Catalogue of the 30,000 or so genes that contain the instructions to make a human or a mouse

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."

To test this, they developed a new vector - A DNA delivery system - that allowed them to cause a mutation in a gene and to return it to its unmutated state. This was used to test mutations in DNA repair systems, which repair the damage to the genome that all cells suffer. Approximately 100 million cells were screened for mutations that affect DNA repair: three genes were identified. One, Msh6, has been implicated in colon cancer. A second, Dnmt1, has a known role in modifying DNA: the new study showed that it also plays a role in DNA repair, maintaining genetic stability.

Mice lacking active Dnmt1 gene have an increased mutation rate and an increased susceptibility to tumours. This large-scale search has for the first time suggested the precise biological role that Dnmt1 plays in tumour development.

With the mouse genome sequence to hand, it becomes possible to search for mutations in all the genes of the genome. This new method can be adapted to produce homozygous mutations in most or all genes in mouse ES cells, where the effects can be validated and studied. The ability to make the mutations homozygous is a vital step in understanding function and, importantly, can reduce the requirement for breeding mice.

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