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bioRxiv2026

CellMAGE: cell-type deconvolution for multi-parent population analysis of gene expression

Single-cell RNA-sequencing remains prohibitively expensive for multiparental population (MPP) studies. Existing deconvolution methods treat bulk RNA-seq as genetically anonymous mixtures, but in MPPs, the proportional contribution of each parental strain to each progeny's transcriptome is already known. CellMAGE (Cell-type deconvolution for Multi-parent Analysis of Gene Expression) weights parental cell-type profiles by each progeny's known genetic composition, requiring no model training and no minimum sample size. Validated in 16 Diversity Outbred mice across 12 prefrontal cortex cell types and 23,116 genes, predicted and measured gene expression were statistically equivalent (0.05) in all cell types (pooled Spearman = 0.923, 95% CI: 0.910, 0.934). CIBERSORTx required 96 additional samples to resolve at most 12.4% of genes and only 3 cell types; CellMAGE outperformed it even within this restricted comparison (per-cell-type median : 0.908-0.974 vs. 0.353-0.641). CellMAGE is applicable to any MPP with parental single-cell data, including diploid crop MAGIC populations.

genomics↗

bioRxiv2025

Behavioral variation across multiple phases of intravenous cocaine self-administration among genetically diverse mouse populations

Genetic and other predisposing factors can influence the progression from initiation of drug intake to compulsive substance use through distinct biobehavioral processes. Operant cocaine self-administration studies in laboratory mice offer a powerful method to dissect the biology of this progression from initiation, dose-response, extinction, and cued reinstatement in a controlled, tractable system. However, many such studies encompass limited genetic diversity and rarely examine self-administration behaviors beyond the acquisition stage. Here, we study three high-diversity mouse populations - 50 strains from the Collaborative Cross (CC) reference panel, a large sample of Diversity Outbred (J:DO) population and their eight founder strains - to characterize the varied phenotypic manifestation of behaviors across multiple phases of cocaine intravenous self-administration (IVSA) in both sexes. We observed distinct strain differences among the founders and CC strains in all phases of self-administration, with heritability estimates ranging from 0 to 0.585 and many CC and J:DO phenotypic values exceeding the range of founders including the C57BL/6J strain. Sex differences were common across behaviors, some manifesting as main effects, others as strain interactions. Finally, by adopting a multi-stage design, we identified extreme strains for various cocaine intake and response traits and evaluated whether these strains exhibited differences in behavioral assays that model compulsive drug seeking. Together, these findings demonstrate the utility of extended self-administration protocols in advanced mouse populations for discovery and characterization of biological mechanisms of substance use traits and for preclinical studies in relevant, complex mouse models.

genetics↗