RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease

Xiong, H. Y., Alipanahi, B., Lee, L. J., Bretschneider, H., Merico, D., Yuen, R. K., Hua, Y., Gueroussov, S., Najafabadi, H. S., Hughes, T. R., Morris, Q., Barash, Y., Krainer, A. R., Jojic, N., Scherer, S. W., Blencowe, B. J., Frey, B. J. (December 2014) RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. Science, 347 (6218). ISSN 0036-8075

URL: http://www.ncbi.nlm.nih.gov/pubmed/25525159
DOI: 10.1126/science.1254806

Abstract

To facilitate precision medicine and whole genome annotation, we developed a machine learning technique that scores how strongly genetic variants affect RNA splicing, whose alteration contributes to many diseases. Analysis of over 650,000 intronic and exonic variants reveals widespread patterns of mutation-driven aberrant splicing. Intronic disease mutations alter splicing nine times more often than common variants, and missense exonic disease mutations that least impact protein function are five times more likely to alter splicing than others. Tens of thousands of disease-causing mutations are detected, including those involved in cancers and spinal muscular atrophy. Examination of intronic and exonic variants found using whole genome sequencing of individuals with autism reveals mis-spliced genes with neurodevelopmental phenotypes. Our approach provides evidence for causal variants and should enable new discoveries in precision medicine.

Item Type: Paper
Subjects: diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing
CSHL Authors:
Communities: CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
CSHL labs > Krainer lab
CSHL Cancer Center Shared Resources > Microscopy Service
Depositing User: Matt Covey
Date: 18 December 2014
Date Deposited: 05 Jan 2015 17:36
Last Modified: 29 Oct 2015 15:49
PMCID: PMC4362528
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31007

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