A Trisomy 21 Model Atlas reveals conserved dosage effects and context-specific transcriptional responses across mouse and human models of Down syndrome

A comprehensive atlas of Trisomy 21, the genetic basis of Down syndrome, has been created, revealing consistent dosage effects and context-specific transcriptional responses across mouse and human models. This study aimed to understand how trisomy 21 propagation occurs across tissues, developmental stages, and model systems.

The Trisomy 21 Model Atlas consists of bulk transcriptomic profiling and histopathology from seven tissues and three developmental timepoints in the Dp(16)1Yey mouse model. Additionally, transcriptional profiles from human iPSC-derived cell types were included. The research found that triplicated genes, those affected by the extra copy of chromosome 21, show consistent increases in expression across all examined tissues, stages, sexes, and species. These expression increases are largely dosage-proportional.

However, nontriplicated genes, which account for the majority of differential expression, display highly context-specific responses. Inflammatory and interferon-related gene sets are enriched in both trisomy 21 models, but the specific genes involved differ in each context. By integrating histopathology data, researchers linked expression signatures to tissue-specific pathological features.

The Trisomy 21 Model Atlas is openly accessible and designed to be expandable, offering a framework for interpreting the conserved and context-specific consequences of chromosome 21 gene dosage.