noisy splicing drives mrna isoform diversity in human cells嘈杂的拼接驱动器mrna同种型多样性在人类细胞.pdfVIP

Noisy Splicing Drives mRNA Isoform Diversity in Human Cells 1 1 1 1,2 Joseph K. Pickrell *, Athma A. Pai *, Yoav Gilad *, Jonathan K. Pritchard * 1 Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America, 2 Howard Hughes Medical Institute, The University of Chicago, Chicago, Illinois, United States of America Abstract While the majority of multiexonic human genes show some evidence of alternative splicing, it is unclear what fraction of observed splice forms is functionally relevant. In this study, we examine the extent of alternative splicing in human cells using deep RNA sequencing and de novo identification of splice junctions. We demonstrate the existence of a large class of low abundance isoforms, encompassing approximately 150,000 previously unannotated splice junctions in our data. Newly- identified splice sites show little evidence of evolutionary conservation, suggesting that the majority are due to erroneous splice site choice. We show that sequence motifs involved in the recognition of exons are enriched in the vicinity of unconserved splice sites. We estimate that the average intron has a splicing error rate of approximately 0.7% and show that introns in highly expressed genes are spliced more accurately, likely due to their shorter length. These results implicate noisy splicing as an important property of genome evolution. Citation: Pickrell JK, Pai AA, Gilad Y, Pritchard JK (2010) Noisy Splicing Drives mRNA Isoform Diversity in Human Cells. PLoS Genet 6(12): e1001236. doi:10.1371/ journal.pgen.1001236 Editor: Emmanouil T. Dermitzakis, University of Geneva Medical School, Switzerland Received July 4, 2010; Accepted November 3, 2010; Published D