U01HG011755

Broad Institute Mendelian Genomic Research Center - Project Summary

Despite significant progress toward deciphering the genetic cause of many rare disease phenotypes in the NHGRI Centers for Mendelian Genetics (CMG), more than half of the genes underlying Mendelian diseases remain undiscovered. However, remarkable developments in genomics technologies and the aggregation of massive reference datasets are poised to advance Mendelian gene discovery, provided these technologies can be exploited using sophisticated analytic tools in large and diverse cohorts.

Importantly, these methods and datasets can only catalyze gene discovery if they are rapidly shared with the community, and enabling this goal has been a primary focus of our Broad Institute CMG. Here, we bring together an extraordinary team of investigators with diverse expertise, complementary technologies, novel analytic methods, an established recruitment network, and platforms that we have developed for data sharing to explore the genetic underpinnings of Mendelian disease and to further enable therapeutic development for rare diseases.

The Broad Institute Mendelian Genomics Research Center (MGRC) builds upon the world-class track record of Mendelian gene discovery, methods development, and data sharing set by the Broad CMG. Our team has invested considerable effort to develop widely adopted tools and platforms empowering variant analysis, such as GATK, GNOMAD, and SEQR, and to facilitate open sharing of variants, data, and analysis tools. Over the last four years, we have generated and shared data for over 15,000 samples from 7,600 families. In the process, we have uncovered 256 novel disease-gene relationships, with 473 additional genes undergoing follow-up.

Our MGRC roadmap will rely on exome sequencing and rapid data sharing as the most efficient frontline approach, given that the vast majority of CMG discoveries are derived from coding variants, followed by genome sequencing on unsolved cases (AIM 1). Complementary approaches to discover variation not captured by conventional methods will include emerging sequencing technologies, reference-free assembly, improved annotation of evolutionary constraint, large-scale data aggregation, and novel analytic methods. Transcriptome sequencing, epigenetic profiling, and CRISPR editing, as well as in vitro and in vivo functional modeling, will then inform functional interpretation and mechanistic dissection (AIM 2). Finally, we will use our platforms to create new tools and approaches for transformative data sharing across the MGRCs and the broader community (AIM 3).

At their conclusion, these studies will significantly contribute to completing the catalog of genes underlying Mendelian disease, providing new biological insights into their functional mechanisms, and openly sharing the data, tools, and discoveries that we produce.

The Broad Institute

NHGRI SUPPORTS THE DEVELOPMENT OF RESOURCES AND TECHNOLOGIES THAT WILL ACCELERATE GENOME RESEARCH AND ITS APPLICATION TO HUMAN HEALTH AND GENOMIC MEDICINE. A CRITICAL PART OF THE NHGRI MISSION CONTINUES TO BE THE STUDY OF THE ETHICAL, LEGAL AND SOCIAL IMPLICATIONS (ELSI) OF GENOME RESEARCH. NHGRI ALSO SUPPORTS THE TRAINING AND CAREER DEVELOPMENT OF INVESTIGATORS AND THE DISSEMINATION OF GENOME INFORMATION TO THE PUBLIC AND TO HEALTH PROFESSIONALS. THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM IS USED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM IS USED TO FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.172 - Human Genome Research

National Human Genome Research Institute (NHGRI) [HHS - NIH]

Cambridge, Massachusetts 021421027 United States

Single Zip Code

Mendelian Genomics Research Centers (U01 Clinical Trial Optional) (RFA-HG-20-007)

Amendment Since initial award the total obligations have increased 389% from $2,501,431 to $12,228,086.