# Massively parallel characterization of variants and elements impacting transcriptional regulation in dynamic cellular systems

> **NIH NIH UM1** · UNIVERSITY OF WASHINGTON · 2022 · $1,798,272

## Abstract

SUMMARY / ABSTRACT
A major fraction of heritability for common diseases, as well as for the penetrance and expressivity of rare
diseases, partitions to distal regulatory elements in the human genome, overwhelmingly cell type-specific
enhancers. However, a rate-limiting challenge for the field has been how to identify the specific variants,
elements and regulated genes that mediate these effects on disease liability. Towards the overall goals of the
Impact of Genomic Variation on Function (IGVF) Consortium, we propose to test over one million human
regulatory elements or variants for their functional effects on transcriptional regulation, as well as to query over
100,000 distal regulatory elements for the gene(s) that they regulate. A first theme of our proposal is the diversity
of multiplex technologies that we will employ to these ends, including massively parallel reporter assays
(MPRAs), crisprQTL, saturation genome editing, multiplex prime editing and single cell combinatorial indexing,
many of which we pioneered. A second theme is a focus on dynamic cellular systems that enable a given library
of variants and/or elements to be tested across a broad range of cell types and states within a single experiment;
these will include ESC-derived neuronal progenitors, cardiomyocytes, embryoid bodies, gastruloids and
organoids, and in select cases, mice. A third theme involves leveraging our experience (e.g. CADD, a widely
used, genome-wide catalog of variant effect predictions) to support the overarching goals of IGVF. Specifically,
we envision using functional measurements generated by us and others to produce well-calibrated predictions
of enhancer activity and variant effects that are continuous along the branching trajectories that comprise human
development. Our specific aims are as follows: (1) To perform massively parallel validation and functional
characterization of candidate human enhancers in a broad range of cell type contexts. (2) To perform massively
parallel characterization of human genetic variants with potential roles in human disease. (3) To contribute to a
comprehensive variant-element-phenotype catalog while taking a leadership role in synergistic interactions
within IGVF, in the dissemination of methods, data and predictions, and in the overarching goals of the
consortium.

## Key facts

- **NIH application ID:** 10471968
- **Project number:** 5UM1HG011966-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Nadav Ahituv
- **Activity code:** UM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,798,272
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10471968

## Citation

> US National Institutes of Health, RePORTER application 10471968, Massively parallel characterization of variants and elements impacting transcriptional regulation in dynamic cellular systems (5UM1HG011966-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10471968. Licensed CC0.

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