With genomic sequencing at The Wellcome Trust Sanger Institute and other centres, researchers now have an extensive catalogue of the 30,000 or so genes that contain the instructions to make a human or a mouse. Understanding the function of these genes and their role in disease is a challenging task.
A major route to understanding gene function is to alter the gene sequence and study the effects of that mutation. For complex organisms that carry two copies of each chromosome, both copies of the gene must be mutated - in biologists' parlance, the mutation is homozygous. Until now, that has been a difficult task requiring, in mice for example, an extensive breeding programme to generate mice in which both copies of a gene carry a mutation.
In a significant publication today in Nature (Wednesday 23 June 2004), Allan Bradley and colleagues at the Wellcome Trust Sanger Institute describe a novel approach to produce homozygous mutations in embryonic stem (ES) cells in culture. Using this new approach, the team have shown that a previously known gene (Dnmt1) is involved in repairing mistakes in DNA and suggests the role this gene plays in cancer. The method will form a part of the Sanger Institute's work to use genomic information to understand human disease.
Professor Allan Bradley, Director of The Wellcome Trust Sanger Institute, said: "The method capitalizes on the tendency of ES cells carrying a mutation in the Blm gene to undergo aberrant exchanges (recombination) between their chromosomes. One consequence is that a gene that carries a mutation in only one chromosome may become homozygous at a much higher rate than in normal cells. Indeed, by the time the Blm-deficient cells have divided 15 times, it is very likely that any given gene will be made homozygous."