TY - JOUR T1 - Variation among intact tissue samples reveals the core transcriptional features of human CNS cell classes JF - bioRxiv DO - 10.1101/265397 SP - 265397 AU - Kevin W. Kelley AU - Hiromi Inoue AU - Anna V. Molofsky AU - Michael C. Oldham Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/02/14/265397.abstract N2 - It is widely assumed that cells must be physically isolated to study their molecular profiles. However, intact tissue samples naturally exhibit variation in cellular composition, which drives covariation of cell-class-specific molecular features. By analyzing transcriptional covariation in 7221 intact CNS samples from 840 individuals representing billions of cells, we reveal the core transcriptional identities of major CNS cell classes in humans. By modeling intact CNS transcriptomes as a function of variation in cellular composition, we identify cell-class-specific transcriptional differences in Alzheimer’s disease, among brain regions, and between species. Among these, we show that PMP2 is expressed by human but not mouse astrocytes and significantly increases mouse astrocyte size upon ectopic expression in vivo, causing them to more closely resemble their human counterparts. Our work is available as an online resource (http://oldhamlab.ctec.ucsf.edu) and provides a generalizable strategy for determining the core molecular features of cellular identity in intact biological systems. ER -