Cryptic genetic variation: evolution's hidden substrate

Key Points

  • Cryptic genetic variation (CGV) is genetic variation that normally has little or no effect on phenotype but that, under atypical conditions that were rare in the history of a population, generates heritable phenotypic variation. Cryptic variants are little exposed to selection and may thus accumulate neutrally.

  • CGV has long provided a theoretical explanation for the presence of standing genetic variation in wild populations that is available to fuel adaptation to new conditions. Early work in Drosophila melanogaster, starting with Waddington's classic experiments, showed that such variation exists and can be 'captured' by selection in a process called genetic assimilation.

  • The mechanisms that conceal CGV are ordinary, familiar genetic phenomena, including dominance, epistasis and gene-by-environment interactions. The ubiquity of these phenomena indicates that CGV is a common feature of populations.

  • CGV is closely related to concepts of robustness and canalization. However, although canalization will promote accumulation of CGV, such variation can accumulate under neutral conditions, and its presence is not necessarily evidence of canalization or robustness.

  • Experimental settings that reveal CGV include production of aberrant phenotypes following inhibition of Hsp90 activity in many different systems; genetic background effects for specific mutations; epistasis in quantitative trait locus mapping populations; genetic modifiers of Mendelian diseases in humans; and increases in additive genetic variance when populations are exposed to novel environments.

  • In principle, CGV can strongly influence the ability of natural populations to adapt to new conditions. Recent experiments have hinted at this potential, and this research field is poised for major advances in the near future.

  • CGV may be playing an important part in the emergence of complex human diseases, but there is currently limited empirical evidence for this hypothesis.

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.

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Figure 1: Cryptic genetic variation is conditional-effect genetic variation.
Figure 2: Waddington's epigenetic landscape, repurposed.
Figure 3: A sampling of experimental systems.
Figure 4: Fitness effect distribution of cryptic genetic variation in new conditions.

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Acknowledgements

The work of the authors is supported by the Charles H. Revson Foundation, the US National Institutes of Health (R01GM089972) and the Ellison Medical Foundation. The authors thank the reviewers for advice and guidance.

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Correspondence to Matthew V. Rockman.

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Glossary

Standing genetic variation

Genetic variation that is present in a population, as opposed to new mutations.

Additive genetic variance

(VA). The transmissible or heritable component of the phenotypic variation of a population. This is the variation due to the additive effects of segregating alleles.

Stabilizing selection

Natural selection that favours an intermediate phenotype and that disfavours phenotypes which depart from it in any direction.

Canalized

Pertaining to canalization, which is the evolved resistance to perturbations, such that an invariant phenotype is produced across a range of genotypes and environments.

Genetic assimilation

The process by which selection converts phenotypes that are revealed by environmental stimuli into phenotypes that are reliably produced in the absence of those stimuli. It relies on genetic variation revealed by those stimuli.

Capacitors

Genes that conceal the phenotypic effects of mutations at other loci, allowing the population to build up a store of cryptic genetic variation available for evolutionary response when a capacitor is overcome by environmental challenge or mutation.

Mutation–selection-drift balance

An equilibrium that arises from the balance between the introduction of alleles by mutation and their elimination by genetic drift and natural selection.

Robustness

A state of reduced phenotypic variance, not necessarily evolved, which can be defined relative either to specific perturbations (such as standing genetic variation) or to perturbations in general (such as the full mutational spectrum).

Near-isogenic lines

(NILs). Inbred strains that are genetically identical to a progenitor strain except for a small region of the genome that is derived from a second strain.

Transgressive segregation

The appearance, in the progeny of a cross, of phenotypes outside the range of phenotypes that are present in the parental generation.

Polyphenism

The phenomenon whereby a single genotype produces multiple discrete phenotypic states under different conditions.

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Paaby, A., Rockman, M. Cryptic genetic variation: evolution's hidden substrate. Nat Rev Genet 15, 247–258 (2014). https://doi.org/10.1038/nrg3688

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