From the Lab: Biotechnology

New Map for Gene Hunters
Midsize DNA variations could aid in search for disease genes

Results: Researchers led by Evan Eichler of the University of Washington have made a map of specific types of variation in the human genome, many of which had never been documented before: insertions, deletions, and inversions of pieces of DNA, the majority of which ranged from 8,000 to 40,000 letters long. By comparing the genomes of two people, they found 297 sites of such variations, including 139 insertions, 102 deletions, and 44 inversions. When they compared these sites to 16 that had been previously documented, they found that their map had identified seven of them, most of which were associated with disease risk or drug sensitivity. This suggests that more of these newly discovered variations may play a role in disease or drug response.

Why It Matters: To find disease-causing genes, researchers need maps showing the locations of genetic variations between individuals. In the last few years, researchers have been mapping single-nucleotide polymorphisms (SNPs), one-letter changes in the DNA sequence, both individually and in sets of thousands that occur together. Researchers have also identified much-larger-scale genomic differences between individuals but hadn’t yet mapped intermediate-size variations such as insertions, deletions, and inversions. To do a comprehensive search for disease genes, researchers need to look at all types of variation. This new map can help them do that.

Methods: The researchers compared the reference human genome decoded in draft form in 2001 with the genome of a second person. This second genome was in the form of a library of one million pieces of DNA, each 40,000 letters long. The researchers sequenced 500 letters on each end of each piece and looked for matching sequences in the reference genome using bioinformatics software. By looking at the distance between two 500-letter-long sections of DNA in the reference genome, which corresponded to the two ends of one piece from the second genome, the researchers could tell whether an insertion or deletion had occurred between them. If the two 500-letter-long sections were in reverse order, that indicated an inversion.

Next Step: The researchers would like to make their map more complete by comparing not just two genomes but 10. They are also developing tests that can quickly identify which variations occur in particular patients. Other researchers could then use these tests to compare the genomic variations of thousands of healthy and diseased individuals to find genes that may be contributing to the disease.

Source: Tuzun, E., et al. 2005. Fine-scale structural variation of the human genome. Nature Genetics 37:727-732.

Stopping Cell Death
Molecule lessens stroke damage via a new biochemical pathway

Results: Harvard Medical School researcher Junying Yuan and colleagues have discovered a molecule that prevented a type of cell death in human cell cultures and lowered the amount of brain damage caused by stroke in live mice by 30 percent. The study suggests that some cases of cell death thought to be the uncontrollable result of injury or disease are instead regulated by a molecular pathway.

Why It Matters: Researchers have long known of one form of regulated cell death called apoptosis. This is a helpful type of cell death that prevents cancer and contributes to early development. Yuan’s research demonstrates the existence of another type of programmed cell death that she and her team call “necroptosis.” This process may be involved in brain trauma, heart attacks, stroke, and other diseases. In showing that necroptosis is the result of a programmed set of steps that a chemical can interrupt, Yuan’s work suggests the possibility of new drug therapies to combat these diseases.

Methods: In order to find an anti-necroptosis molecule, the researchers tested 15,000 chemicals concurrently in cells grown in separate wells. Yuan’s team induced cell death and examined which chemicals prevented the cells from dying. Once they found a promising compound, they administered it to live mice whose brains had been temporarily deprived of blood, and compared the resulting damage to that induced in a control group.

Next Step: Yuan and her team have discovered eight other necroptosis-blocking molecules and are using them to identify the steps in the necroptosis pathway by observing how each molecule affects dying cells. They are also seeking funding to develop a drug therapy for stroke based on their findings.

Sources: Yuan, J., et al. 2005. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chemical Biology 1:112-119.