Hybrid crosses reveal a cell-type-specific landscape of mouse regulatory variation

2026 · doi:10.64898/2026.04.02.716195
preprint OA: closed
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This study generated a single-nucleus RNA-seq resource of 6.7 million nuclei from seven C57BL/6J × Collaborative Cross F1 hybrids and parental strains across eight tissue groups, aiming to map how genetic variation affects gene regulation at cell-type resolution. Across 92 cell types, the authors report 25,777 genes showing non-conserved regulatory behavior in at least one cross, with cis-acting effects mainly driving divergence while trans-acting effects are more cell-type specific and influenced by tissue environment. They emphasize that bulk tissue analyses often mask these patterns, especially in smaller cell populations such as astrocytes, and that increasing genetic divergence mainly expands the cis landscape while trans effects stay stable across genetic distances within species. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Understanding the genetic architecture of gene expression is fundamental to evolutionary biology and medicine. As part of the IGVF Consortium, we present a single-nucleus RNA-seq resource of 5.3 million nuclei across eight tissue groups, featuring seven F1 hybrids from C57BL/6J dams crossed with the other Collaborative Cross founder strains for comparison against parental strains. We identify 25,864 genes (91% of those detected) exhibiting non-conserved regulatory behavior in at least one of 92 cell types in one or more crosses. Our results show that while cis-acting variation primarily drives divergence, trans-acting effects are substantially more cell-type specific and sensitive to tissue environment. Notably, bulk tissue analyses frequently mask these signals, particularly in smaller populations such as astrocytes. Furthermore, increasing genetic divergence primarily expands the landscape of cis-acting variation, while trans-acting effects remain stable across genetic distances within species. This atlas establishes a foundational framework for decoding the complex interplay between genetic variation and cell-type-specific regulation across the mammalian body.
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Abstract Understanding the genetic architecture of gene expression is fundamental to evolutionary biology and medicine. As part of the IGVF Consortium, we present a single-nucleus RNA-seq resource of 6.7 million nuclei across eight tissue groups, featuring seven F1 hybrids from C57BL/6J dams crossed with the other Collaborative Cross founder strains for comparison against parental strains. We identify 25,777 genes (91% of those detected) exhibiting non-conserved regulatory behavior in at least one of 92 cell types in one or more crosses. Our results show that while cis-acting variation primarily drives divergence, trans-acting effects are substantially more cell-type specific and sensitive to tissue environment. Notably, bulk tissue analyses frequently mask these signals, particularly in smaller populations such as astrocytes. Furthermore, increasing genetic divergence primarily expands the landscape of cis-acting variation, while trans-acting effects remain stable across genetic distances within species. This atlas establishes a foundational framework for decoding the complex interplay between genetic variation and cell-type-specific regulation across the mammalian body. Competing Interest Statement The authors have declared no competing interest. Footnotes Fixed Figure 2, Fixed Figure S6, added a Caltech coauthor that had been accidentally left out.

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