Mapping disease genes

The new approach of reverse genetics makes it possible to map genes influencing susceptibility to diseases without knowing which abnormally functioning proteins are involved in pathogenesis. Once the gene is mapped then its product can be characterised and its contribution to aetiology defined.

Techniques available to aid gene-mapping

• Cytogenetic studies - gross chromosomal abnormalities may provide a clue to the location of disease genes

• Linkage studies - depend on observing the cosegregation of disease with genetic markers in multiply affected families

• Association studies - may detect alleles which influence susceptibility themselves or which are in linkage disequilibrium with the disease mutation

• Transmission/disequilibrium test - aims to detect linkage disequilibrium but uses parents as internal controls to avoid spurious positive results from population stratifications

• Association tests using discordant sibs - use siblings as controls if parents are unavailable for TDT

• Mutation screening - intensive study of individual genes aims to detect variations which may be aetiologically significant

A "success story"

• Alzheimer's disease