WORCESTER, MA - Scientists at the University of Massachusetts Medical School have applied a powerful tool in a new way to characterize genetic variants associated with human disease. The work, published today in Cell, will allow scientists to more easily and efficiently describe genomic variations underlying complex, multi-gene diseases.
"Up to this point, we've only been able to investigate one disease-causing mutation at a time," said principal investigator Marian Walhout, PhD, co-director of the Program in Systems Biology and professor of molecular medicine at UMMS. "We now have a robust platform that allows us to interrogate hundreds of mutations in a single experiment. This will help us develop a map of the interactions that make up the networks that control gene expression and determine how mutations in the genome give rise to a variety of human diseases."
An explosion in whole genome studies, often called genome-wide association studies or GWAS, was brought about by vast improvements in gene sequencing technology that has helped scientists locate thousands of genetic variations associated with hundreds of different diseases. Yet, as many as 90 percent these mutations are found in areas of the genome that don't code for proteins, according to Dr. Walhout.
Mutations in transcription factors or their DNA binding sites can contribute to disease by disrupting gene regulation. This leads to too much, or not enough, of a target protein. A wide variety of diseases including cancer, neurological disorders, blood disorders and metabolic diseases have been linked to aberrant gene regulation.
"Most of the disease-associated mutations these GWAS have identified don't actually change the protein itself, but are located in regulatory regions and could, therefore, change the levels of the protein," said Juan Fuxman Bass, PhD, post-doctoral fellow and lead author of the Cell study. "The challenge for us has always been to identify how and why these mutations give rise to disease."
Using the enhanced, gene-centered yeast one-hybrid (eY1H) assays developed in 2011 by the Walhout group, the researchers were able to perform thousands of experiments involving 1,000 transcription factors and more than 100 genetic variants. As a result, they were able to detect both loss and gain of interactions between DNA sites and transcription factors that were consistent with changes in gene expression that were found in the associated diseases.
"This system provides a tool for the in-depth interrogation of the role that genetic variation and differences in transcription factor interactions play in disrupting the gene regulatory network," Walhout concluded. "It's a blueprint for understanding these networks and how this connectivity is affected in disease."
About the University of Massachusetts Medical School
The University of Massachusetts Medical School (UMMS), one of five campuses of the University system, comprises the School of Medicine, the Graduate School of Biomedical Sciences, the Graduate School of Nursing, a thriving research enterprise and an innovative public service initiative, Commonwealth Medicine. Its mission is to advance the health of the people of the commonwealth through pioneering education, research, public service and health care delivery with its clinical partner, UMass Memorial Health Care. In doing so, it has built a reputation as a world-class research institution and as a leader in primary care education. The Medical School attracts more than $240 million annually in research funding, placing it among the top 50 medical schools in the nation. In 2006, UMMS's Craig C. Mello, PhD, Howard Hughes Medical Institute Investigator and the Blais University Chair in Molecular Medicine, was awarded the Nobel Prize in Physiology or Medicine, along with colleague Andrew Z. Fire, PhD, of Stanford University, for their discoveries related to RNA interference (RNAi). The 2013 opening of the Albert Sherman Center ushered in a new era of biomedical research and education on campus. Designed to maximize collaboration across fields, the Sherman Center is home to scientists pursuing novel research in emerging scientific fields with the goal of translating new discoveries into innovative therapies for human diseases.