Decanalization and the origin of complex disease

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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.

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

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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.

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