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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Introduction to Quantitative Genetics.
Edwards, A. W. F., & Falconer, D. S. (1982) · Biometrics · doi:10.2307/2529912 · Cited by 21,447
The genetical theory of natural selection
Fisher, R. A. (1930) · doi:10.5962/bhl.title.27468 · Cited by 17,617
Genetics and Analysis of Quantitative Traits
(2002) · Journal of Animal Breeding and Genetics · doi:10.1046/j.1439-0388.2002.00356.x · Cited by 6,176
Introduction to Quantitative Genetics
J.-M., G., & Falconer, D. S. (1962) · Population · doi:10.2307/1525780 · Cited by 3,773
Hsp90 as a capacitor for morphological evolution
Rutherford, S. L., & Lindquist, S. (1998) · Nature · doi:10.1038/24550 · Cited by 2,270
Systematic Genetic Analysis with Ordered Arrays of Yeast Deletion Mutants
Tong, A. H. Y., Evangelista, M., Parsons, A. B., Xu, H., Bader, G. D., Pagé, N., Robinson, M., Raghibizadeh, S., Hogue, C. W. V., Bussey, H., et al. (2001) · Science · doi:10.1126/science.1065810 · Cited by 2,138
A vision for the future of genomics research
Collins, F. S., Green, E. D., Guttmacher, A. E., Guyer, M. S., & on behalf of the US National Human Genome Research Institute (2003) · Nature · doi:10.1038/nature01626 · Cited by 1,752
Manual of Nearctic Diptera
McAlpine, J. F., Peterson, B. V., Shewell, G. E., Teskey, H. J., Vockeroth, J. R., & Wood, D. M. (1981) · Research Branch, Agriculture Canada, eBooks · Cited by 1,611
Genetics of gene expression surveyed in maize, mouse and man
Schadt, E. E., Monks, S. A., Drake, T. A., Lusis, A. J., Che, N., Colinayo, V. V., Ruff, T. G., Milligan, S. B., Lamb, J. R., Cavet, G., et al. (2003) · Nature · doi:10.1038/nature01434 · Cited by 1,501
GENETIC ASSIMILATION OF AN ACQUIRED CHARACTER
Waddington, C. H. (1953) · Evolution · doi:10.1111/j.1558-5646.1953.tb00070.x · Cited by 1,494

Show all 90 references

Research works printed but not linked: 5

Ptashne, M. A Genetic Switch: Phage Lambda and Higher Organisms (Blackwell Scientific, Oxford, 1992).
Dworkin, I. in Variation (eds Hallgrimsson, B. & Hall, B. K.) Ch. 14 (Academic, San Francisco, 2004).
Gibson, G. et al. Extensive non-additivity of gene expression in Drosophila. Genetics (in the press).
Waddington, C. H. The Stratgey of the Genes (Allen and Unwin, London, 1957).
Rendel, J. M. Canalization and gene control. (Logos, New York, 1967).

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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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