In Silico Gene Prioritization by Integrating Multiple Data Sources

被引:37
作者
Chen, Yixuan [1 ]
Wang, Wenhui [1 ]
Zhou, Yingyao [2 ]
Shields, Robert [1 ]
Chanda, Sumit K. [3 ]
Elston, Robert C. [4 ]
Li, Jing [1 ,4 ,5 ]
机构
[1] Case Western Reserve Univ, Dept Elect Engn & Comp Sci, Cleveland, OH 44106 USA
[2] Novartis Res Fdn, Genom Inst, San Diego, CA USA
[3] Burnham Inst Med Res, Infect & Inflammatory Dis Ctr, La Jolla, CA USA
[4] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA
[5] Jilin Univ, Joint Inst Syst Biol, Coll Comp Sci & Technol, Changchun 130023, Peoples R China
基金
美国国家卫生研究院;
关键词
DISEASE-GENES; FUNCTION PREDICTION; NETWORK; WALKING; MOUSE;
D O I
10.1371/journal.pone.0021137
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Identifying disease genes is crucial to the understanding of disease pathogenesis, and to the improvement of disease diagnosis and treatment. In recent years, many researchers have proposed approaches to prioritize candidate genes by considering the relationship of candidate genes and existing known disease genes, reflected in other data sources. In this paper, we propose an expandable framework for gene prioritization that can integrate multiple heterogeneous data sources by taking advantage of a unified graphic representation. Gene-gene relationships and gene-disease relationships are then defined based on the overall topology of each network using a diffusion kernel measure. These relationship measures are in turn normalized to derive an overall measure across all networks, which is utilized to rank all candidate genes. Based on the informativeness of available data sources with respect to each specific disease, we also propose an adaptive threshold score to select a small subset of candidate genes for further validation studies. We performed large scale cross-validation analysis on 110 disease families using three data sources. Results have shown that our approach consistently outperforms other two state of the art programs. A case study using Parkinson disease (PD) has identified four candidate genes (UBB, SEPT5, GPR37 and TH) that ranked higher than our adaptive threshold, all of which are involved in the PD pathway. In particular, a very recent study has observed a deletion of TH in a patient with PD, which supports the importance of the TH gene in PD pathogenesis. A web tool has been implemented to assist scientists in their genetic studies.
引用
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页数:13
相关论文
共 34 条
[1]   SUSPECTS: enabling fast and effective prioritization of positional candidates [J].
Adie, EA ;
Adams, RR ;
Evans, KL ;
Porteous, DJ ;
Pickard, BS .
BIOINFORMATICS, 2006, 22 (06) :773-774
[2]   Gene prioritization through genomic data fusion [J].
Aerts, S ;
Lambrechts, D ;
Maity, S ;
Van Loo, P ;
Coessens, B ;
De Smet, F ;
Tranchevent, LC ;
De Moor, B ;
Marynen, P ;
Hassan, B ;
Carmeliet, P ;
Moreau, Y .
NATURE BIOTECHNOLOGY, 2006, 24 (05) :537-544
[3]   Prediction of human disease genes by human-mouse conserved coexpression analysis [J].
Ala, Ugo ;
Piro, Rosario Michael ;
Grassi, Elena ;
Damasco, Christian ;
Silengo, Lorenzo ;
Oti, Martin ;
Provero, Paolo ;
Di Cunto, Ferdinando .
PLOS COMPUTATIONAL BIOLOGY, 2008, 4 (03)
[4]   The Biomolecular Interaction Network Database and related tools 2005 update [J].
Alfarano, C ;
Andrade, CE ;
Anthony, K ;
Bahroos, N ;
Bajec, M ;
Bantoft, K ;
Betel, D ;
Bobechko, B ;
Boutilier, K ;
Burgess, E ;
Buzadzija, K ;
Cavero, R ;
D'Abreo, C ;
Donaldson, I ;
Dorairajoo, D ;
Dumontier, MJ ;
Dumontier, MR ;
Earles, V ;
Farrall, R ;
Feldman, H ;
Garderman, E ;
Gong, Y ;
Gonzaga, R ;
Grytsan, V ;
Gryz, E ;
Gu, V ;
Haldorsen, E ;
Halupa, A ;
Haw, R ;
Hrvojic, A ;
Hurrell, L ;
Isserlin, R ;
Jack, F ;
Juma, F ;
Khan, A ;
Kon, T ;
Konopinsky, S ;
Le, V ;
Lee, E ;
Ling, S ;
Magidin, M ;
Moniakis, J ;
Montojo, J ;
Moore, S ;
Muskat, B ;
Ng, I ;
Paraiso, JP ;
Parker, B ;
Pintilie, G ;
Pirone, R .
NUCLEIC ACIDS RESEARCH, 2005, 33 :D418-D424
[5]   Guilt by association [J].
Altshuler, D ;
Daly, M ;
Kruglyak, L .
NATURE GENETICS, 2000, 26 (02) :135-137
[6]   A Rare Novel Deletion of the Tyrosine Hydroxylase Gene in Parkinson Disease [J].
Bademci, Gueney ;
Edwards, Todd L. ;
Torres, Andre L. ;
Scott, William K. ;
Zuechner, Stephan ;
Martin, Eden R. ;
Vance, Jeffery M. ;
Wang, Liyong .
HUMAN MUTATION, 2010, 31 (10) :E1767-E1771
[7]   MINT: the molecular INTeraction database [J].
Chatr-aryamontri, Andrew ;
Ceol, Arnaud ;
Palazzi, Luisa Montecchi ;
Nardelli, Giuliano ;
Schneider, Maria Victoria ;
Castagnoli, Luisa ;
Cesareni, Gianni .
NUCLEIC ACIDS RESEARCH, 2007, 35 :D572-D574
[8]   Improved human disease candidate gene prioritization using mouse phenotype [J].
Chen, Jing ;
Xu, Huan ;
Aronow, Bruce J. ;
Jegga, Anil G. .
BMC BIOINFORMATICS, 2007, 8 (1)
[9]   Misframed Proteins and Neurodegeneration: A Novel View on Alzheimer's and Parkinson's Diseases [J].
Dennissen, F. J. A. ;
Kholod, N. ;
Steinbusch, H. W. M. ;
Van Leeuwen, F. W. .
NEURODEGENERATIVE DISEASES, 2010, 7 (1-3) :76-79
[10]   Reconstruction of a functional human gene network, with an application for prioritizing positional candidate genes [J].
Franke, Lude ;
van Bakel, Harm ;
Fokkens, Like ;
de Jong, Edwin D. ;
Egmont-Petersen, Michael ;
Wijmenga, Cisca .
AMERICAN JOURNAL OF HUMAN GENETICS, 2006, 78 (06) :1011-1025