Biology subjects

Dewey, H. B.

Publications and source records attributed to Dewey, H. B..

5 recordsLinked to original sources

bioRxiv2026

The Flame Retardant Triphenyl Phosphate Induces Varying Responses in Genetically Diverse Mouse Induced Pluripotent Stem Cells

Genetic variation impacts biological response to chemical and environmental exposures, contributing to differences in resistance or susceptibility. Forward genetic screens of genetically diverse cell populations can be used to identify the precise genetic variants that drive response variation. Cell lines from laboratory mouse genetic reference populations like the Diversity Outbred (DO) population are well powered for genetic mapping. Diverse stem cell panels are especially beneficial for studying early developmental effects of chemical exposures like triphenyl phosphate (TPHP), an organophosphate flame retardant linked to adverse developmental effects, including altered cell cycle in stem cells. Self-renewal and pluripotency are defining properties of stem cells during development; therefore, it is important to understand how chemicals like TPHP may alter these critical characteristics. To better understand the influence of genetic variation on TPHP exposure response, we utilized a genetically diverse panel of DO induced pluripotent stem cells (DO iPSCs). Our analyses characterize interline variation in gene expression through differential gene expression analysis and expression quantitative trait locus (eQTL) mapping. We identified genomic loci that contribute to variation in gene expression following TPHP exposure, including a regulatory hotspot on chromosome 15. Gene set enrichment highlighted several pathways affected by TPHP including lipid metabolism, steroid hormone signaling, and cell cycle. Our study shows that genetic variation modulates the effects of TPHP on gene expression and cell cycle in stem cells. Additionally, our work demonstrates that genetically diverse cell panels like the DO iPSC resource offer a tractable and scalable approach for identifying the genetic determinants of chemical toxicity.

genomics↗

bioRxiv2026

A panel of Diversity Outbred mouse embryonic stem cells: enabling the functional characterization of natural genetic variation in vitro

Phenotypic variation in pluripotent stem cells arises largely from genetic variants that impact stability of the pluripotent state, response to differentiation cues, and cell fate diversification. Panels derived from genetic reference populations leverage genetic diversity to map the loci influencing these molecular and cellular traits. Here we describe the first publicly available resource for in vitro systems genetics in Mus musculus: 299 genetically diverse, highly heterozygous embryonic stem cell lines derived from Diversity Outbred mice, with minimal kinship across the panel. We characterize genomic integrity and allelic variation across the panel and describe differences in pluripotency and differentiation networks in embryoid bodies. Mapping the genetic determinants of gene expression differences in response to cadmium exposure in embryoid bodies identified 13 regulatory hotspots, the largest acting on ribosome biogenesis genes. This panel enables mapping of loci and gene-by-environment interactions that influence molecular identity in pluripotent cells and their derived cell types.

systems biology↗

bioRxiv2026

Molecular and genetic heterogeneity in iPSCs derived from an outbred laboratory mouse population

Genetically diverse panels of human pluripotent stem cells enable genetic dissection of cellular phenotypes, but comparable induced pluripotent stem cell (iPSC) resources in model organisms remain limited. We generated a panel of iPSCs from the Diversity Outbred (DO) mouse population and established 288 genetically unique lines that retain the allele frequency distribution, heterozygosity, and low population structure of the source population. The lines exhibit consistent growth, pluripotent gene expression profiles, and capacity to form embryoid bodies. Transcriptomic profiling of the lines revealed significant variation in gene expression driven in part by genetic background. We used expression quantitative trait locus (eQTL) mapping to identify over 10,000 regulatory loci that influence gene expression variation, including multiple distal eQTL hotspots that are key gene regulatory hubs and are shared with DO embryonic stem cells (ESCs). The largest hotspot, mediated by Lifr, showed a shift in founder allele effects relative to ESCs, consistent with differences in cellular state and culture conditions. These results establish the DO iPSC panel as a genetically diverse, publicly accessible platform derived from a laboratory mouse genetic reference population, enabling integration of in vitro cellular phenotypes with in vivo traits within a closed, outbred population.

genetics↗

bioRxiv2026

Simplifying Systems Genetics with QTLretrievR: An R Package for Molecular QTL Identification

MotivationOver the past two decades, integrating "-omics" scale molecular profiling with genetic mapping in diverse populations--termed "systems genetics"--has proven powerful for linking complex disease phenotypes to genetic variants and their regulatory effects. However, these combined genomic and genetic analyses remain computationally intensive and often inaccessible to researchers without a strong computational background, a problem compounded in studies with multiple tissues or thousands of molecular -omics phenotypes. ResultsWe developed QTLretrievR, an R package designed to simplify and streamline the identification and downstream analysis of molecular quantitative trait loci in genetically diverse populations. QTLretrievR builds on widely used R packages such as r/qtl2 for quantitative trait locus mapping and r/intermediate for mediation analysis, and incorporates substantial parallelization features to improve computational efficiency. Benchmarking demonstrates that QTLretrievR can reproduce results from previous quantitative trait locus studies while significantly reducing the time required for quantitative trait locus peak detection and downstream analyses. Additionally, QTL-retrievR includes plotting functions to visualize results of the included downstream analyses. AvailabilitySource code is available at https://github.com/deweyhannah/QTLretrievR. ContactSteven Munger, steven.munger@jax.org

genetics↗

bioRxiv2022

Whole genome functional characterization of RE1 silencers using a modified massively parallel reporter assay

Both upregulation and downregulation by cis-regulatory elements help establish precise gene expression. Our understanding of how elements repress transcriptional activity is far more limited than activating elements. To address this gap, we characterized RE1, a group of transcriptional silencers bound by REST, on a genome-wide scale using an modified massively parallel reporter assay (MPRAduo). MPRAduo empirically defined a minimal binding strength of REST required for silencing (REST m-value), above which multiple cofactors colocalize and act to directly silence transcription. We identified 1,500 human variants that alter RE1 silencing and found their effect sizes are predictable when they overlap with REST binding sites above the m-value. In addition, we demonstrate that non-canonical REST binding motifs exhibit silencer function only if they precisely align two half sites with specific spacer length. Our results show mechanistic insights into RE1 silencer which allows us to predict its activity and effect of variants on RE1, providing a paradigm for performing genome-wide functional characterization of transcription factors binding sites.

genomics↗