# Elucidating Genes Regulating Sleep Using Diversity Outbred Mice

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2022 · $218,515

## Abstract

ABSTRACT
 Most aspects of sleep and circadian rhythm are heritable, i.e., are in part determined by sequence variations
in DNA. Multiple approaches are currently being applied to identify relevant genes influence sleep. One cutting-
edge strategy being employed is high-diversity mouse models – particularly Diversity Outbred mice. These mice
are derived through a novel randomized outbreeding approach seeded by the Collaborative Cross mice. This
creates a genetically heterogeneous population of mice with genetic diversity approaching that in human
populations. The genome of each Diversity Outbred mouse is a unique mosaic inherited from the original 8
Founder strains of mice. Accurate measurement of the genetic variation across the whole genome can be
obtained using a specialized genotyping array. This data can then be combined with careful phenotyping of large
numbers of Diversity Outbred mice to identify small quantitative trait loci containing only a few candidate causal
genes. To utilize this resource to identify genes relevant for sleep, we have developed a high-throughput
phenotyping pipeline that assesses multiple heritable aspects of sleep and circadian rhythm, including amounts
of sleep, degree of sleep consolidation, vigilance, sleep drive, and circadian period. After discovering important
loci using this high-throughput approach, robust validation of identified genes is carried out with gold-standard
EEG/EMG recording of sleep in relevant strains of Collaborative Cross mice and, subsequently, in mice with a
knockout of the predicted causal gene. Using this exact approach, we have already identified a novel gene
regulating sleep in mice. Since this discovery, we have further increased the size of our phenotyped and
genotyped sample of Diversity Outbred mice, and have now identified several other interesting quantitative trait
loci containing candidate causal genes requiring validation. While existing analyses have shown promise in
identifying important genes for sleep in mice, evidence from our work supports sleep as a complex genetic trait.
That is, the phenotype is not simply determined by a single gene variant. Rather, there are likely to be complex
genetic effects involving multiple interacting genes that determine additional variability in sleep/wake behavior.
However, current analysis approaches in Diversity Outbred mice focus on additive genetic associations, and do
not allow us to adequately address this concept. Thus, to uncover these more complex genetic effects, we
propose to employ novel machine learning approaches to the wealth of available genetic and phenotypic data
we have for hundreds of Diversity Outbred mice. Altogether, this is a high-risk, high-impact proposal appropriate
for an R21 given the novel analytic strategy based on machine learning and the focus on validation of candidate
causal genes affecting sleep. If successful, this proposal will provide new insights into the genetic underpinnings
of sleep and a novel an...

## Key facts

- **NIH application ID:** 10432369
- **Project number:** 1R21HL163717-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Allan I Pack
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $218,515
- **Award type:** 1
- **Project period:** 2022-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10432369

## Citation

> US National Institutes of Health, RePORTER application 10432369, Elucidating Genes Regulating Sleep Using Diversity Outbred Mice (1R21HL163717-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10432369. Licensed CC0.

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