|DNA Melting Map: Finding Rare Mutations for Common Diseases|
By Nancy Touchette
May 16, 2003
A new map of the human genome will be unveiled this summer that could help researchers uncover rare genetic mutations that contribute to common diseases.
The “DNA melting map” shows the temperatures at which short segments of the human genome come apart, or melt. Because genetic mutations melt at lower temperatures than “normal” DNA, researchers can use the map to identify genes that have rare mutations. These genes can then be sequenced and the mutations pinpointed.
The map’s potential value is that is could save time and money over other ways of hunting for rare mutations, such as sequencing large numbers of genes.
For instance, diabetes researchers might want to find rare mutations in a particular gene in a thousand people. Using the mapping strategy, they could determine which of these thousand genes melt at different temperatures, and then sequence only those genes.
In fact, the creators of the map, Peoples Genetics, Inc., in Woburn, Massachusetts, are using the strategy to search for rare mutations in a gene associated with type 2 diabetes. The major limitation of the technology right now is that researchers can only analyze one gene or region of the genome at a time.
Peoples Genetics, in collaboration with PubGene, Inc., in Oslo, Norway, is planning to make a version of the map available in the coming months on their Web site. The melting map is based on data from private and public sequencing efforts.
The map, used in concert with a DNA separation technique called Constant Denaturant Capillary Electrophoresis, will allow researchers to pick out as few as five mutant genes within a sample of 100,000 genes, according to William Thilly of the Massachusetts Institute of Technology in Cambridge, and Co-Chief Science Officer at Peoples Genetics.
The technique involves processing DNA samples so that mutant and normal DNA sequences can be separated easily, based on their melting temperatures.
The company has used the technique to look for mutations in the [beta]-globin gene in African-American and Han Chinese populations. They detected a known mutation that causes sickle-cell anemia in four percent of the African-Americans, but was absent in the Han Chinese. They also found three previously unknown and extremely rare mutations—two in the Han Chinese group and one in the African-American group.
Transgenomic, Inc., based in Omaha Nebraska, has developed a similar technology, called the WAVE system, that separates gene variants from normal sequences based on melting properties and could also benefit from the melting map.
One theory of disease says that common genetic diseases are due to common mutations. Another says that they are caused by rare genetic variants.
The theories are not mutually exclusive, but how researchers study disease may be influenced by which camp they belong to, according to Bruce Beutler of the Scripps Research Institute in La Jolla, California, who studies rare mutations that confer susceptibility to infectious disease.
“People are passionate about the theory they favor,” Beutler says.
The “rare variant” theory has received less attention in part because researchers have lacked the tools to identify rare mutations, according to Leonid Kruglyak at Fred Hutchinson Cancer Research Center in Seattle, and a scientific advisor to Peoples Genetics.
“It’s a bit of a chicken-and-egg thing,” says Kruglyak. “You have to have the technology before you can think about rare variants playing a role in disease.”
The ideal technology would allow researchers to screen large portions of the genome in large numbers of samples rather than one gene at a time.
Thilly says his company is developing a high-throughput prototype instrument for analyzing larger DNA segments in shorter periods of time. They plan to assess all 35,000 genes in the human genome for mutations that contribute to the 100 most common genetic diseases.
If Peoples Genetics accomplishes this goal, the field of genetics would change dramatically. “If you could pick out people with rare mutations and sequence their genomes in a minute, all kinds of things could fall out,” says Beutler. “It would be the end of genetics as we know it.”
The prototype machine is expected to be ready in two years.
Link to: www.peoplesgenetics.com
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