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

> **NIH NIH K99** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $136,014

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10427710
- **Project number:** 1K99HD108392-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Chelsea Lowther
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $136,014
- **Award type:** 1
- **Project period:** 2022-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427710

## Citation

> US National Institutes of Health, RePORTER application 10427710, Disruption of three-dimensional genome organization as a noncoding mechanism of disease in human developmental disorders (1K99HD108392-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10427710. Licensed CC0.

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