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  • Review Article
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Uncovering cryptic genetic variation

Key Points

  • Cryptic genetic variation (CGV) is genetic variation that is not normally expressed, but that is available to modify abnormal phenotypes produced by environmental or genetic perturbation.

  • CGV is relevant to understanding the expressivity of disease phenotypes, mechanisms of animal and plant breeding, and the relationship between macro- and micro-evolution.

  • CGV is thought to arise as a result of unusually large genotype-by-environment and/or genotype-by-genotype (epistatic) interactions.

  • Threshold-dependent effects might help to hide CGV in natural populations.

  • Some alleles that contribute to CGV might modify standing variation for different (pleiotropic) traits, but in general, the factors that help to maintain CGV are unknown.

  • The same tools that are used to examine visible complex phenotypes can be used to examine CGV, including complementation testing, quantitative trait locus mapping and association studies.

Abstract

Cryptic genetic variation is the dark matter of biology: it is variation that is not normally seen, but that might be an essential source of physiological and evolutionary potential. It is uncovered by environmental or genetic perturbations, and is thought to modify the penetrance of common diseases, the response of livestock and crops to artificial selection and the capacity of populations to respond to the emergence of a potentially advantageous macro-mutation. We argue in this review that cryptic genetic variation is pervasive but under-appreciated, we highlight recent progress in determining the nature and identity of genes that underlie cryptic genetic effects and we outline future research directions.

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Figure 1: Quantitative genetic formulation of cryptic genetic variation.
Figure 2: Mechanistic formulation of cryptic genetic variation.
Figure 3: Experimental investigation of cryptic genetic variation.

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Acknowledgements

We would particularly like to express our gratitude to the many colleagues who have encouraged and fostered our interest in this topic. Conversations with B. Hill and J. Hermisson helped us in thinking about some of the specific concepts, and the comments of three anonymous reviewers were enormously useful. G.G.'s research on cryptic genetic variation has been supported by the David and Lucille Packard Foundation and by the National Institutes of Health.

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DATABASES

Entrez

CFTR

cv

Egfr

hb

pn

sc

sd

Sevenless

Ubx

OMIM

arrhythmia

cystic fibrosis

diabetes

FURTHER INFORMATION

Genetic Association Database

Greg Gibson's laboratory

Glossary

MODERN SYNTHESIS

The theoretical synthesis of evolutionary biology with genetics, which occurred in the 1940s and included the recognition of the roles of genetic drift, genic selection and speciation in micro-evolutionary change.

CANALIZATION

The tendency of traits to evolve a reduction in variability — namely, resistance to mutational or environmental perturbation. Canalization can be revealed by comparing the variance of a trait under normal and perturbed circumstances, or by measuring the robustness of a trait to new mutations in two different species.

GENETIC ARCHITECTURE

General features of standing quantitative genetic variation in relation to a particular trait, including parameters such as the number of loci, the degree of dominance and epistasis, and the frequency of quantitative trait locus alleles in a population.

ADDITIVE EFFECT

When two alleles have an effect on a trait, they are said to be additive if the average phenotype of heterozygotes is intermediate between those of the two classes of homozygote. Similarly, if the differences in phenotype among genotypes at two different loci are independent of one another, the effects at the two loci are said to be additive.

QUANTITATIVE TRAIT LOCUS

(QTL). One of several loci that contributes to quantitative genetic variation. QTLs are usually detected by mapping the association between anonymous genetic markers and a continuous or discrete phenotype in the progeny of a cross between two lines.

HOMEOTIC TRANSFORMATION

The conversion of one body part into another as a result of misexpression of a developmental regulatory gene. Another classic example is the antenna-to-leg transformations that result from misexpression of Antennapedia in Drosophila melanogaster.

HALTERE

In Diptera (true flies), the pair of club-like balancing organs that act as gyroscopes during flight. They are evolutionarily modified hind wings.

MUTATIONAL VARIANCE

Tendency towards dispersion of data about the mean due to new mutations that arise in each generation.

ADMIXTURE

The mixture of two genetically differentiated populations of a species, generally as a result of the migration or breakdown of a reproductive barrier, which leads to rapid changes of even common allele frequencies.

GENOTYPE-BY-ENVIRONMENT INTERACTION

In quantitative genetics, an interaction in which the degree of additivity or dominance at the locus is a function of the environment. Consequently, the difference in the mean value of each of the homozygote and heterozygote classes varies according to the environment.

EXPRESSIVITY

The degree to which a novel phenotype is aberrant. Not to be confused with penetrance, which is the proportion of individuals with a predisposing genotype that express the trait.

THRESHOLD-DEPENDENT

A response marked by a phase transition once the causal variable exceeds some threshold. An example is the switch in cell fate that occurs when receptor–ligand interactions exceed a threshold. In statistical terms, threshold-dependence refers to discrete trait states that are thought to arise at high or low levels of an underlying continuous variable.

SECOND-SITE MODIFIER SCREENS

Genetic screens designed to detect a mutation in a second locus that enhances or suppresses the effect of a dominant visible mutation.

INTROGRESSION

The deliberate movement of a chromosomal interval into a different genetic strain, generally by repeated backcrossing with selection for the allele in each generation.

ASSOCIATION STUDIES

An approach to identifying the genes that contribute to disease or other traits on the basis of a correlation between the genotype and some measure of the phenotype.

EPISTASIS

In quantitative genetics, an interaction between two or more genotypes, such that the degree of additivity or dominance at one locus is a function of the genotype at another locus.

SIGMOIDAL [RESPONSE]

A classic response in which the relationship between the dependent and independent variables shows a characteristic S-shaped curve, indicating a transition from slow-to-rapid response followed by a plateau.

QUANTITATIVE TRAIT NUCLEOTIDE

(QTN). A nucleotide that associates with a quantitative trait, but that is detected in an outbred population or a set of unrelated inbred lines.

HAPLOTYPE

An experimentally determined profile of genetic markers that is present on a single chromosome of any given individual.

SYNTHETIC LETHAL MUTANTS

Pairs of mutations that are individually viable, but in combination result in lethality.

RECOMBINANT INBRED LINES

A set of lines used in linkage mapping that consists of alternating patches of the genomes of two different parental lines.

LINKAGE DISEQUILIBRIUM MAPPING

A type of association study in which a locus is inferred to contribute to a trait on the basis of a correlation between one or more SNPs that are in linkage disequilibrium with the true causal site(s), which might not actually be genotyped.

TRANSMISSION DISEQUILIBRIUM

A distortion from the expected ratio of 1:1 in the transmission of 2 alleles from a heterozygous parent to offspring of a particular class, typically affected individuals.

CONDITIONAL SELECTION

Selection at the molecular level that operates only under a subset of environmental conditions or in the presence of particular modifying genotypes.

HYBRID INCOMPATIBILITY

The inviability, infertility or infirmity of the progeny of a cross between two species, generally attributed to incompatibility between allelic combinations that never occurred in either lineage as they diverged.

SOFT SELECTION

Natural selection that acts on an allele that is initially at an intermediate frequency, as opposed to hard selection, which acts on a newly arising mutation. Selection on cryptic variation will generally entail soft selection, as the perturbation exposes intermediate-frequency alleles that were previously neutral.

F ST

A statistic that compares the level of genetic variation within two or more subpopulations relative to all subpopulations combined (that is, the total population).

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Gibson, G., Dworkin, I. Uncovering cryptic genetic variation. Nat Rev Genet 5, 681–690 (2004). https://doi.org/10.1038/nrg1426

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