Journal article
Investigating DNA-, RNA-, and protein-based features as ameans to discriminate pathogenic synonymous variants
Human mutation, Vol.38(10), pp.1336-1347
25/06/2017
PMID: 28649752
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Source: InCites
Abstract
Synonymous single-nucleotide variants (SNVs), although they do not alter the encoded protein sequences, have been implicated in many genetic diseases. Experimental studies indicate that synonymous SNVs can lead to changes in the secondary and tertiary structures of DNA and RNA, thereby affecting translational efficiency, cotranslational protein folding as well as the binding of DNA-/RNA-binding proteins. However, the importance of these various features in disease phenotypes is not clearly understood. Here, we have built a support vector machine (SVM) model (termed DDIG-SN) as a means to discriminate disease-causing synonymous variants. The model was trained and evaluated on nearly 900 disease-causing variants. The method achieves robust performance with the area under the receiver operating characteristic curve of 0.84 and 0.85 for protein-stratified 10-fold cross-validation and independent testing, respectively. We were able to show that the disease-causing effects in the immediate proximity to exon-intron junctions (13 bp) are driven by the loss of splicing motif strength, whereas the gain of splicing motif strength is the primary cause in regions further away from the splice site (4-69 bp). The method is available as a part of the DDIG server at http://sparks-lab.org/ddig.
Details
- Title
- Investigating DNA-, RNA-, and protein-based features as ameans to discriminate pathogenic synonymous variants
- Creators
- Mark Livingstone - Griffith UniversityLukas Folkman - Griffith UniversityYuedong Yang - Griffith UniversityPing Zhang - Griffith UniversityMatthew Mort - Cardiff UniversityDavid N. Cooper - Cardiff UniversityYunlong Liu - Indiana University – Purdue University IndianapolisBela Stantic - Griffith UniversityYaoqi Zhou - Griffith University
- Publication Details
- Human mutation, Vol.38(10), pp.1336-1347
- Publisher
- Wiley
- Grant note
- National Health and Medical Research Council of Australia: 1059775, 1083450 Qiagen Inc. (Cardiff University)
Contract grant sponsors: National Health and Medical Research Council of Australia (1059775 and 1083450); Qiagen Inc. (through a License Agreement with Cardiff University).
- Identifiers
- 991013348039802368
- Copyright
- © 2017 Wiley Periodicals, Inc.
- Academic Unit
- Faculty of Science and Engineering
- Language
- English
- Resource Type
- Journal article