Integrating Human and Fly Genetics to Facilitate Gene Discovery

Top Quote Cross-species strategy may be powerful tool for studying human disease. End Quote
  • (1888PressRelease) March 28, 2011 - Boston, MA - A new study from Brigham and Women's Hospital (BWH) takes advantage of similarities between humans and fruit flies to enhance gene discovery relevant to human disease. The new strategy, published by Cell Press in the American Journal of Human Genetics on February 3, has the potential to be an effective approach for unraveling genetically complex human disorders and to yield insights into the molecular mechanisms underlying human disease.

    Genome-wide association studies (GWAS) involve sifting through the complete set of DNA of hundreds of individuals to identify genetic variations associated with a particular disease. Although this technique has proven to be a powerful tool for developing a better understanding of diseases that involve multiple genetic variations, such as Alzheimer's disease (AD), there are substantial limitations.

    Recent success has generated a wealth of promising genetic associations with common diseases but has simultaneously created a research bottleneck for follow-up studies that explore the functional consequences of human genetic variation. Such investigations of gene function in humans requires very significant efforts for each targeted polymorphism. However, alternative strategies for testing large numbers of genes exist.

    "Simple genetic models of human disease, such as in the fruit fly, have been important experimental tools for many years, particularly for large-scale functional testing of genes," explains asenior study author, Mel B. Feany, MD, PhD, of the Pathology Department at BWH. "We therefore hypothesized that the fly disease model might fulfill the growing need for efficient strategies for validation of association signals identified by GWAS."

    The current study is part of wider program of collaborative investigations into the genetic and epigenetic architecture of the aging brain that involve neurogeneticists at the Neurosciences Institute at BWH ,and Dr. David Bennett and his team of investigators at the AD Research Center at Rush University Medical Center.

    In the current study, Dr. Joshua M. Shulman, and colleagues implemented a two-stage strategy to enhance a GWAS of AD neuropathology by integrating the results of gene discovery in humans with functional screening in a fly model system relevant to AD biology. Specifically, the researchers evaluated nineteen genes from fifteen distinct genomic regions identified in a human GWAS designed to look for genes that influence AD pathology. In six out of these fifteen genomic regions, a causal gene was subsequently identified in the fly disease model based on interactions with the neurotoxicity of Tau protein, a well-known constituent of AD pathology.

    The authors also discuss the potential for application of their method to studies examining other human diseases. "Evidence is emerging in support of a polygenic model of inheritance for complex genetic disorders, in which hundreds or even thousands of common genetic variants collectively contribute to disease risk," says Philip L. De Jager, MD, PhD, a senior study author and physician in the Neurology Department at BWH. "Our strategy of coupling human GWAS with functional genetic screening in a model organism will likely be a powerful strategy for follow-up of such signals in the future in order to prioritize genes and pathways for further investigation."

    Brigham and Women's Hospital (BWH) is a 777-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery network. In July of 2008, the hospital opened the Carl J. and Ruth Shapiro Cardiovascular Center, the most advanced center of its kind. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. The BWH medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in quality improvement and patient safety initiatives and its dedication to educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 860 physician-investigators and renowned biomedical scientists and faculty supported by more than $416 M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative. For more information about BWH, please visit

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