%0 Journal Article %A Ira W. Deveson %A Marion E. Brunck %A James Blackburn %A Elizabeth Tseng %A Ting Hon %A Tyson A. Clark %A Michael B. Clark %A Joanna Crawford %A Marcel E. Dinger %A Lars K. Nielsen %A John S. Mattick %A Tim R. Mercer %T Universal alternative splicing of noncoding exons %D 2017 %R 10.1101/136275 %J bioRxiv %P 136275 %X The human genome encodes an unknown diversity of genes and isoforms. RNA Sequencing (RNA-Seq) suffers from an expression-dependent bias that impedes discovery of low-abundance transcripts and has prevented a complete census of human gene expression. Here we performed targeted single-molecule and short-read RNA-Seq to survey the transcriptional landscape of a single human chromosome (Hsa21) at unprecedented resolution. Our analysis reaches the lower limits of the transcriptome and identifies a fundamental distinction in the architecture of protein-coding and noncoding genes. Unlike their coding counterparts, and in contrast to the impression from more shallow surveys, noncoding exons undergo near-universal alternative splicing to produce an effectively inexhaustible variety of isoforms. Targeted RNA-Seq analysis of syntenic regions of the mouse genome indicates that few noncoding exons are shared between human and mouse. Despite this divergence, human alternative splicing profiles are recapitulated on Hsa21 in mouse nuclei, implying regulation by a local splicing code that is more strongly conserved than the noncoding isoforms themselves. We propose that noncoding exons are functionally modular, with combinatorial alternative splicing generating an enormous repertoire of potential regulatory RNAs and a rich transcriptional reservoir for adaptive gene evolution. %U https://www.biorxiv.org/content/biorxiv/early/2017/05/10/136275.full.pdf