title: Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes.
abstract: Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: M N
authors.initials: MN
authors.lastname: Loviglio
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.|School of Life Sciences, EPFL (Ecole Polytechnique Fédérale de Lausanne), Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Leleu
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.|Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: K
authors.initials: K
authors.lastname: Männik
authors.affiliation: Service of Medical Genetics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Passeggeri
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Giannuzzi
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: van der Werf
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.|School of Life Sciences, EPFL (Ecole Polytechnique Fédérale de Lausanne), Lausanne, Switzerland.|Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
authors.forename: S M
authors.initials: SM
authors.lastname: Waszak
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Zazhytska
authors.affiliation: Service of Medical Genetics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Roberts-Caldeira
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Gheldof
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Migliavacca
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: A A
authors.initials: AA
authors.lastname: Alfaiz
authors.affiliation: Service of Medical Genetics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Hippolyte
authors.affiliation: Service of Medical Genetics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: A M
authors.initials: AM
authors.lastname: Maillard
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Van Dijck
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: R F
authors.initials: RF
authors.lastname: Kooy
authors.affiliation: Service de Génétique, Hôpital Femme Mère Enfant, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, CRNL, CNRS UMR5292, INSERM U1028, Université Claude Bernard Lyon I, Bron, France.
authors.forename: D
authors.initials: D
authors.lastname: Sanlaville
authors.affiliation: Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA, USA.|Department of Molecular &Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Paw Print Genetics, Genetic Veterinary Sciences, Inc., Spokane, WA, USA.
authors.forename: L G
authors.initials: LG
authors.lastname: Shaffer
authors.affiliation: Institut de Génétique Médicale, CHRU de Lille - Hôpital Jeanne de Flandre, Lille, France.
authors.forename: J
authors.initials: J
authors.lastname: Andrieux
authors.affiliation: Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, USA.
authors.forename: C
authors.initials: C
authors.lastname: Marshall
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, USA.|McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, ON, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA, USA.|Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA, USA.|Shanghai Jiaotong University, School of Medicine, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Departments of Genetics and Neurology, Harvard Medical School, Boston, MA, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: deCODE Genetics, Amgen, Reykjavik, Iceland.
authors.forename: U
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: deCODE Genetics, Amgen, Reykjavik, Iceland.
authors.forename: G
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.|Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: E T
authors.initials: ET
authors.lastname: Dermitzakis
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.|School of Life Sciences, EPFL (Ecole Polytechnique Fédérale de Lausanne), Lausanne, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Deplancke
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.|Service of Medical Genetics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.|Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: J S
authors.initials: JS
authors.lastname: Beckmann
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.|School of Life Sciences, EPFL (Ecole Polytechnique Fédérale de Lausanne), Lausanne, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Rougemont
authors.affiliation: Service of Medical Genetics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Jacquemont
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Reymond
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000067877:Autism Spectrum Disorder / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics*; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000378:metabolism / Q000502:physiology; D002872:Chromosome Deletion; D058674:Chromosome Duplication; D002874:Chromosome Mapping / Q000379:methods*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics / Q000502:physiology*; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D058627:Megalencephaly / Q000235:genetics; D008831:Microcephaly / Q000235:genetics; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D010641:Phenotype
chemical_list: D002843:Chromatin