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Genetic complexity in single gene diseases

BMJ 1996; 312 doi: (Published 27 January 1996) Cite this as: BMJ 1996;312:196
  1. Joseph S Alper
  1. Professor and director Department of Chemistry and Center for Genetics and Public Policy, University of Massachusetts-Boston, Boston, MA 02125, USA

    No simple link between genotype and phenotype

    Remarkable scientific progress in the study of human genetics has been parallelled by the public's growing awareness of the role of genes in health and disease. Media reports of genetic advances have encouraged the view that genes are real biological entities rather than mysterious abstract determinants of human characteristics. Not only do we talk about genes for individual diseases but we talk about detecting that gene, examining it, testing for it, and even replacing the altered copy with a healthy one. Though we may recognise the technical difficulties of such procedures, the philosophy behind them is regarded as straightforward and widely applicable: many diseases, as well as patterns of behaviour, are genetically controlled and result from the presence of one or, at most, a few altered genes.

    It is now becoming evident that this view is inadequate. Even the simplest genetic traits, diseases caused by a single altered gene, exhibit bewildering complexity.1 This has been found in such diseases as Huntington's disease, cystic fibrosis, fragile X, and hereditary breast cancer. A typical gene consists of thousands of base pairs, any of which may be subject to mutation. In different people the disorder may not appear at all (reduced penetrance) or may appear with different degrees of severity (variable expressivity), different sets of symptoms (pleiotropy), …

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