# Core B - Technical Services

> **NIH NIH P50** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $619,888

## Abstract

PROJECT ABSTRACT
The Center for Reproductive Medicine (CRM) represents a multi-disciplinary program to explore the genetic
architecture of infertility. The CRM Genomics Core (GC) described herein envisages providing a centralized and
catalytic resource for genomic variation, statistical association, and functional perturbations for all components
of this overarching CRM program. This genomics hub will specifically catalyze discoveries by providing expertise
in the data and methods that will be leveraged for deeper insights into rare and common forms of infertility in
Projects 1 and 2, respectively. The GC will also serve as the focal point for cross-fertilization of data, analyses,
and functional modeling across the program. Over the last several years, we have developed a compendium of
computational tools, statistical approaches, and functional genomics methods to interrogate the mutational
spectrum of variation in human diseases. Our methods incorporate joint analyses of short variants (SNVs, indels)
and structural variants (SVs), including canonical balanced SVs and copy number variants (CNVs), as well as a
diverse catalog of complex SVs that are surprisingly abundant and associated with an array of human disease.
These studies have required methods to uniformly generate, process, and rigorously analyze genomics datasets
for association studies. In the GC, we will discover and annotate variation, interpret association against
population-scale datasets in excess of 1,000,000 genomes from our related studies, and perform scalable
engineering to generate an allelic series of perturbations in genes associated with rare and common forms of
infertility using human induced pluripotent stem cell (hiPSC) derived GnRH models. Overall, we will support the
CRM by completing three objectives related to providing datasets, methods, and functional resources.
Objective 1 will develop a comprehensive genomics resource from exome, genome and long-read
sequencing, and uniform data processing of the CRM cohorts. Objective 2 will perform integrated rare variant
association and interpretation of these datasets by jointly analyzing CRM cohorts with population-scale
datasets generated in our genome aggregation database (gnomAD) project and complex disease consortia
studies. Objective 3 will then perform scalable CRISPR perturbation of infertility genes in GnRH neuronal
models by engineering loss-of-function mutations and an allelic series for select infertility genes.
Transcriptional profiling in the genomics core will identify signatures associated with perturbation of these
infertility genes, and will seek convergence of these signatures on a small number of infertility relevant pathways.
All CRISPR-engineered models will be distributed relevant projects for further functional assays, and all data
and models will be made openly available for distribution to the community. These objectives in the genomics
hub of the CRM will thus provide datasets, gene discoveries, ...

## Key facts

- **NIH application ID:** 10463548
- **Project number:** 5P50HD104224-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** MICHAEL E TALKOWSKI
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $619,888
- **Award type:** 5
- **Project period:** 2021-08-10 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463548

## Citation

> US National Institutes of Health, RePORTER application 10463548, Core B - Technical Services (5P50HD104224-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10463548. Licensed CC0.

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