Genetics Building a genetics parts list for understanding health, disease

Terms such as systems genetics and gene networks are currently getting all the buzz in genetics research. To truly understand what happens in health and disease, the theory goes, we have to know how they all fit together within a larger context.

That concept is valid, but there remains a fundamental problem. We know what some genes do, but we know very little about a large majority of them. That’s what makes the huge and ambitious International Knockout Mouse Consortium so vital.

The Consortium is a partnership founded six years ago by the European Commission, Genome Canada, and the U.S.’s National Institutes of Health. The goal? Knock out every one of the mouse’s approximately 21,000 protein-coding genes and characterize the result, one knockout mouse strain at a time. The effort, funded by the NIH, is known as KOMP, or "Knockout Mouse Project," and The Jackson Laboratory is playing a key role in the newest phase of the program.

Think about it. How can you construct accurate and useful system and network models if there are still a large number of missing pieces? For example, if you are making a model car and have the body, engine, tires and steering wheel, you know the general shape. But you can’t assemble the model—or know how things connect or how they work—without a drive train or axles. In essence, KOMP is working to collect a complete parts list and a partial set of instructions. The systems and network researchers can then use the tools to assemble the pieces and figure out how they work together.

"The overall goal of KOMP is to provide a comprehensive collection of mouse knockout data, which will greatly advance our knowledge of gene function," says Steve Murray, a research scientist with the Genetic Resource Science group at JAX. "This will translate into a deeper understanding of human biology and disease mechanisms, thanks to the close similarity between the human and mouse genome and the power of the mouse model. It’s exciting to be a significant contributor to such an important collaborative effort."

Creating the parts list is well under way. More than 14,000 knockouts have been started, with most currently in the form of embryonic stem cell lines. But while creating the knockouts in stem cells is a prodigious effort, obtaining useful knowledge requires generating mice and characterizing them. Therefore the second phase, called the Knockout Mouse Phenotyping Project (KOMP2), has been funded by the NIH and is underway at JAX and two separate international multi-institute consortia. The BaSH Consortium is a collaboration between the Baylor College of Medicine, The Wellcome Trust Sanger Institute (UK) and MRC Harwell (UK). The DTCC Consortium combines the efforts of the University of California at Davis, The Toronto Center for Phenogenomics (Canada), Children’s Hospital Oakland Research Institute and Charles River Laboratories.

KOMP2 will generate live mice and phenotype, or characterize, them to develop the partial set of instructions. The JAX portion of the project begins with the challenging task of making sure the source cells produce mice that have the correct genes actually knocked out of their genomes. Following careful quality control and thorough genetic characterization, there will be 833 new, distinct strains of mice here. When ready, the strains will be made available to the research community.

The phenotyping at JAX involves measuring hundreds of traits displayed by each knockout mouse strain, from basic size measurements to behavior to metabolism to chemistry. The mice will be thoroughly measured for more than 200 traits, creating a comprehensive data source for the knockouts and providing vital insight into the role of each knockout gene. These data will be delivered to the central KOMP2 Data Coordination Center Database and again made available to other researchers around the world.

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