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PMID: 25583119 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

An integrative approach to predicting the functional effects of non-coding and coding sequence variation.

Bioinformatics (Oxford, England) ·Vol. 31 ·No. 10 ·2015-05-15 ·Pages 1536-43

Shihab HA, Rogers MF, Gough J, Mort M, Cooper DN, Day IN, Gaunt TR, Campbell C

Abstract

Technological advances have enabled the identification of an increasingly large spectrum of single nucleotide variants within the human genome, many of which may be associated with monogenic disease or complex traits. Here, we propose an integrative approach, named FATHMM-MKL, to predict the functional consequences of both coding and non-coding sequence variants. Our method utilizes various genomic annotations, which have recently become available, and learns to weight the significance of each component annotation source. We show that our method outperforms current state-of-the-art algorithms, CADD and GWAVA, when predicting the functional consequences of non-coding variants. In addition, FATHMM-MKL is comparable to the best of these algorithms when predicting the impact of coding variants. The method includes a confidence measure to rank order predictions.

MeSH Terms
Algorithms Genetic Variation/genetics Genome, Human Genome-Wide Association Study Genomics/methods Humans Molecular Sequence Annotation Open Reading Frames/genetics Phenotype Untranslated Regions/genetics
Chemicals
Untranslated Regions
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Shihab Hashem A
MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol BS8 2BN, UK, Bristol Centre for Systems Biomedicine, University of Bristol, Bristol BS8 2BN, UK, Intelligent Systems Laboratory, University of Bristol, Bristol BS8 1UB, UK, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK and Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol BS8 2BN, UK, Bristol Centre for Systems Biomedicine, University of Bristol, Bristol BS8 2BN, UK, Intelligent Systems Laboratory, University of Bristol, Bristol BS8 1UB, UK, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK and Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK.
Rogers Mark F
MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol BS8 2BN, UK, Bristol Centre for Systems Biomedicine, University of Bristol, Bristol BS8 2BN, UK, Intelligent Systems Laboratory, University of Bristol, Bristol BS8 1UB, UK, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK and Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK.
Gough Julian
MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol BS8 2BN, UK, Bristol Centre for Systems Biomedicine, University of Bristol, Bristol BS8 2BN, UK, Intelligent Systems Laboratory, University of Bristol, Bristol BS8 1UB, UK, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK and Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK.
Mort Matthew
MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol BS8 2BN, UK, Bristol Centre for Systems Biomedicine, University of Bristol, Bristol BS8 2BN, UK, Intelligent Systems Laboratory, University of Bristol, Bristol BS8 1UB, UK, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK and Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK.
Cooper David N
MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol BS8 2BN, UK, Bristol Centre for Systems Biomedicine, University of Bristol, Bristol BS8 2BN, UK, Intelligent Systems Laboratory, University of Bristol, Bristol BS8 1UB, UK, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK and Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK.
Day Ian N M
MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol BS8 2BN, UK, Bristol Centre for Systems Biomedicine, University of Bristol, Bristol BS8 2BN, UK, Intelligent Systems Laboratory, University of Bristol, Bristol BS8 1UB, UK, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK and Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK.
Gaunt Tom R
MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol BS8 2BN, UK, Bristol Centre for Systems Biomedicine, University of Bristol, Bristol BS8 2BN, UK, Intelligent Systems Laboratory, University of Bristol, Bristol BS8 1UB, UK, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK and Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol BS8 2BN, UK, Bristol Centre for Systems Biomedicine, University of Bristol, Bristol BS8 2BN, UK, Intelligent Systems Laboratory, University of Bristol, Bristol BS8 1UB, UK, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK and Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK.
Campbell Colin
MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol BS8 2BN, UK, Bristol Centre for Systems Biomedicine, University of Bristol, Bristol BS8 2BN, UK, Intelligent Systems Laboratory, University of Bristol, Bristol BS8 1UB, UK, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK and Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK.
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Article Info
Journal
Bioinformatics (Oxford, England)
Abbr.
Bioinformatics
ISSN
1367-4811
DOI
10.1093/bioinformatics/btv009
Published
2015-05-15
Epub
2015-00-11
Pages
1536-43
Language
English
Region
England
NLM ID
9808944
PMCID
PMC4426838
Subset
IM
Grants
Biotechnology and Biological Sciences Research Council · BB/G022771/1 · United Kingdom
Biotechnology and Biological Sciences Research Council · BB/G022771 · United Kingdom
Medical Research Council · G1000427/1 · United Kingdom
Medical Research Council · MC_UU_12013/8 · United Kingdom
External Links
PubMed source DOI: 10.1093/bioinformatics/btv009 PMC Full Text View journal details
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