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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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).
Flatt, T. The evolutionary genetics of canalization. Q. Rev. Biol. 80, 287–316 (2005).
Gibson, G. & Wagner, G. P. Canalization in evolutionary genetics: a stabilizing theory? Bioessays 22, 372–380 (2000).
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).
McCarthy, M. I. & Hirschhorn, J. N. Genome-wide association studies: potential next steps on a genetic journey. Hum. Mol. Genet. 17, R156–R165 (2008).
Di Rienzo, A. & Hudson, R. R. An evolutionary framework for common diseases: the ancestral-susceptibility model. Trends Genet. 21, 596–601 (2005).
Iles, M. M. What can genome-wide association studies tell us about the genetics of common disease? PLoS Genet. 4, e33 (2008).
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).
Gibson, G. & Goldstein, D. B. Human genetics: the hidden text of genome-wide associations. Curr. Biol. 17, R929–R932 (2007).
Hermisson, J. & Wagner, G. P. The population genetic theory of hidden variation and genetic robustness. Genetics 168, 2271–2284 (2004).
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).
Rice, S. H. Theoretical approaches to the evolution of development and genetic architecture. Ann. NY Acad. Sci. 1133, 67–86 (2008).
Gherman, A. et al. Population bottlenecks as a potential major shaping force of human genome architecture. PLoS Genet. 3, e119 (2007).
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).
Neiman, M. & Linksvayer, T. A. The conversion of variance and the evolutionary potential of restricted recombination. Heredity 96, 111–121 (2006).
Turelli, M. & Barton, N. H. Will population bottlenecks and multilocus epistasis increase additive genetic variance? Evolution 60, 1763–1776 (2006).
Kahn, S. E., Hull, R. L. & Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).
Diamond, J. The double puzzle of diabetes. Nature 423, 599–602 (2003).
Helgason, A. et al. Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nature Genet. 39, 218–225 (2007).
Renauld, J. C. New insights into the role of cytokines in asthma. J. Clin. Pathol. 54, 577–589 (2001).
Cookson, W. The alliance of genes and environment in asthma and allergy. Nature 402 (Suppl.), B5–B11 (1999).
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).
Bustamante, C. D. et al. Natural selection on protein-coding genes in the human genome. Nature 437, 1153–1157 (2005).
Strachan, D. P. Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax 55 (Suppl. 1), S2–S10 (2000).
Hugot, J. P., Alberti, C., Berrebi, D., Bingen, E. & Cézard, J. P. Crohn's disease: the cold chain hypothesis. Lancet 362, 2012–2015 (2003).
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).
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).
Ezzati, M. & Lopez, A. D. Estimates of global mortality attributable to smoking in 2000. Lancet 362, 847–852 (2003).
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).
Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).
Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).
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).
Crusio, W. E. Flanking gene and genetic background problems in genetically manipulated mice. Biol. Psychiatry 56, 381–385 (2004).
True, J. R. & Haag, E. S. Developmental system drift and flexibility in evolutionary trajectories. Evol. Dev. 3, 109–119 (2001).
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).
Hazra, A. et al. Common variants of FUT2 are associated with plasma vitamin B12 levels. Nature Genet. 40, 1160–1162 (2008).
Weidinger, S. et al. Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet. 4, e1000166 (2008).
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).
Palsson, A. & Gibson, G. Association between nucleotide variation in Egfr and wing shape in Drosophila melanogaster. Genetics 167, 1187–1198 (2004).
Khaitovich, P. et al. Metabolic changes in schizophrenia and human brain evolution. Genome Biol. 9, R124 (2008).
Gibson, G. & Dworkin, I. Uncovering cryptic genetic variation. Nature Rev. Genet. 5, 681–690 (2004).
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).
Morrow, E. M. et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218–223 (2008).
Haegert, D. G. Analysis of the threshold liability model provides new understanding of causation in autoimmune diseases. Med. Hypotheses 63, 257–261 (2004).
Weedon, N. M. et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nature Genet. 40, 575–583 (2008).
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).
Rhesus Macaque Genome Sequencing and Analysis Consortium. Evolutionary and biomedical insights from the rhesus macaque genome. Science 316, 222–234 (2007).
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).
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).
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).
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.
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.
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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