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Gene Discovery

Complex Diseases

The sequencing of the human genome and the advancement of bioinformatics and molecular tools to identify genes has made the process of gene discovery much easier. Most of the human genome sequence is now available on the Internet, with known and predicted genes annotated. This has reduced the need to laboriously build contigs.

Many of the common single-gene diseases have already been associated with a gene, and research efforts are now shifting to the more difficult task of finding genes that give susceptibility to developing complex diseases. (Such diseases show familial aggregation but do not follow any clear Mendelian inheritance pattern.)

It is thought that a combination of several genetic predisposition factors interact with environmental factors to trigger complex diseases, and that it is not a single gene but multiple genes that contribute to such traits, and the identification of each of these genes is correspondingly more difficult.

Complex traits can constitute various other challenges for researchers. Genetic heterogeneity is where alleles at more than one locus trigger the same phenotype, or mutations in the same gene cause different phenotypes. Reduced penetrance is where a predisposing genotype does not necessarily cause the phenotype to manifest itself. Phenocopy is where a trait looks identical but has a different cause than the one being studied.

To address these challenges, scientists use association studies, which are based on the principle that if a particular allele and trait occur simultaneously at a statistically significant frequency, the allele is likely to be involved in the development of the trait. (Linkage studies, by contrast, are based on finding DNA markers and traits that are linked within families.)

Alzheimer's disease is one example of a complex trait. Three genes have been found to contribute to the rare, early forms of the disease. Genetic screens have found that a fourth locus is linked to the common, late-onset form of the disease. Association studies have revealed that one allele of this fourth locus increases a patient's risk of developing Alzheimer's in a dose-dependent fashion, where the risk posed by having two alleles is greater than the risk posed by having just one.

Sofia A. Oliveria

and Jeffery M. Vance


Lewis, Ricki. Human Genetics: Concepts and Applications, 5th ed. Boston: McGraw-Hill,2002.

Peltonen, Leena, and Victor A. McKusick. "Dissecting Human Disease in the Postgenomic Era." Science 291 (2001): 1224-1229.

Additional topics

Medicine EncyclopediaGenetics in Medicine - Part 2Gene Discovery - Positional Cloning, Complex Diseases - Approaches for Identifying Genes