Cell. 2014 Nov 20;159(5):1212-1226. doi: 10.1016/j.cell.2014.10.050.

A proteome-scale map of the human interactome network.

Rolland T¹, Taşan M², Charloteaux B¹, Pevzner SJ³, Zhong Q⁴, Sahni N¹, Yi S¹, Lemmens I⁵, Fontanillo C⁶, Mosca R⁷, Kamburov A¹, Ghiassian SD⁸, Yang X¹, Ghamsari L¹, Balcha D¹, Begg BE¹, Braun P¹, Brehme M¹, Broly MP¹, Carvunis AR¹, Convery-Zupan D¹, Corominas R⁹, Coulombe-Huntington J¹⁰, Dann E¹, Dreze M¹, Dricot A¹, Fan C¹, Franzosa E¹⁰, Gebreab F¹, Gutierrez BJ¹, Hardy MF¹, Jin M¹, Kang S⁹, Kiros R¹, Lin GN⁹, Luck K¹, MacWilliams A¹, Menche J⁸, Murray RR¹, Palagi A¹, Poulin MM¹, Rambout X¹¹, Rasla J¹, Reichert P¹, Romero V¹, Ruyssinck E⁵, Sahalie JM¹, Scholz A¹, Shah AA¹, Sharma A⁸, Shen Y¹, Spirohn K¹, Tam S¹, Tejeda AO¹, Trigg SA¹, Twizere JC¹¹, Vega K¹, Walsh J¹, Cusick ME¹, Xia Y¹⁰, Barabási AL¹², Iakoucheva LM⁹, Aloy P¹³, De Las Rivas J⁶, Tavernier J⁵, Calderwood MA¹, Hill DE¹, Hao T¹, Roth FP¹⁴, Vidal M¹⁵.

Author information

1: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
2: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, ON M5S 3E1, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
3: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Boston University School of Medicine, Boston, MA 02118, USA.
4: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA.
5: Department of Medical Protein Research, VIB, 9000 Ghent, Belgium.
6: Cancer Research Center (Centro de Investigación del Cancer), University of Salamanca and Consejo Superior de Investigaciones Científicas, Salamanca 37008, Spain.
7: Joint IRB-BSC Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
8: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Complex Network Research (CCNR) and Department of Physics, Northeastern University, Boston, MA 02115, USA.
9: Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
10: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Bioengineering, McGill University, Montreal, QC H3A 0C3, Canada.
11: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Protein Signaling and Interactions Lab, GIGA-R, University of Liege, 4000 Liege, Belgium.
12: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Complex Network Research (CCNR) and Department of Physics, Northeastern University, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
13: Joint IRB-BSC Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.
14: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, ON M5S 3E1, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Canadian Institute for Advanced Research, Toronto M5G 1Z8, Canada. Electronic address: fritz.roth@utoronto.ca.
15: Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: marc_vidal@dfci.harvard.edu.

Abstract

Just as reference genome sequences revolutionized human genetics, reference maps of interactome networks will be critical to fully understand genotype-phenotype relationships. Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. At equal quality, this map is ?30% larger than what is available from small-scale studies published in the literature in the last few decades. While currently available information is highly biased and only covers a relatively small portion of the proteome, our systematic map appears strikingly more homogeneous, revealing a "broader" human interactome network than currently appreciated. The map also uncovers significant interconnectivity between known and candidate cancer gene products, providing unbiased evidence for an expanded functional cancer landscape, while demonstrating how high-quality interactome models will help "connect the dots" of the genomic revolution.

Comment in

Systems biology: an expanded human interactome. [Nat Methods. 2015]

PMID:: 25416956
PMCID:: PMC4266588
DOI:: 10.1016/j.cell.2014.10.050

[Indexed for MEDLINE]

Free PMC Article

Images from this publication.See all images (7)Free text

Figure 1

Vast uncharted interactome zone in literature and generation of a systematic binary dataset

(A) Validation of binary literature pairs extracted from public databases (; ; ; ; ; ; ). Fraction of pairs recovered by MAPPIT at increasing RRS recovery rates (top left) and at 1% RRS recovery rate (bottom left), found to co-occur in the literature as reported in the STRING database (upper right), and recovered by Y2H (lower right). Shading and error bars indicate standard error of the proportion. P values, two-sided Fisher’s exact tests. For n values, see .
(B) Adjacency matrix showing Lit-BM-13 interactions, with proteins in bins of ~350 and ordered by number of publications along both axes. Upper and right histograms show the median number of publications per bin. The color intensity of each square reflects the total number of interactions between proteins for the corresponding bins. Total number of interactions per bin (lower histogram). Number of gene products from GWAS loci (), Mendelian disease genes () and Sanger Cancer Gene Census (Cancer Census) () genes per bin (circles).
(C) Improvements from first-generation to second-generation interactome mapping based on an empirically-controlled framework (). Completeness: fraction of all pairwise protein combinations tested; Assay sensitivity: fraction of all true biophysical interactions that are identifiable by a given assay; Sampling sensitivity, fraction of identifiable interactions that are detected in the experiment; Precision: fraction of reported pairs that are true positives.
(D) Experimental pipeline for identifying high-quality binary protein-protein interactions (left). ORF: Open Reading Frame. Fraction of HI-II-14, PRS and RRS pairs (right) recovered by MAPPIT, PCA and wNAPPA at increasing assay stringency. Shading indicates standard error of the proportion. P > 0.05 for all assays when comparing PRS and HI-II-14 at 1% RRS, twosided Fisher’s exact tests. For n values, see .
See also and and and .

A proteome-scale map of the human interactome network

Cell. ;159(5):1212-1226.