16 Feb 2000

Genetic tests based on polymerase chain reactions often fail to detect mutations when both a mutant and a wildtype gene exist in the genome. The key to "unmasking" the mutant allele, according to the authors of a study in tommorow's issue of Nature, is to create single (or haploid) versions of human DNA by fusing human chromosomes with those of another species.

Bert Vogelstein, Hai Yan and colleagues of the Howard Hughes Institute at Johns Hopkins and a number of other sites describe a diploid-to-haploid "conversion" technique whereby they fuse human and rodent cells to create hybrid cells that contain only a subset of the human chromosomes. In experiments with human lymphocyte donor cells and mouse E2 recipient cells, the researchers were able to generate single copies of the human chromosomes in 28 percent of the cells, on average.

To test drive their approach, Vogelstein and his colleagues showed that they could detect disease-causing mutations in all 22 subjects of a test group of hereditary colorectal cancer patients, whereas conventional methods found mutations in only 12 of the 22.

The authors say that diploid-to-haploid conversion can be used to tweak the sensitivity of many existing genetic tests, and will be especially useful in research on diseases, such as Alzheimer's, that involve multiple genes on different chromosomes.—Hakon Heimer