Loss of exon identity is a common mechanism of human inherited disease
- Timothy Sterne-Weiler1,2,
- Jonathan Howard1,
- Matthew Mort3,
- David N. Cooper3 and
- Jeremy R. Sanford1,4
- 1Department of Molecular, Cellular and Developmental Biology, University of California Santa Cruz, Santa Cruz, California 95064, USA;
- 2Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA;
- 3Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom
Abstract
It is widely accepted that at least 10% of all mutations causing human inherited disease disrupt splice-site consensus sequences. In contrast to splice-site mutations, the role of auxiliary cis-acting elements such as exonic splicing enhancers (ESE) and exonic splicing silencers (ESS) in human inherited disease is still poorly understood. Here we use a top-down approach to determine rates of loss or gain of known human exonic splicing regulatory (ESR) sequences associated with either disease-causing mutations or putatively neutral single nucleotide polymorphisms (SNPs). We observe significant enrichment toward loss of ESEs and gain of ESSs among inherited disease-causing variants relative to neutral polymorphisms, indicating that exon skipping may play a prominent role in aberrant gene regulation. Both computational and biochemical approaches underscore the relevance of exonic splicing enhancer loss and silencer gain in inherited disease. Additionally, we provide direct evidence that both SRp20 (SRSF3) and possibly PTB (PTBP1) are involved in the function of a splicing silencer that is created de novo by a total of 83 different inherited disease mutations in 67 different disease genes. Taken together, we find that ∼25% (7154/27,681) of known mis-sense and nonsense disease-causing mutations alter functional splicing signals within exons, suggesting a much more widespread role for aberrant mRNA processing in causing human inherited disease than has hitherto been appreciated.
Footnotes
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↵4 Corresponding author.
E-mail jsanfor2{at}ucsc.edu.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.118638.110.
- Received December 20, 2010.
- Accepted June 30, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press