Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Decanalization and the origin of complex disease

Abstract

Complex genetic disease is caused by the interaction between genetic and environmental variables and is the predominant cause of mortality globally. Recognition that susceptibility arises through the combination of multiple genetic pathways that influence liability factors in a nonlinear manner suggests that a process of 'decanalization' contributes to the epidemic nature of common genetic diseases. The rapid evolution of the human genome combined with marked environmental and cultural perturbation in the past two generations might lead to the uncovering of cryptic genetic variation that is a major source of disease susceptibility.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Canalization owing to interaction between genetic vectors.
Figure 2: Canalization and specific instances of complex disease.

References

  1. Abegunde, D. O., Mathers, C. D., Adam, T., Ortegon, M. & Strong, K. The burden and costs of chronic diseases in low-income and middle-income countries. Lancet 370, 1929–1938 (2007).

    Article  Google Scholar 

  2. Flatt, T. The evolutionary genetics of canalization. Q. Rev. Biol. 80, 287–316 (2005).

    Article  Google Scholar 

  3. Gibson, G. & Wagner, G. P. Canalization in evolutionary genetics: a stabilizing theory? Bioessays 22, 372–380 (2000).

    Article  CAS  Google Scholar 

  4. Iyengar, S. K. & Elston, R. C. The genetic basis of complex traits: rare variants or “common gene, common disease”? Methods Mol. Biol. 376, 71–84 (2007).

    Article  CAS  Google Scholar 

  5. McCarthy, M. I. & Hirschhorn, J. N. Genome-wide association studies: potential next steps on a genetic journey. Hum. Mol. Genet. 17, R156–R165 (2008).

    Article  CAS  Google Scholar 

  6. Di Rienzo, A. & Hudson, R. R. An evolutionary framework for common diseases: the ancestral-susceptibility model. Trends Genet. 21, 596–601 (2005).

    Article  CAS  Google Scholar 

  7. Iles, M. M. What can genome-wide association studies tell us about the genetics of common disease? PLoS Genet. 4, e33 (2008).

    Article  Google Scholar 

  8. Cauchi, S. et al. Post genome-wide association studies of novel genes associated with type 2 diabetes show gene–gene interaction and high predictive value. PLoS ONE 3, e2031 (2008).

    Article  Google Scholar 

  9. Gibson, G. & Goldstein, D. B. Human genetics: the hidden text of genome-wide associations. Curr. Biol. 17, R929–R932 (2007).

    Article  CAS  Google Scholar 

  10. Hermisson, J. & Wagner, G. P. The population genetic theory of hidden variation and genetic robustness. Genetics 168, 2271–2284 (2004).

    Article  Google Scholar 

  11. Rice, S. H. The evolution of canalization and the breaking of von Baer's laws: modeling the evolution of development with epistasis. Evolution 52, 647–656 (1998).

    Article  Google Scholar 

  12. Rice, S. H. Theoretical approaches to the evolution of development and genetic architecture. Ann. NY Acad. Sci. 1133, 67–86 (2008).

    Article  Google Scholar 

  13. Gherman, A. et al. Population bottlenecks as a potential major shaping force of human genome architecture. PLoS Genet. 3, e119 (2007).

    Article  Google Scholar 

  14. Naciri-Graven, Y. & Goudet, J. The additive genetic variance after bottlenecks is affected by the number of loci involved in epistatic interactions. Evolution 57, 706–716 (2003).

    Article  Google Scholar 

  15. Neiman, M. & Linksvayer, T. A. The conversion of variance and the evolutionary potential of restricted recombination. Heredity 96, 111–121 (2006).

    Article  CAS  Google Scholar 

  16. Turelli, M. & Barton, N. H. Will population bottlenecks and multilocus epistasis increase additive genetic variance? Evolution 60, 1763–1776 (2006).

    Article  Google Scholar 

  17. Kahn, S. E., Hull, R. L. & Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).

    Article  CAS  Google Scholar 

  18. Diamond, J. The double puzzle of diabetes. Nature 423, 599–602 (2003).

    Article  CAS  Google Scholar 

  19. Helgason, A. et al. Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nature Genet. 39, 218–225 (2007).

    Article  CAS  Google Scholar 

  20. Renauld, J. C. New insights into the role of cytokines in asthma. J. Clin. Pathol. 54, 577–589 (2001).

    Article  CAS  Google Scholar 

  21. Cookson, W. The alliance of genes and environment in asthma and allergy. Nature 402 (Suppl.), B5–B11 (1999).

    Article  CAS  Google Scholar 

  22. Dean, M., Carrington, M. & O'Brien, S. J. Balanced polymorphism selected by genetic versus infectious human disease. Annu. Rev. Genomics Hum. Genet. 3, 263–292 (2002).

    Article  CAS  Google Scholar 

  23. Bustamante, C. D. et al. Natural selection on protein-coding genes in the human genome. Nature 437, 1153–1157 (2005).

    Article  CAS  Google Scholar 

  24. Strachan, D. P. Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax 55 (Suppl. 1), S2–S10 (2000).

    Article  Google Scholar 

  25. Hugot, J. P., Alberti, C., Berrebi, D., Bingen, E. & Cézard, J. P. Crohn's disease: the cold chain hypothesis. Lancet 362, 2012–2015 (2003).

    Article  CAS  Google Scholar 

  26. Feinerman, O., Veiga, J., Dorfman, J. R., Germain, R. N. & Altan-Bonnet, G. Variability and robustness in T cell activation from regulated heterogeneity in protein levels. Science 321, 1081–1084 (2008).

    Article  CAS  Google Scholar 

  27. Smolin, B., Klein, E., Levy, Y. & Ben-Shachar, D. Major depression as a disorder of serotonin resistance: inference from diabetes mellitus type II. Int. J. Neuropsychopharmacol. 10, 839–850 (2007).

    Article  CAS  Google Scholar 

  28. Ezzati, M. & Lopez, A. D. Estimates of global mortality attributable to smoking in 2000. Lancet 362, 847–852 (2003).

    Article  Google Scholar 

  29. Hill, W. G., Goddard, M. E. & Visscher, P. M. Data and theory point to mainly additive genetic variance for complex traits. PLoS Genet. 4, e1000008 (2008).

    Article  Google Scholar 

  30. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).

    Article  CAS  Google Scholar 

  31. Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).

    Article  CAS  Google Scholar 

  32. Phillips, P. C. Epistasis — the essential role of gene interactions in the structure and evolution of genetic systems. Nature Rev. Genet. 9, 855–867 (2008).

    Article  CAS  Google Scholar 

  33. Crusio, W. E. Flanking gene and genetic background problems in genetically manipulated mice. Biol. Psychiatry 56, 381–385 (2004).

    Article  CAS  Google Scholar 

  34. True, J. R. & Haag, E. S. Developmental system drift and flexibility in evolutionary trajectories. Evol. Dev. 3, 109–119 (2001).

    Article  CAS  Google Scholar 

  35. Lango, H. et al. Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk. Diabetes 57, 3129–3135 (2008).

    Article  CAS  Google Scholar 

  36. Hazra, A. et al. Common variants of FUT2 are associated with plasma vitamin B12 levels. Nature Genet. 40, 1160–1162 (2008).

    Article  CAS  Google Scholar 

  37. Weidinger, S. et al. Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet. 4, e1000166 (2008).

    Article  Google Scholar 

  38. Paré, G. et al. Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women. PLoS Genet. 4, e1000118 (2008).

    Article  Google Scholar 

  39. Palsson, A. & Gibson, G. Association between nucleotide variation in Egfr and wing shape in Drosophila melanogaster. Genetics 167, 1187–1198 (2004).

    Article  CAS  Google Scholar 

  40. Khaitovich, P. et al. Metabolic changes in schizophrenia and human brain evolution. Genome Biol. 9, R124 (2008).

    Article  Google Scholar 

  41. Gibson, G. & Dworkin, I. Uncovering cryptic genetic variation. Nature Rev. Genet. 5, 681–690 (2004).

    Article  CAS  Google Scholar 

  42. Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature Genet. 40, 955–962 (2008).

    Article  CAS  Google Scholar 

  43. Morrow, E. M. et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218–223 (2008).

    Article  CAS  Google Scholar 

  44. Haegert, D. G. Analysis of the threshold liability model provides new understanding of causation in autoimmune diseases. Med. Hypotheses 63, 257–261 (2004).

    Article  CAS  Google Scholar 

  45. Weedon, N. M. et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nature Genet. 40, 575–583 (2008).

    Article  CAS  Google Scholar 

  46. Wray, N. R., Goddard, M. E. & Visscher, P. M. Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res. 17, 1520–1528 (2007).

    Article  CAS  Google Scholar 

  47. Rhesus Macaque Genome Sequencing and Analysis Consortium. Evolutionary and biomedical insights from the rhesus macaque genome. Science 316, 222–234 (2007).

  48. Idaghdour, Y., Storey, J. D., Jadallah, S. J. & Gibson, G. A genome-wide gene expression signature of environmental geography in leukocytes of Moroccan Amazighs. PLoS Genet. 4, e1000052 (2008).

    Article  Google Scholar 

  49. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  50. Ge, D., Need, A. C. et al. A genome-wide association study indicates that common SNPs have little effect on schizophrenia risk. PLoS Genet. (in the press).

Download references

Author information

Authors and Affiliations

Authors

Related links

Related links

FURTHER INFORMATION

Greg Gibson's laboratory homepage

National Human Genome Research Institute's Catalog of Published Genome-Wide Association Studies

Glossary

Canalization

Pertaining to populations, the evolution of robustness to genetic or environmental perturbation. In canalized populations, most individuals tend to cluster around the optimal phenotype.

Cold chain hypothesis

The hypothesis that inflammatory bowel diseases are promoted by cold-tolerant gut bacteria that have crept into the human environment by surviving refrigeration of food.

Cryptic genetic variation

Genetic variation that only has an effect on a phenotype under abnormal, or perturbed, conditions, including a novel diet or pathogen exposure.

Endophenotype

A typically unobserved phenotype, such as the quantity of a metabolite or other biomarker, that is thought to contribute to the aetiology of a visible phenotype or of disease susceptibility.

Extended haplotype homozygosity analysis

An approach to detecting rare disease-promoting variants. It aims to detect extensive homozygous haplotypes hundreds of kilobases or more in length that are unique to, or enriched in, affected individuals.

Familial attributable risk

The proportion of the excess of disease that is observed in families with multiple affected individuals that can be attributed to a genotypic risk factor.

Genetic buffering

Pertaining to individuals, the state of being resistant to environmental or genetic perturbation. Persistent stabilizing selection can lead to canalization, resulting in an excess of genetically buffered individuals.

Heritability

The proportion of the phenotypic variance in a population that can be attributed to genetic variance.

Hygiene hypothesis

The hypothesis that immune disorders have increased in prevalence because reduced childhood exposure to pathogens in hygienic modern homes causes improper priming of the immune system.

Impaired glucose tolerance

A pre-diabetic condition characterized by partial loss of the capacity to regulate blood glucose levels appropriately, generally as a result of resistance to insulin.

Inflammatory bowel disease

Inflammatory intestinal disorders including Crohn's disease and ulcerative colitis.

Mutation–selection balance

The concept that genetic variation is maintained in a population by a dynamic balance between mutations that add new variance, and selection that tends to remove it.

Population attributable risk

(PAR). The portion of the incidence of a disease in the population that is due to exposure to the risk. It is equivalent to the incidence of the disease in the population that would be eliminated if the risk exposure (or genotype) were not present.

Population structure

The observation of genetic differences between distinct populations.

Relative risk

The ratio of the probability of an event (such as disease) occurring in an at-risk group to the probability of it occurring in a population that is not considered to be at risk. For example, a risk of 1.2 in heterozygotes relative to common homozygotes implies that the heterozygotes are 20% more likely to suffer from the disease.

Stabilizing selection

Natural selection against individuals that deviate from an intermediate optimum; this process tends to stabilize the phenotype. By contrast, directional selection pushes it towards either extreme.

T-helper cell

A class of lymphocyte that activates or regulates other classes of T cell that exert cytotoxic or phagocytic effects.

Thrifty genes

Refers to variants that were once favoured for their capacity to promote storage of scarce energy reserves and that are now promoting obesity in food-rich contemporary societies. There is a commonly cited but questionable notion that such variants lead to type 2 diabetes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gibson, G. Decanalization and the origin of complex disease. Nat Rev Genet 10, 134–140 (2009). https://doi.org/10.1038/nrg2502

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2502

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing