Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function

Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, generating a cross-tissue atlas of 209,126 nuclei profiles, which we integrated across tissues, donors, and laboratorymethods with a conditional variational autoencoder. Using the resulting cross-tissue atlas, we highlight shared and tissuespecific features of tissue-resident cell populations; identify cell types that might contribute to neuromuscular, metabolic, and immune components of monogenic diseases and the biological processes involved in their pathology; and determine cell types and gene modules that might underlie disease mechanisms for complex traits analyzed by genome-wide association studies.

Automated summary

Understanding the function and regulation of genes in homeostasis and disease requires knowledge of their expression in different cellular and tissue contexts. In this study, we performed single-nucleus RNA sequencing on various frozen tissue types, generating a cross-tissue atlas of cellular profiles. By integrating this atlas, we identified shared and tissue-specific features of cell populations, as well as cell types and gene modules associated with neuromuscular, metabolic, and immune components of monogenic diseases and complex traits analyzed by genome-wide association studies.