecious analysis by Sellis et al Figure 5 The efficacy of selection differs between mechanisms of balancing selection. Results show the distributions (means and 75% confidence intervals) of a andq for mutations under each of the three forms of balancing selection.…”

“…In the absence of sex differences, where x A = rO(n)/(2z), Equation 6 is identical to previous, high-dimension approximations (n . 10) for the probability of a beneficial mutation in Fisher's geometric model (Fisher 1930;Kimura 1983;Orr 1998;Sellis et al 2011). Alleles selected to invade the population may go to fixation or evolve to an intermediate balanced polymorphic state.…”

The course of gastric cancer following surgery is associated with genetic variations of the interleukin-1 receptor antagonist and interleukin-1β

“…However, heterosis has been postulated for several other variations in common genetic diseases, e.g., malaria, and has been postulated to be a natural consequence of adaption in diploids [26,27]. Regarding the inflammatory response, heterozygosity of the mannose binding lectin genotype predicts an advantage to fatal outcome of sepsis patients [28].…”