45NCBI Bookshelf. A service of the National Library of Medicine, NationalInstitutes of Health.Chapter 15Identifying human disease genesA more accurate, though less snappy title for this chapter might be ‘Identifying genetic determinants of human phenotypes’. Some mendelian phenotypes, like red-green color blindness, may be regarded as normal variants rather than diseases. Nor would the many genetic variants that contribute in a minor way to our susceptibility to common nonmendelian diseases normally be called disease genes, since they are neither necessarynor sufficient for developing the disease. But for all genetically determined phenotypic variants, one can in principle use the methods described here to discover what DNA sequence variants are responsible. Such variants will be found in many but not all the 80 000 or so human genes. Some genes are indispensable to embryonic function, so that deleterious mutations result in embryonic lethality and go unrecorded in humans. In other cases, abolition of gene function may normally have no effect on the phenotype because other non-allelic genes also supply the same function (genetic redundancy).15.1. Principles and strategies in identifying disease genesFew areas have moved as fast as human disease gene identification. Before 1980, very few human genes had been identified as disease loci. The few early successes involved a handful of diseases with a known biochemical basis where it was possible to purify the gene product. In the 1980s, advances in recombinant DNA technology allowed a new approach, positional cloning, sometimes given the rather meaningless label ‘reverse genetics’. The number of disease genes identified started to increase, but these early successes were hard won, heroic efforts. With the advent of PCR for linkage studies and mutation screening, it all became much easier. Now the human and other genome projects have made available a vast range of resources - maps, clones, sequences, expression data and phenotypic data. Identifying novel disease genes has become commonplace and is currently occurring on a weekly basis. Soon the landscape will change again, as the complete human genome sequence Strachan T, Read AP. Human Molecular Genetics. 2nd edition. New York: Wiley-Liss; 1999.
