# Cross-species conservation of cell-type and single-cell specific isoform expression

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $536,034

## Abstract

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.

## Key facts

- **NIH application ID:** 9860459
- **Project number:** 1R01GM135247-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** HAGEN ULRICH TILGNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $536,034
- **Award type:** 1
- **Project period:** 2020-03-16 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9860459

## Citation

> US National Institutes of Health, RePORTER application 9860459, Cross-species conservation of cell-type and single-cell specific isoform expression (1R01GM135247-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9860459. Licensed CC0.

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