Academic journal article Genetics

Heterozygote Advantage Is a Common Outcome of Adaptation in Saccharomyces Cerevisiae

Academic journal article Genetics

Heterozygote Advantage Is a Common Outcome of Adaptation in Saccharomyces Cerevisiae

Article excerpt

THE most immediate difference between diploids and haploids is that diploids have twice as many gene copies and thus roughly twice as many expected mutations per individual per generation, assuming the same mutation rate per nucleotide. If adaptation is limited by the waiting time for new adaptive mutations, this suggests that diploids might enjoyanadaptive advantage overhaploids;indeed, ithasbeen argued that the rate of adaptive evolution in diploids might be double that in haploids (Paquin and Adams 1983; Anderson et al. 2004) [although see Zeyl et al. (2003) and Gerstein et al. (2011)].

Diploids, however, might also suffer an adaptive disadvantage. New mutations in diploids are heterozygous, and their effect is thus "diluted" or even completely masked by the presence of the ancestral allele. Unless mutations are fully dominant in fitness, this reduces the probability of fixation of new beneficial mutations and increases the expected frequency that can be reached by deleterious mutations. This fitness effect "dilution" also slows down fixation of adaptive alleles in diploids by roughly twofold when adaptive mutations are codominant in fitness, and by more than that when adaptive mutations are either recessive (they spread in the population slowly) or fully dominant (they suffer a slowdown at high frequencies). This suggests that haploids should gain an advantage in adapting to new environments when the rate of spread of adaptive mutations is the limiting step in adaptation.

These considerations have underpinned a large body of theory (Otto and Gerstein 2008) and generated some specific predictions. One of these is known as Haldane's sieve, and states that adaptive mutations in diploids that do contribute to adaptation are unlikely to be fully recessive in fitness, i.e., adaptive mutations need to be beneficial at least to some extent in heterozygotes (Haldane 1924, 1927; Turner 1981). There is substantial evidence that Haldane's sieve does operate in evolution, at least to some extent. For instance, fungicide resistance in haploid vs. diploid yeast is driven by distinct sets of mutations, and at least some of these differences can be attributed to the fact that many of the adaptive mutations in haploids are recessive in resistance and would be invisible in diploids (Anderson et al. 2004).

Haldane's sieve is a claim about the expected fitness of the mutant heterozygote compared with the ancestral homozygote. However, it does not make specific predictions about the fitness of the mutant homozygote. Consider, for example, a simple case of an enzyme under stabilizing selection for its concentration. In a simple scenario of additive phenotypes, each copy in a diploid genome contributes half to the total enzyme concentration (Eopt ¼ x þ x). Let us further consider a shift in the environment that doubles the required enzyme concentration, moving the optimal concentration to Eonpetw ¼ 4x. In this new environment, a heterozygote individual with a new adaptive mutation that triples the expression level would be strongly selected for, as it would achieve the new optimal phenotype (3x þ x ). However, in individuals homozygous for the new mutation, the enzyme concentration (3x þ 3x) will overshoot the new 4x optimum, leading to overdominance. The evolution of overdominance in adaptive mutations does not strictly require overshooting the phenotypic optimum in a single dimension as in the previous simple example. Consider a slightly more realistic case of an enzymatic reaction under Michaelis-Menten kinetics. Let us further assume that increased catalytic activity is adaptive. A mutation that increases the amount of the enzyme in heterozygotes should generally increase it even further as a homozygote. At first glance this would suggest that such a mutation would thus be even more adaptive as a homozygote, and hence partially dominant in fitness. However, consider further that an increase in the level of expression of this enzyme might have additional pleiotropic costs. …

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