Concordance of gene expression in human protein complexes reveals tissue specificity and pathology

TY - JOUR

T1 - Concordance of gene expression in human protein complexes reveals tissue specificity and pathology

AU - Börnigen, Daniela

AU - Pers, Tune H

AU - Thorrez, Lieven

AU - Huttenhower, Curtis

AU - Moreau, Yves

AU - Brunak, Søren

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

KW - Disease

KW - Gene Expression

KW - Humans

KW - Lamin Type A

KW - Multiprotein Complexes

KW - Organ Specificity

KW - Phenotype

KW - Protein Interaction Mapping

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

U2 - 10.1093/nar/gkt661

DO - 10.1093/nar/gkt661

M3 - SCORING: Journal article

C2 - 23921638

VL - 41

SP - e171

JO - NUCLEIC ACIDS RES

JF - NUCLEIC ACIDS RES

SN - 0305-1048

IS - 18

ER -