Concordance of gene expression in human protein complexes reveals tissue specificity and pathology.
Disease-causing variants in human genes usually lead to phenotypes specific to only a few tissues. Here, we present a method for predicting tissue specificity based on quantitative deregulation of protein complexes. The underlying assumption is that the degree of coordinated expression among proteins in a complex within a given tissue may pinpoint tissues that will be affected by a mutation in the complex and coordinated expression may reveal the complex to be active in the tissue. We identified known disease genes and their protein complex partners in a high-quality human interactome. Each susceptibility gene's tissue involvement was ranked based on coordinated expression with its interaction partners in a non-disease global map of human tissue-specific expression. The approach demonstrated high overall area under the curve (0.78) and was very successfully benchmarked against a random model and an approach not using protein complexes. This was illustrated by correct tissue predictions for three case studies on leptin, insulin-like-growth-factor 2 and the inhibitor of NF-κB kinase subunit gamma that show high concordant expression in biologically relevant tissues. Our method identifies novel gene-phenotype associations in human diseases and predicts the tissues where associated phenotypic effects may arise.
Department of Electrical Engineering, ESAT-SCD, IBBT-KU Leuven Future Health Department, KU Leuven, 3001 Leuven, Belgium, Biostatistics Department, Harvard School of Public Health, Harvard University, Boston, 02115 MA, USA, Broad Institute of MIT and Harvard, Cambridge, 02142 MA, USA, Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, DK-2800 Lyngby, Denmark, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, 02142 MA, USA, Division of Endocrinology and Center for Basic and Translational Obesity Research, Children's Hospital Boston, Boston, 02115 MA, USA, Department of Development and Regeneration @ Kulak, KU Leuven, E. Sabbelaan 53, 8500 Kortrijk, Belgium, and NNF Center for Protein Research, Health Sciences Faculty, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Daniela
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Börnigen
Tune H
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Pers
Lieven
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Thorrez
Curtis
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Huttenhower
Yves
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Moreau
Søren
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Brunak
D004194:Disease / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D010641:Phenotype; D025941:Protein Interaction Mapping
C494847:LMNA protein, human; D034904:Lamin Type A; D046912:Multiprotein Complexes