Cryptic genetic variation: evolution's hidden substrate

Abstract

Cryptic genetic variation (CGV) is invisible under normal conditions, but it can fuel evolution when circumstances change. In theory, CGV can represent a massive cache of adaptive potential or a pool of deleterious alleles that are in need of constant suppression. CGV emerges from both neutral and selective processes, and it may inform about how human populations respond to change. CGV facilitates adaptation in experimental settings, but does it have an important role in the real world? Here, we review the empirical support for widespread CGV in natural populations, including its potential role in emerging human diseases and the growing evidence of its contribution to evolution.

Figure 1

Cryptic genetic variants are conditional-effect genetic variants. Each plot in the figure shows phenotype (y-axis) as a function of condition (environment or genetic background, x-axis) for three genotypes at a locus (AA homozygote in black, Aa heterozygote in red, and aa homozygote in blue). At the top, unconditionally penetrant genetic variation affects phenotype independent of condition. At the bottom, unconditionally silent variation has no effect under any circumstances (the three lines are superimposed). Between these extremes are variants whose effects depend on circumstances. Under each scenario shown, as conditions change (represented by movement along the arrow), cryptic genetic variation is revealed. In some cases, the genetic variants are completely cryptic in the initial condition, while in others their effect-sizes differ across conditions, hiding cryptic genetic variance in the initial condition. These panels illustrate just a few of the infinite possibilities for conditional-effect genetic variation.

Figure 2

Waddington's epigenetic landscape, repurposed. Waddington's original conception of canalization arose from his observation that as the germ develops, tissues adopt discrete types: the eye or the gut, for example, never an intermediate. His classic illustration depicts a ball atop a bifurcating landscape, poised to roll down the path of least resistance into valleys, or “canals,” whose endpoints represent terminal differentiation. His brilliantly literal depiction of genetic underpinnings shows guy-ropes pulling down, from the underside of the bifurcating landscape, the undulating topology of the canals and fastening to anchors representing genes. Here we repurpose Waddington's landscape to illustrate how cryptic genetic underpinnings can induce different phenotypic fates. These genetic underpinnings vary at the molecular level (represented by guy-ropes of different strengths and configurations) but produce a consistent phenotype. After disruption (breakage of the main rope, representing a null mutation in a major gene), variation elsewhere produces deformities to the landscape.

Figure 3

A sampling of experimental systems. a | Spadefoot toad (Spea) tadpoles are facultatively carnivorous, and meat-eating tadpoles are larger and have shorter guts than their conspecifics that consume a plant-based diet. These two siblings are the same age, but the tadpole on the left developed on a diet of plants and detritus. Ledón-Rettig et al. fed a related species, the non-carnivorous Scaphiopus couchii, a shrimp diet and observed increased heritability for body size, developmental stage and gut length, indicating that the dietary transition to the novel carnivorous feeding strategy in the Spea ancestor may have released cryptic genetic variation for these resource-use traits. (Image courtesy of David Pfennig.) b-d | Female yellow dung flies almost always have three sperm storage compartments, or spermathecae; Berger et al. perturbed spermathecae development by increasing rearing temperature to reveal cryptic genetic variation for four spermathecae. (Mating pair image courtesy of Peter Jann; spermathecae images courtesy of David Berger and reproduced with permission from John Wiley and Sons.) e-f | Queitsch et al. demonstrated that Arabidopsis plants exposed to the drug geldanamycin (GDA), an Hsp90 inhibitor, exhibit a variety of morphological abnormalities. Untreated, different accessions consistently develop into the wild-type phenotype (e). On GDA, different accessions exhibited abnormalities at different frequencies. For example, the Shadara accession was most likely to exhibit juxtaposed cotyledons (f) and deformed and radially symmetrical true leaves (g). Col more frequently exhibited dwarf plants with dark pigmentatio (h) and Ler more frequently produced curled hypocotyls (i). (Images courtesy of Christine Queitsch and reproduced with permission from Nature Publishing Group.)

Figure 4. Fitness effect distribution of CGV in new conditions

Here, three simple scenarios illustrate alternative outcomes for exposure of CGV. In black is the population's heritable variation in fitness under the normal condition; in red, the transformed fitness distribution following a change of environment or genetic background. a | Under a buffering scenario, a large fraction of the cryptic variants will be strongly damaging, and their exposure will primarily generate low-fitness monsters. b | Under an enrichment model, occasional exposure of CGV in a population's history will weed out the strongly deleterious alleles, leaving the CGV pool enriched for variation that improves the population's fit to its environment. c | Under a symmetrical scenario, newly exposed CGV simply increases the heritable phenotypic variance around the same mean.