# Project I - Transcriptomic Analysis of Structural Birth Defects in Mouse Developmental Mutants

> **NIH NIH P01** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $814,294

## Abstract

PROJECT SUMMARY
In this project we plan to apply a powerful and scaleable technique of combinatorial indexing to characterize
gene expression at the single-cell level in mice carrying mutations that are either known to or likely to result in
structural birth defects. We propose to assess whether single-cell expression can be utilized as a phenotype;
specifically, we aim to organize these data sets to assess whether there are signatures of single-cell gene
expression that facilitate grouping mutant lines based on presumptive pathways of developmental signaling
perturbation. This analysis will be complemented by the anatomical analysis that is proposed in Project 2.
Given the novelty of this method, we will initially analyze 10 lines that are mutated for genes in the Shh
signaling pathway, in order to correlate single-cell transcriptomic data with well-studied developmental
phenotypes. To maximize the opportunity for new gene discovery, we will also examine novel genes that have
not been previously annotated with respect to human structural birth defects. Specifically, using an analysis of
human exome sequencing data, we have identified a large cohort of genes that are likely haploinsufficient; i.e.,
they are not compatible with survival when heterozygous null. We have furthermore developed a heterozygote
selection (shet) statistic that correlates remarkably well with human disease severity. We aim to characterize 75
lines from the top quintile shet set that have limited functional annotation; these genes will be chosen either a)
based on evidence from single-cell expression during embryogenesis (Cao et al. 2019) that they are novel cell-
type-specific index genes or b) are known lethal genes (in mice) that have a high frequency of protein
interactions.
As part of this effort we will develop bioinformatic tools to facilitate comparisons across different datasets.
These can identify mutant lines with common abnormalities of developmental signaling, as well as potentially
serving as a means to understand the mechanistic basis for human congenital abnormalities.

## Key facts

- **NIH application ID:** 10327737
- **Project number:** 5P01HD104435-02
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** DAVID R. BEIER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $814,294
- **Award type:** 5
- **Project period:** 2021-01-11 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10327737

## Citation

> US National Institutes of Health, RePORTER application 10327737, Project I - Transcriptomic Analysis of Structural Birth Defects in Mouse Developmental Mutants (5P01HD104435-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10327737. Licensed CC0.

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