Cell-type and single-cell specific isoform expression in human and model organisms Model organisms (here mouse/rat) are often used to model human disease of complex organs, including brain, blood and skin. In human, mouse and rat, these tissues are comprised of highly dissimilar cell types. Successful modeling of human disease in mouse/rat depends in part on whether molecular expression patterns across human cell types mimic those in the same cell types for mouse/rat. Such molecular expression patterns include simple gene expression and RNA isoform abundance. While the single-cell research revolution gave much insight into conservation of cell-type specific gene expression, little is known about the conservation of cell- type specific expression of full-length isoforms. This lack of knowledge represents a critical gap, which renders understanding the causes for failed clinical trials that followed animal research difficult. Our overall objective is to define cell-type specific isoforms that are conserved between human and rodents and to decide between one (of three) explanations for each non-conserved human pattern. The rationale is that knowing affected cell types (i) when misregulated isoform expression is observed in bulk tissue can inform thousands of researchers and (ii) helps explain cases where animal modeling of human disease is unsuccessful. The central hypothesis is that cell-type specific isoforms (I) are often conserved across species, (II) reveals specific targets (isoform+cell type) for intervention and (III) that this information, if freely available, helps choose animal models. Our pilot work allows single-cell isoform RNA-seq (Gupta*, Collier*, …, Tilgner, 2018, Nature Biotechnol1) in tissues. Aim 1 defines cell-type specific isoform expression in three tissues of young adult male and female mice. This will highlight the cell types, from which sex-specific isoform expression originates. It will furthermore reveal, which of three models causes each case of sex-specific isoform expression observed in bulk. Aim 2 defines cell-type specific isoform expression in the same tissues in human and rat. We reveal cell-type specific isoform patterns that are conserved between human and rodents. For each case of divergent cell-type specific isoform expression, we define, which of three possible models accounts for this divergence. Rat isoforms enable a GENCODE-like rat annotation and all cell-type and single-cell specific isoform data in human, mouse and rat are made available through an online interface. This project will allow researchers to probe cell-type and single-cell specific isoform expression in three tissues across three species. This work is innovative, because it defines for the first time, which cell-type specific isoform expression patterns are conserved and which model (out of three) explains non-conservation.