The findings, reported in the March issue of Nature Genetics, were made using a database of more than 25,000 protein-protein interactions compiled by the Hopkins-IOB team. The result is believed to be the most detailed human "interactome" yet describing the interplay of proteins that occur in cells during health and disease.
"Genes are important because they are the blueprints for proteins, but proteins are where the action is in human life and health," says Akhilesh Pandey, M.D., Ph.D., an assistant professor at the Institute of Genetic Medicine and the departments of Biological Chemistry, Oncology and Pathology at The Johns Hopkins University School of Medicine. "This ability to find links between sets of proteins involved in different genetic disorders offers a novel approach for more rapidly identifying new candidate genes involved in human diseases," he says.
The analysis included interactions among 1,077 genes coding for proteins linked to 3,133 diseases, the researchers report. Significantly, it showed that proteins encoded by genes that are mutated in inherited disorders were likely to interact with proteins already known to cause similar disorders. In addition, the researchers disproved the long-held belief among scientists that the relative importance of a specific protein is always reflected by the number of other proteins it interacts with in the cell.
According to Pandey, the team's comparison of almost 25,000 human, 16,000 yeast, 5,500 worm, and 25,000 fly protein-protein interactions showed that, among these more than 70,000 links, only 16 were common to all four species.
Researchers say this low level of interactome overlap among species was surprising. It showed that current rapid-testing methods for identifying protein interactions are likely to miss true interactions.
Much of the Hopkins-Bangalore work was based on information compiled in the Human Protein Reference Database (HPRD), a repository of information on protein-protein interactions collected from the published literature and stored in a format suitable for rapid study and comparison with other animal cells. HPRD was developed by the IOB and the Pandey laboratory.
"Using HPRD and several other databases, we have been able to develop a gold mine of new information for researchers seeking new ways of finding candidate genes involved in genetic diseases," Pandey says. "And our demonstration that a protein's importance is not based on the number of interactions it has with other proteins is an important conceptual breakthrough. It eliminates a blind alley that could mislead researchers investigating the roles of specific proteins in the cell."
Pandey is the chief scientific advisor to the IOB and senior author of the Nature Genetics article. The team's conceptual advance was made by comparing human data with 6,014 genes in yeast and 2,284 genes in mice whose effect on survival was known, according to Pandey. "Our much larger database on genes and proteins gave us the information to set the record straight on how to measure a protein's importance," he says.
Using this kind of comprehensive comparison of information about human and other organisms allowed Pandey's group to identify 36 previously unknown protein-protein interactions, nine of which were tested in the laboratory to verify what the analysis suggested. "We proved they were valid," Pandey says. "By linking computerized sleuthing to laboratory experiments to confirm those findings, we expect to be able to eventually fill in many blanks in human protein-protein interactions."
All the analyses were primarily carried out at the IOB, a nonprofit research institute founded by Pandey in May 2002. The Human Protein Reference Database was developed with funding from the National Institutes of Health and the Institute of Bioinformatics. Pandey serves as chief scientific advisor to the Institute of Bioinformatics. He is entitled to a share of licensing fees paid to The Johns Hopkins University by commercial entities for use of the database. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.
The URL of the Human Protein Reference Database is (http://www.hprd.org).
Other investigators on this study were: Giovanni Parmigiani, Joel Bader and Jef Boeke from Johns Hopkins and Stefan Pinkert and Joerg Schultz from the University of Wuerzburg.
Journal
Nature Genetics