New method that will revolutionize the search for genes

Medical researchers know that most common human diseases, such as hypertension and diabetes, have a large genetic component. Many genes, interacting with the environment, contribute to these diseases. For researchers, a major challenge is finding all the genes involved with a particular disease.

Researchers from Case Western Reserve University School of Medicine, the Whitehead Institute for Biomedical Research, and Baylor College of Medicine have developed a new method that they believe will revolutionize the search for these genes. In a new research paper, they report that by swapping one chromosome at a time in mice, they can more simply, yet thoroughly, detect the locations of genes involved with complex medical conditions. Their study appears in the April 16 issue of the journal Science.

Through breeding two mouse strains, called AJ and B6, they substituted each chromosome in B6 with one from AJ. They tracked the substitutions through molecular labels marking the ends of each chromosome. The resulting strains are called Chromosome Substitution Strains (CCSs). They developed 22 CSSs of mice, one for each of the 21 chromosomes (including the two sex chromosomes), plus a strain with substituted mitochondria.

They put theory into practice by searching the mice for genetic factors involved with 53 complex traits, related to cholesterol/lipid levels, diet-induced obesity, anxiety and amino acids. By holding everything constant except one chromosome, the researchers could then ask if there were anything on that chromosome causing a change in the mouse. If something did change, it allowed the researchers to know that at least one gene related to the disease was located on that chromosome.

For diet-induced obesity, they found 17 locations compared with past studies by others identifying only two to four genes. In lipids (sitosterol and campesterol, linked with heart disease), they identified 20 locations for genes, compared with a past study by others finding only three genetic locations. With cholesterol, the present study found eight locations for genes compared with one to four locations in three previous studies by others.

CSS allows these and other researchers to know with which chromosome to begin their search for specific genes. “We deal with complexity through simplicity,” says Joseph Nadeau, Ph.D., one of the authors of the paper and the chairman of the Department of Genetics at the Case School of Medicine and University Hospitals of Cleveland.

Once the gene location is found, researchers can look on the genetic maps created by Celera, Inc., to find the gene sequences, and through Nadeau’s previous research, they can find the human genes that correspond to the mouse genes.

“The more genes we know about, the more potential candidates there are for drug targets to treat the disease,” Nadeau says.

Eric Topol, M.D., chairman of the cardiovascular medicine department at the Cleveland Clinic Foundation and not an author on the paper, says, “This is phenomenal work that will undoubtedly have a major impact in understanding the next frontier of human diseases–the complex traits, such as obesity, metabolic syndrome, or coronary heart disease. With whole chromosome substitution, Dr. Nadeau and colleagues have set a new standard for the use of models to fully dissect human traits and disease. This is one of the most important and impressive body of work to have been done to date to unravel the genes underpinning complex disease.”

Nadeau’s lab is making the mice available to other labs for research as a community service. The study occurred over seven years using 17,000 mice. Through the knowledge gained, the time can be cut by three years to produce new strains, which Nadeau believes is a better interval than other methods for discovering complex disease genes. The study was funded by the National Institutes of Health.