International Team Uses Genomic Tools to Find Genes that Link Between Diabetes and Exercise

The researchers developed a powerful new analytical strategy called Gene Set Enrichment Analysis (GSEA), to unravel the web-like relationship of multiple genes that cause diseases like type 2 diabetes. The technique can also be applied to other common diseases that, like diabetes, are difficult to study because they involve subtle alteration in groups of genes that, when combined, form disease. In order to undertake this project, the researchers assembled a team with diverse expertise, drawn from multiple institutions in Boston at Harvard Medical School, Brigham and Women's Hospital, Dana Farber Cancer Institute, Children's Hospital, Massachusetts General Hospital, and at Lund University, in Sweden.

l. to r.: J. Hirschhorn, D. Altshuler, V. Mootha, T. Golub, P. Tamayo

"The findings provide a clear link between mitochondrial activity and diabetes, and more precisely define the sets of genes that work together in disease," says Vamsi Mootha, of the Brigham and Women's Hospital, and Whitehead Genome Center, who co-led the collaborative project along with Cecilia Lindgren from Lund University. "It helps us begin to understand why interventions such as aerobic exercise help people with diabetes." Specifically, the scientists found that the group of genes involved in oxidative phosphorylation -- an ancient metabolic pathway used by cell mitochondria to fuel muscles -- were less active in the muscle of people with type 2 diabetes.

"It has long been known that people predisposed to type 2 diabetes have a thrifty metabolism, they use less of the energy they ingest than people who are not prone to diabetes. This epidemic of diabetes has been ascribed to a collision between thrifty genes and an affluent, Western society," says co-author Leif C. Groop, Department of Endocrinology, Wallenberg Laboratory, University Hospital MAS, of University Hospital MAS, Lund University, Malmö, Sweden.

In the project, researchers in Sweden took muscle samples from 18 men with diabetes, as well as from age-matched controls. The scientists then used DNA microarrays to reveal the expression of each of the 22,000 human genes in each diabetic volunteer and each control.

"DNA microarrays provide a snapshot of nearly all human genes in action," Mootha says. "We were able to determine which genes were turned on or off, for example, in the diabetic samples."

The microarrays created a tremendous amount of data, and a tremendous challenge to interpret because, "no single gene jumped out as involved," Mootha says. The scientists decided to look at a large number of gene sets known to be involved in common, metabolic pathways, such as the Kreb's cycle and oxidative phosphorylation, which are suspected of being problematic in people with type 2 diabetes. Although many such gene sets (also known as "pathways") have been shown to be involved in the basic biology of diabetes, which are characteristically altered in human patients has remained unclear.

"We reasoned that groups of genes may be working together," says Cecilia Lindren.

Because of global cooperation in biology and genomics, gene sets are freely available on the internet. The scientists downloaded 149 gene sets related to metabolism, each consisting of 20-250 genes.

With gene sets in hand, the researchers needed to develop a new analytical strategy, Gene Set Enrichment Analysis, to analyze them. The results pointed to aberrations in expression among the genes involved with oxidative phosphorylation.

"GSEA allowed us to discover that genes involved in the mitochondria -- the cell's power generator -- are coordinately decreased in activity in patients with diabetes," says David Altshuler. "This is very interesting, because it is already known that in very rare patients, a mutation in the mitochondria can be sufficient to cause diabetes. Combining these new results with the data from this rare, genetic condition, we hypothesize that alteration in mitochondria may play a more general role in the disease. We are currently testing that hypothesis in a number of ongoing projects."

The scientists believe that Gene Set Enrichment Analysis can be applied to other diseases that, like type 2 diabetes, have defied understanding at the genetic level, because they are driven by genes that when viewed singly are so subtlety different that their aberrance cannot be distinguished from the general background "noise" of the genome. It is only when viewed as a group, and measured as a group with the new statistical technique, that a clear signal can be detected.

In addition to the study's lead authors (Dr.'s Mootha and Lindgren) and senior authors (Altshuler and Groop), other contributors include Karl-Fredrik Eriksson, Aravind Subramanian, Smita Sihag, Joseph Lehar, Pere Puigserver, Emma Carlsson, Martin Ridderstråle, Esa Laurila, Nicholas Houstis, Mark Daly, Nick Patterson, Jill Mesirov, Todd Golub, Pablo Tamayo, Bruce Spiegelman, Eric Lander, and Joel Hirschhorn.

The Diabetes Research Group at the Wallenberg Laboratory in Malmö, Sweden is a forerunner in the search for the underlying causes of type 2 diabetes. The Wallenberg laboratory is affiliated with the Department of Endocrinology and part of Lund University, which has made diabetes research one of its priorities. The combination of basic molecular research with comprehensive clinical investigations, and a fruitful collaboration with the Whitehead Genome Center, have significantly advanced the laboratory's understanding of the causes leading to the devastating disease type 2 diabetes.

The Whitehead Institute/MIT Center for Genome Research is an international leader in the field of genomics, the study of all of the genes in an organism and how they function together in health and disease. A flagship of the Human Genome Project, the Center today houses a broad range of thriving research programs combining structural genomics, medical and population genetics and clinical medicine. The Center's annual budget is $80 million, and it employs 350 people, including scientists and medical researchers from Whitehead, MIT and Harvard.

For more information, contact:
Lisa Marinelli, 617.252.1967