A Bioinformatics-Based Alternative mRNA Splicing Code that May Explain Some Disease Mutations Is Conserved in Animals

Deep sequencing of cDNAs made from spliced mRNAs indicates that most coding genes in many animals and plants have pre-mRNA transcripts that are alternatively spliced. In pre-mRNAs, in addition to invariant exons that are present in almost all mature mRNA products, there are at least 6 additional typ...

Full description

Saved in:
Bibliographic Details
Published inFrontiers in genetics Vol. 8; p. 38
Main Authors Qu, Wen, Cingolani, Pablo, Zeeberg, Barry R, Ruden, Douglas M
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 11.04.2017
Subjects
Online AccessGet full text

Cover

Loading…
More Information
Summary:Deep sequencing of cDNAs made from spliced mRNAs indicates that most coding genes in many animals and plants have pre-mRNA transcripts that are alternatively spliced. In pre-mRNAs, in addition to invariant exons that are present in almost all mature mRNA products, there are at least 6 additional types of exons, such as exons from alternative promoters or with alternative polyA sites, mutually exclusive exons, skipped exons, or exons with alternative 5' or 3' splice sites. Our bioinformatics-based hypothesis is that, in analogy to the genetic code, there is an "alternative-splicing code" in introns and flanking exon sequences, analogous to the genetic code, that directs alternative splicing of many of the 36 types of introns. In humans, we identified 42 different consensus sequences that are each present in at least 100 human introns. 37 of the 42 top consensus sequences are significantly enriched or depleted in at least one of the 36 types of introns. We further supported our hypothesis by showing that 96 out of 96 analyzed human disease mutations that affect RNA splicing, and change alternative splicing from one class to another, can be partially explained by a mutation altering a consensus sequence from one type of intron to that of another type of intron. Some of the alternative splicing consensus sequences, and presumably their small-RNA or protein targets, are evolutionarily conserved from 50 plant to animal species. We also noticed the set of introns within a gene usually share the same splicing codes, thus arguing that one sub-type of splicesosome might process all (or most) of the introns in a given gene. Our work sheds new light on a possible mechanism for generating the tremendous diversity in protein structure by alternative splicing of pre-mRNAs.
Bibliography:Edited by: Florent Hubé, UMR7216 Epigenetics and Cell Fate (CNRS - Paris Diderot), France
Reviewed by: Tohru Yoshihisa, University of Hyogo, Japan; Yuichiro Watanabe, University of Tokyo, Japan
These authors have contributed equally to this work.
This article was submitted to RNA, a section of the journal Frontiers in Genetics
ISSN:1664-8021
1664-8021
DOI:10.3389/fgene.2017.00038