Genotype–Phenotype Relationships

David J Weatherall, University of Oxford, Oxford, UK

Published online: March 2009

DOI: 10.1002/9780470015902.a0003403.pub2

Abstract

Many diseases due to a single defective gene show wide clinical variability. This results from the interaction of a number of other modifying genes, variability in adaptive mechanisms and the effects of the environment. Less commonly, phenotypic diversity reflects peculiarities in the distribution of mutations in mitochondrial deoxyribonucleic acid (DNA) or from mutations at different genes that result in a similar but highly variable clinical disorder. The multilayer complexity of this type of genetic system is only just starting to be appreciated, but provides some indication of the problems that will be encountered in analysing common multigenic disease. Their solution has important implications for the future practice of clinical genetics. Accurate phenotype prediction is essential for all aspects of genetic counselling, particularly in cases where couples are being advised about the likely outcome of a serious genetic disease if they are being offered the possibility of prenatal diagnosis and potential termination of affected pregnancies.

Key concepts

  • Most genetic diseases that follow a Mendelian pattern of inheritance show considerable clinical (phenotypic) diversity.

  • In many cases phenotypic diversity of Mendelian disease can be explained by the heterogeneity of mutations at a particular locus.

  • Phenotypic diversity of Mendelian disease may also result from the action of modifier genes that increase or decrease the severity of the effect of the primary mutation or which act at a distance from the mutation in further modifying the complications of the disease.

  • The clinical features of a single‐gene disorder may also be modified by variation in X‐chromosome inactivation, genomic imprinting and other epigenetic factors.

  • An increasing number of monogenic neurological diseases are being identified which result from variable degrees of expansion of repeat elements within or close to particular genes.

  • Many common diseases such as heart disease, stroke and diabetes result from the interaction of environmental factors with genetic susceptibility which is mediated through polymorphisms of a variable number of different genes.

  • The phenotypic effects of drug administration, both efficacy and complications, are modified by genes involving a wide range of physiological functions.

  • The vast majority of common forms of cancer are caused by mutations of cellular oncogenes which occur during an individuals lifetime.

  • Individual variability and the likelihood of contracting communicable disease, and its clinical course, also reflects the action of a wide variety of genes.

  • Future dissection of the complex interactions between the genome and the environment in the case of both monogenic and multigenic disease has the potential for improving the public health control of these diseases and for developing new therapeutic agents.

Keywords: genotype; phenotype; genetic disease

References

Antonarakis SE and Beckmann JS (2006) Mendelian disorders deserve more attention. Nature Reviews Genetics 7: 277–282.

Badano JL and Katsanis N (2002) Beyond Mendel: an evolving view of human genetic disease transmission. Nature Reviews Genetics 3: 779–789.

Frayling TM (2007) Genome‐wide association studies provide new insights into type 2 diabetes aetiology. Nature Reviews Genetics 8: 657–662.

Gatchel JR and Zoghbi HY (2005) Diseases of unstable repeat expansion: mechanisms and common principles. Nature Reviews Genetics 6: 743–755.

Haverfield EV, McKenzie CA, Forrester T et al. (2005) UGT1A1 variation and gallstone formation in sickle cell disease. Blood 105: 968–972.

Mathew CG (2008) New links to the pathogenesis of Crohn disease provided by genome‐wide association scans. Nature Reviews Genetics 9: 9–14.

Moudgil A, Fredrich R, Kangarloo H and Jordan SC (2002) Renal cystic diseases. In: Rimoin DL, Connor JM, Pyeritz RE and Korf BR (eds) Principles and Practice of Medical Genetics vol. 2, pp. 1693–1702. London: Churchill Livingstone.

O'Donnell A, Premawardhena A, Arambepola M et al. (2007) Age‐related changes in adaptation to severe anemia in childhood in developing countries. Proceedings of the National Academy of Sciences of the USA 104: 9440–9444.

Premawardhena A, Fisher CA, Fathiu F et al. (2001) Genetic determinants of jaundice and gallstones in haemoglobin E beta thalassaemia. Lancet 357: 1945–1946.

Robertson KD (2005) DNA methylation and human disease. Nature Reviews Genetics 6: 597–610.

Steinberg MH, Forget BG, Higgs DR and Weatherall DJ (eds) (2008) Disorders of Hemoglobin. New York: Cambridge University Press.

Taylor RW and Turnbull DM (2005) Mitochondrial DNA mutations in human disease. Nature Reviews Genetics 6: 389–402.

Todd JA (1999) From genome to aetiology in a multifactorial disease, type 1 diabetes. BioEssays 21: 164–174.

Weatherall DJ (2001) Phenotype‐genotype relationships in monogenic disease: lessons from the thalassaemias. Nature Reviews Genetics 2: 245–255.

Weatherall DJ (2008) Genetic variation and susceptibility to infection: the red cell and malaria. British Journal of Haematology 141: 276–286.

Weatherall DJ and Clegg JB (2001) The Thalassaemia Syndromes. Oxford: Blackwell Science.

Williams TN (2006) Red blood cell defects and malaria. Molecular and Biochemical Parasitology 149: 121–127.

Further Reading

Hunter DJ, Altshuler D and Reder DJ (2008) From Darwin's Finches to Canaries in the coal mine – mining the genome for new biology. The New England Journal of Medicine 358: 2760–2763.

Roses AD (2000) Pharmacogenetics and future drug development and delivery. Lancet 355: 1358–1361.

Rutter M (ed.) (2008) Genetic Effects on Environmental Vulnerability to Disease. Chichester: Wiley.

Suzuki MM and Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nature Reviews Genetics 9: 465–473.

Weinberg RA (2007) The Biology of Cancer. New York: GS Garland Science.

Related Sub-Topics:

Specific Genetic Disorders | Molecular Genetics of Common and Complex Disease | Inter-Individual Variation and Polymorphism | Gene Expression Profiling of Genetic Disease | Quantitative Genetics
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Article Title: Genotype–Phenotype Relationships
 
How to Cite close
Weatherall, David J(Mar 2009) Genotype–Phenotype Relationships. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003403.pub2]