Journal Article

Selective Constraint on Human Pre-mRNA Splicing by Protein Structural Properties

Jean-Christophe Gelly, Hsuan-Yu Lin, Alexandre G. de Brevern, Trees-Juen Chuang and Feng-Chi Chen

in Genome Biology and Evolution

Published on behalf of Society for Molecular Biology and Evolution

Volume 4, issue 9, pages 842-851
Published in print January 2012 |
Published online August 2012 | e-ISSN: 1759-6653 | DOI: https://dx.doi.org/10.1093/gbe/evs071

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Alternative splicing (AS) is a major mechanism of increasing proteome diversity in complex organisms. Different AS transcript isoforms may be translated into peptide sequences of significantly different lengths and amino acid compositions. One important question, then, is how AS is constrained by protein structural requirements while peptide sequences may be significantly changed in AS events. Here, we address this issue by examining whether the intactness of three-dimensional protein structural units (compact units in protein structures, namely protein units [PUs]) tends to be preserved in AS events in human. We show that PUs tend to occur in constitutively spliced exons and to overlap constitutive exon boundaries. Furthermore, when PUs are located at the boundaries between two alternatively spliced exons (ASEs), these neighboring ASEs tend to co-occur in different transcript isoforms. In addition, such PU-spanned ASE pairs tend to have a higher frequency of being included in transcript isoforms. ASE regions that overlap with PUs also have lower nonsynonymous-to-synonymous substitution rate ratios than those that do not overlap with PUs, indicating stronger negative selection pressure in PU-overlapped ASE regions. Of note, we show that PUs have protein domain- and structural orderness-independent effects on messenger RNA (mRNA) splicing. Overall, our results suggest that fine-scale protein structural requirements have significant influences on the splicing patterns of human mRNAs.

Keywords: protein unit; alternative splicing; protein structural constraint

Journal Article.  5954 words.  Illustrated.

Subjects: Bioinformatics and Computational Biology ; Evolutionary Biology ; Genetics and Genomics

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