Cited by 546Evolution and Genetic DynamicsGenetic and phenotypic traits in livestockGenetic Associations and Epidemiology

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Uncovering cryptic genetic variation

Gibson, Greg, Dworkin, Ian·2004·Nature Reviews Genetics

DOI 10.1038/nrg1426

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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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“CGV has been presented as an important means by which rapid adaptation can occur (Gibson & Dworkin, 2004; Ledón-Rettig et al., 2014; Paaby & Rockman, 2014; Rouzic & Carlborg, 2008; Schlichting, 2008; Waddington, 1953), as the environment-depen-dant nature of this hidden variation limits the action…”
Background
Pharmacogenomics
Nebert, D. W., & Zhang, G. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-812537-3.00016-0 · Cited by 10
Reduced within-population quantitative genetic variation is associated with climate harshness in maritime pine
Archambeau, J., Garzón, M. B., de Miguel, M., Brachi, B., Barraquand, F., & González‐Martínez, S. C. (2023) · Heredity · doi:10.1038/s41437-023-00622-9 · Cited by 10
“Differences in genetic variation for early height growth among populations were unlikely to originate from the expression of hidden genetic variation in novel environments (i.e., cryptic genetic variation caused by genotype-by-environment interactions; Gibson and Dworkin 2004, Schlichting 2008).”
Background
Trade-offs in modeling context dependency in complex trait genetics
Weine, E., Smith, S. P., Knowlton, R. K., & Harpak, A. (2025) · eLife · doi:10.7554/elife.99210.3 · Cited by 8
Cancer as the Disintegration of Robustness: Population-Level Variance in Gene Expression Identifies Key Differences Between Tobacco- and HPV-Associated Oropharyngeal Carcinogenesis
Ben‐Dayan, M., MacCarthy, T., Schlecht, N. F., Belbin, T. J., Childs, G. J., Smith, R. V., Prystowsky, M. B., & Bergman, A. (2015) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2014-0624-oa · Cited by 7
“That is, robustness allows for the harboring of cryptic genetic variation without disrupting the complex genotypic-phenotypic maps.(23,24) This enables individuals to exhibit genetic variation without compromising important cellular functions.”
Background
Enzyme Evolution in Secondary Metabolism
Chevrette, M. G., Hoskisson, P. A., & Barona‐Gómez, F. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-409547-2.14712-2 · Cited by 7
Genetic buffering and potentiation in metabolism
Poyatos, J. F. (2020) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1008185 · Cited by 7
“Canalization, or robustness, also leads to the accumulation of cryptic genetic variation (Gibson and Dworkin, 2004; Paaby and Rockman, 2014) that is normally hidden under typical conditions.”
Background
Tag-based regulation of modules in genetic programming improves context-dependent problem solving
Lalejini, A., Moreno, M. A., & Ofria, C. (2021) · Genetic Programming and Evolvable Machines · doi:10.1007/s10710-021-09406-8 · Cited by 9
“Cryptic variation is pervasive in nature and thought to play an important role in evolution, potentially acting as a cache of diverse phenotypic effects in novel environments [20, 54].”
An Evo-devo View of Post-genomic African Cichlid Biology: Enhanced Models for Evolution and Biomedicine
Parsons, K. J., McWhinnie, K., & Armstrong, T. (2021) · Springer eBooks · doi:10.1007/978-94-024-2080-7_21 · Cited by 7
Diverse environmental perturbations reveal the evolution and context-dependency of genetic effects on gene expression levelsPreprint
Lea, A. J., Peng, J., & Ayroles, J. F. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.11.04.467311 · Cited by 6
Heterozygosity and asymmetry: Ectodysplasin as a form of genetic stress in marine threespine stickleback
Morris, M. R. J., Kaufman, R., & Rogers, S. M. (2018) · Evolution · doi:10.1111/evo.13678 · Cited by 6
Genetic and environment-induced pathways to innovation: on the possibility of a universal relationship between robustness and adaptation in complex biological systems
Whitacre, J. M. (2011) · Evolutionary Ecology · doi:10.1007/s10682-011-9464-z · Cited by 6
Genes under weaker stabilizing selection increase network evolvability and rapid regulatory adaptation to an environmental shift
Laarits, T., Bordalo, P., & Lemos, B. (2016) · Journal of Evolutionary Biology · doi:10.1111/jeb.12897 · Cited by 5
The variable echinoid Micraster woodi sp. nov. – Trait variability patterns in a taxonomic nightmare
Schlüter, N., & Wiese, F. (2017) · Cretaceous Research · doi:10.1016/j.cretres.2017.05.019 · Cited by 6
Evolution in novel environments: Do restored prairie populations experience strong selection?
Magnoli, S. M., & Lau, J. A. (2020) · Ecology · doi:10.1002/ecy.3120 · Cited by 6
Structural Capacitance in Protein Evolution and Human Diseases
Li, C., Clark, L. V. T., Zhang, R., Porebski, B. T., McCoey, J. M., Borg, N. A., Webb, G. I., Kass, I., Buckle, M., Song, J., et al. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.06.051 · Cited by 6
EVOLUTION AND INHERITANCE OF EARLY EMBRYONIC PATTERNING IN DROSOPHILA SIMULANS AND D. SECHELLIA
Lott, S. E., Ludwig, M. Z., & Kreitman, M. (2010) · Evolution · doi:10.1111/j.1558-5646.2010.01206.x · Cited by 6
“The presence of some genetic variation in this trait is important because robust traits are generally believed to be capable of building up large stores of “cryptic” genetic variation (Gibson and Dworkin 2004).”
Background
Text-based analysis of genes, proteins, aging, and cancer
Semeiks, J. R., Grate, L. R., & Mian, S. I. (2004) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2004.09.028 · Cited by 6
“One hypothesis is related to cryptic genetic variation, variation that is not observed in a population under normal conditions but is uncovered by environmental or genetic perturbations (Gibson and Dworkin, 2004).”
Background
Increase in Quantitative Variation After Exposure to Environmental Stresses and/or Introduction of a Major Mutation: G × E Interaction and Epistasis or Canalization?
Zhang, X. (2008) · Genetics · doi:10.1534/genetics.108.091611 · Cited by 6
Hsp90 Selectively Modulates Phenotype in Vertebrate Development
Yeyati, P. L., Bancewicz, R. M., Maule, J., & van Heyningen, V. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0030043.eor · Cited by 7
Cryptic genetic variation in brain gene expression precedes the evolution of cannibalism in spadefoot toad tadpoles
Nesta, D. J., & Ledón‐Rettig, C. C. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2418431122 · Cited by 7
The Role of Standing Genetic Variation in Adaptation of Digital Organisms to a New Environment
Anderson, C. J. R. (2012) · Conference on Artificial Life (ALIFE) · doi:10.1162/978-0-262-31050-5-ch001 · Cited by 5
Evolution of Plasticity in Response to Ethanol between Sister Species with Different Ecological Histories ( Drosophila melanogaster and D. simulans )
Signor, S. A. (2020) · The American Naturalist · doi:10.1086/710763 · Cited by 7
Trait variation in a successful global invader: a large-scale analysis of morphological variance and integration in the brown trout
Vignon, M., Zhou, M., McIntosh, A. R., Correa, C., Westley, P. A. H., Jacquin, L., Labonne, J., & Hendry, A. P. (2023) · Biological Invasions · doi:10.1007/s10530-023-03003-9 · Cited by 5
“Second, genotype-byenvironmental interactions can mean that exposure to new conditions, such as following introduction to a novel environment, can reveal “cryptic” genetic variation that was not evident in the ancestral environment (Gibson and Dworkin 2004; Paaby and Rockman 2014).”
Background
Cryptic genetic variation of expression quantitative trait locus architecture revealed by genetic perturbation in Caenorhabditis elegans
van Wijk, M. H., Riksen, J. A. G., Elvin, M., Poulin, G. B., Maulana, M. I., Kammenga, J. E., Snoek, B. L., & Sterken, M. G. (2023) · G3 Genes Genomes Genetics · doi:10.1093/g3journal/jkad050 · Cited by 3
“The effect of this hidden genetic variation can be unlocked by environmental or genetic perturbation (Gibson and Dworkin 2004).”
Molecular mechanisms underlying the evolution of a color polyphenism by genetic accommodation in the tobacco hornworm, Manduca sexta
Suzuki, Y., Amaya, S., González, P., Becerril, D., Aquit, S., Davis, M., Hoesel, M., Chou, E., Khong, H., Zaia, K., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2425004122 · Cited by 5
“The process of genetic accommodation relies on hidden genetic variation, also known as cryptic genetic variation, which is revealed when the environmental conditions change ( 2 ).”
Systematic assessment of the Atelostomata (Spatangoida and Holasteroida; irregular echinoids) based on spine microstructure
Schlüter, N., Wiese, F., & Reich, M. (2015) · Zoological Journal of the Linnean Society · doi:10.1111/zoj.12291 · Cited by 5
“Those perturbations have an effect on the gene regulatory cascade, and thus potentially reveal cryptic genetic variation (Gibson & Dworkin, 2004).”
Background
Developmental genetics and psychopathology: Some new feathers for a fine old hat
Johnson, W. (2012) · Development and Psychopathology · doi:10.1017/s0954579412000624 · Cited by 5
“There is considerable and growing evidence for these reservoirs (Gibson & Dworkin, 2004).”
Background

Authors: Gibson, G., & Dworkin, I.
Affiliations: North Carolina State University (US)
Corresponding author: Gibson, Greg
ORCID: Gibson, Greg
Dworkin, Ian
Venue: Nature Reviews Genetics
Publisher: Springer Science and Business Media LLC
Published: 2004-09
Volume: 5
Issue: 9
Pages: 681-690
ISSN: 1471-0056 (ISSN-L)
1471-0064
DOI: 10.1038/nrg1426
OpenAlex: W2079319076
Cited by: 546
References: 90
Citations by year: 2026: 21 · 2025: 15 · 2024: 22 · 2023: 19 · 2022: 14 · 2021: 24 · 2020: 32 · 2019: 30 · 2018: 28 · 2017: 18 · 2016: 40 · 2015: 38 · 2014: 28 · 2013: 36 · 2012: 34
FWCI: 2.36
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Reviews Genetics (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords: cryptic genetic variation, susceptibility genes, gene perturbation, selective breeding, disease penetrance, adaptive potential
MeSH terms: Animals, Drosophila melanogaster, Selection, Genetic, Genetic Variation, Linkage Disequilibrium, Quantitative Trait, Heritable

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Uncovering cryptic genetic variation

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