Disruption of three-dimensional genome organization as a noncoding mechanism of disease in human developmental disorders

点击翻译按钮获取中文摘要

Abstract The purpose of this training and research application is to identify novel noncoding mechanisms of disease associated with developmental disorders (DDs) using a suite of statistical and functional genomics strategies. Approximately 30-40% of DDs can be explained by a rare de novo protein-truncating variant or structural variant (SV; genomic alterations larger than 50 base pairs) in genes that are under strong evolutionary constraint. What is currently unknown, and represents a major void in genetic architecture studies, is the contribution of rare noncoding genetic variation to DDs. There have been a handful of examples of pathogenic long-range positional effects (LRPEs) caused by noncoding SVs that result in DDs, and preliminary work by our group and others have suggested that disruption of three-dimensional (3D) genome structures called topologically associated domains (TADs) may be responsible for the strong regulatory effects observed at these loci. To systematically assess the relationship between SVs, TAD disruption, and risk for DDs we will: (1) define novel candidate LRPE loci via the identification of TADs intolerant to disruption and build models to predict the pathogenicity of noncoding SVs; (2) determine the impact of TAD disruption on gene expression; and (3) elucidate the added diagnostic value of identifying pathogenic LRPEs in DDs. The proposed application will also develop an extensive research program for Dr. Chelsea Lowther whose goal it is to become an independent investigator. Dr. Lowther is a computational genomicist trained in the identification and interpretation of SVs from chromosomal microarray and whole genome sequencing data who now seeks to obtain new expertise in advanced statistical modeling and functional genomics to examine the impact of 3D chromatin disruption as a mechanism of disease. Dr. Michael Talkowski is the Director of the Center for Genomic Medicine at Massachusetts General Hospital, with appointments at Harvard Medical School and the Broad Institute, and will serve as the primary mentor, while Dr. Erez Lieberman- Aiden, an Associate Professor in Molecular and Human Genetics and the Director of the Center for Genome Architecture at Baylor College of Medicine, will serve as the co-mentor and close collaborator. Drs. Talkowski and Lieberman-Aiden are world-leaders in statistical, computational, and functional genomics as well as in genome organization and nuclear function. The mentorship team also consists of diverse expertise in genome diagnostics and variant interpretation (Dr. Heidi Rehm), genome evolution and regulation (Dr. Katie Pollard), the functional annotation of SVs associated with neurodevelopmental and neuropsychiatric conditions (Dr. Douglas Ruderfer), and in noncoding mechanisms of disease associated with human malformations (Dr. Stefan Mundlos). This outstanding mentorship team and training program will facilitate Dr. Lowther’s transition to independence and will strongly support her trajectory towards becoming a leader in the field of genomic medicine.