Genetic goldmine
A TEAM of researchers led by geneticist Yosef Shiloh of the Tel Aviv University in Israel has tracked a defective gene that not only causes a rare balance disorder called ataxia telangiectasia or AT, but may also be the single largest hereditary cause of breast cancer (Science, Vol 268, No 5218).
Recent studies have indicated that female carriers of this mutant gene show five-fold higher incidence of breast cancer. Named ATM (for AT mutated) by its discoverers, the healthy gene encodes a protein that plays a key role in the cell's regulatory mechanism - and could shed light on what makes cells grow, live and die. "The discovery Of AT gene is one of the greatest accomplishments of the century and may spark off a biomedical re search bonanza," say the researchers.
just as the original Rosetta Stone - one of the greatest archaeologRal findings of the 18th century - was the key to a better understanding of the ancient Egyptian culture, "this single gene promises to solve a host of biomedical and epiderniologic mysteries," says team member Richard Gatti of the University of California, Los Ageles (ULCA).
Shiloh is believed to have initiated the 25-year-old study of the disease AT in the '70s. In the '80s, with the advent of positional cloning technique'- a method used to isolate defective genes - scientists were able to gather some important clues about the chemistry of AT cells. By 1988, Gatti of the ULCA had tracked the gene to the bottom third of the long arm of chromosome 11. After that, Shiloh's team joined an international effort - including Gatti, Malcolm Taylor of the University of Birmingham, UK, and Pat Concannon of the Seattle-based Virginia Mason Research Cent re, Washington, to track down the defective gene.
The international consortium split into member teams in 1994 -- each began extensive research by pulling out the most promising looking genes in the region and analysing them for mutations. But it was the Tel Aviv team led by Shiloh which hit the jackpot when it found that the second gene they examined contained mutations that occur only in AT patients.
Now that the researchers have identified the gene, their next task is to work out its precise functions. "The protein (that the gene encodes for) may have more than one function. If the healthy AT protein is involved in DNA repair - as is indicated by its resemblance to the yeast protein - it can help cells recognise the damaged DNA SO that it can be repaired before cells divide," say the researchers.
Though the biochemical role of the ATM is yet to be deciphered, the discovery of the gene has resolved one of the key debates in AT research, that is, whether AT is caused by more than one gene. Shiloh's research confirms that there is no evidence that more than one gene causes AT. This implies that the genetic markers identified during the hunt for ATM could be easily used for screening AT carriers and for pre-natal testing within at-risk families.
Gatti and many others believe that the discovery of the gene may open flood gates of information because it encodes a protein that plays an important role in the cell's internal regulatory mechanism. The sequence of the protein suggests that it is necessary for blocking cell growth and division until the damage is repaired - or both. Says cell biologist Michael Kastan of the Johns Hopkins University School of Medicine, in the us, "The gene is going to give insight into what makes cells grow, live and die because it is involved in all those cellular decisions."