title: Chromosome-wise Protein Interaction Patterns and Their Impact on Functional Implications of Large-Scale Genomic Aberrations.
abstract: Gene copy-number changes influence phenotypes through gene-dosage alteration and subsequent changes of protein complex stoichiometry. Human trisomies where gene copy numbers are increased uniformly over entire chromosomes provide generic cases for studying these relationships. In most trisomies, gene and protein level alterations have fatal consequences. We used genome-wide protein-protein interaction data to identify chromosome-specific patterns of protein interactions. We found that some chromosomes encode proteins that interact infrequently with each other, chromosome 21 in particular. We combined the protein interaction data with transcriptome data from human brain tissue to investigate how this pattern of global interactions may affect cellular function. We identified highly connected proteins that also had coordinated gene expression. These proteins were associated with important neurological functions affecting the characteristic phenotypes for Down syndrome and have previously been validated in mouse knockout experiments. Our approach is general and applicable to other gene-dosage changes, such as arm-level amplifications in cancer.
authors.affiliation: Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, 2800 Lyngby, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Isa Kristina
authors.initials: IK
authors.lastname: Kirk
authors.affiliation: Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, 2800 Lyngby, Denmark; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nils
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, 2800 Lyngby, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Belling
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet and University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Niels Erik
authors.initials: NE
authors.lastname: Skakkebæk
authors.affiliation: Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, 2800 Lyngby, Denmark.
authors.forename: Thomas Skøt
authors.initials: TS
authors.lastname: Jensen
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet and University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Leffers
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet and University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Juul
authors.affiliation: Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, 2800 Lyngby, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: soren.brunak@cpr.ku.dk.
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000502:physiology*; D002891:Chromosomes, Human, Pair 21 / Q000378:metabolism; D004314:Down Syndrome / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics / Q000502:physiology; D020869:Gene Expression Profiling / Q000379:methods; D023281:Genomics / Q000379:methods; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D025941:Protein Interaction Mapping / Q000379:methods*; D059467:Transcriptome / Q000235:genetics; D014314:Trisomy / Q000235:genetics*
keywords: aneuploidy; genome structure; protein complex; protein interaction data; stoichiometry; systems biology; topology-associated domain (TAD); trisomy