SCIENCE / It's all in the family: As the first UK trial of gene therapy is approved, Steve Connor begins a three-part series by looking at how scientists hunt the genes responsible for inherited diseases

THE famous protruding lower lip of the Habsburgs, which cropped up time and again in successive generations of this royal dynasty, was a classic example of how traits are passed on within a family. For scientists hunting for genes that cause disease, families remain the most important starting point in the search. The bigger the family, the easier it is to go gene hunting.

Family members who suffer from a genetic disease have obviously inherited the condition from one or both of their parents. Geneticists can quickly decide whether the gene in question is dominant (when only one copy of the gene from one of the parents causes disease) or recessive (when two defective copies, one from each parent, are needed for the disorder to manifest itself). Sex-linked genes, which are positioned on either the X or Y sex chromosomes, are equally obvious because they discriminate between male and female members of the family. The essential principle is to look for physical traits inherited along with the disease gene. Geneticists can find the approximate position of a gene on a chromosome by studying sufferers from the disease who have something else wrong with them. Sometimes this is because a portion of the chromosome carrying the gene in question has been lost, along with other genes nearby that result in the second complaint. Scientists can look at which part of the chromosome is missing, and deduce the rough position of the gene.

This sort of gene hunting relies to a large extent on 'classical genetics', which stems from research on peas in the 1860s by an Austrian monk, Gregor Mendel. More recently, with the discovery of the DNA double helix and the increasing refinement of the powerful techniques of genetic engineering, gene hunting can call upon the far more precise methods of molecular biology to pinpoint and identify genes. Peter Goodfellow, professor of genetics at Cambridge and co-discoverer of the sex-determining gene on the Y chromosome, says it is the marriage of these techniques - molecular biology and classical genetics - that has revolutionised gene searching.

Scientists have now discovered hundreds of naturally occurring enzymes in living organisms that can cut the long DNA molecule at specific sites. These enzymes are used in the laboratory to snip the DNA molecule into manageable fragments. By inserting these fragments into microbes that can be grown in a test tube, scientists can produce enough to study. One of the most revolutionary methods of manipulating fragments of human DNA is to insert them into artificial chromosomes made from yeast cells. These 'yacs' (yeast artificial chromosomes) are being used to great effect in producing the first complete maps of the most prominent 'landmarks', or genetic markers, of the DNA in a human chromosome.

Genetic markers are actually specific sequences of the chemical building blocks of the DNA molecule. They can be identified because they literally stick to a complementary DNA sequence that scientists can synthesise in the laboratory as short fragments. These synthetic fragments, called gene probes, play a crucial role in homing in on a particular gene. They can, in effect, locate the 'address' of a gene down to the street name, but are usually not good enough to identify the house number.

The full panoply of genetic tools allows scientists to get very close to the gene they are looking for, but how quickly they can find it depends largely on luck. In 1983, for instance, researchers in the US said they had located the gene responsible for Huntington's chorea, a lethal disorder that strikes in mid-life. Nearly 10 years later, they have still not identified the actual gene because the region they are searching in is packed with about 40 other genes, any one of which could be the gene in question. The researchers who discovered the gene for cystic fibrosis in 1989 were fortunate in that it was an exceptionally large gene and there were few other candidates in the vicinity.

Final proof that a gene is responsible for a genetic disorder comes when researchers can identify mutations - changes in the genetic sequence within the DNA - that are found only in people suffering from the disease. Robin Lovell- Badge, a senior scientist at the National Institute of Medical Research near London and the other co-discoverer of the sex gene, says it is important to eliminate non-functioning genes, rusty wrecks that evolution has made obsolescent. 'You have to recognise you have a real gene, not an irrelevant piece of DNA; a pseudo-gene or relic that doesn't work.' Only when that is done can scientists say their gene hunt has bagged the quarry.