RNA splicing programs define tissue compartments and cell types at single-cell resolution

Elife. 2021 Sep 13;10:e70692. doi: 10.7554/eLife.70692.


The extent splicing is regulated at single-cell resolution has remained controversial due to both available data and methods to interpret it. We apply the SpliZ, a new statistical approach, to detect cell-type-specific splicing in >110K cells from 12 human tissues. Using 10X Chromium data for discovery, 9.1% of genes with computable SpliZ scores are cell-type-specifically spliced, including ubiquitously expressed genes MYL6 and RPS24. These results are validated with RNA FISH, single-cell PCR, and Smart-seq2. SpliZ analysis reveals 170 genes with regulated splicing during human spermatogenesis, including examples conserved in mouse and mouse lemur. The SpliZ allows model-based identification of subpopulations indistinguishable based on gene expression, illustrated by subpopulation-specific splicing of classical monocytes involving an ultraconserved exon in SAT1. Together, this analysis of differential splicing across multiple organs establishes that splicing is regulated cell-type-specifically.

Keywords: RNA; computational biology; genetics; genomics; human; mouse; mouse lemur; scRNA-seq; splicing; statistics; systems biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cheirogaleidae / genetics*
  • Mice / genetics*
  • RNA Splicing*
  • Single-Cell Analysis*

Associated data

  • GEO/SRR6459190
  • GEO/SRR6459191
  • GEO/SRR6459192
  • GEO/SRR6459155
  • GEO/SRR6459156
  • GEO/SRR6459157
  • figshare/10.6084/m9.figshare.14531721