title: Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes.
abstract: The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arbogast
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Abdel-Mouttalib
authors.initials: AM
authors.lastname: Ouagazzal
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Chevalier
authors.affiliation: Synome Ltd, Moneta Building, Babraham Research Campus, Cambridge, United Kingdom.
authors.forename: Maksym
authors.initials: M
authors.lastname: Kopanitsa
authors.affiliation: Synome Ltd, Moneta Building, Babraham Research Campus, Cambridge, United Kingdom.
authors.forename: Nurudeen
authors.initials: N
authors.lastname: Afinowi
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Migliavacca
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Cowling
authors.affiliation: PHENOMIN, Institut Clinique de la Souris, ICS; CNRS, INSERM, University of Strasbourg, Illkirch-Graffenstaden, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Birling
authors.affiliation: PHENOMIN, Institut Clinique de la Souris, ICS; CNRS, INSERM, University of Strasbourg, Illkirch-Graffenstaden, France.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Champy
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Reymond
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.|PHENOMIN, Institut Clinique de la Souris, ICS; CNRS, INSERM, University of Strasbourg, Illkirch-Graffenstaden, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Herault
mesh_terms: D050154:Adiposity; D000483:Alleles; D000818:Animals; D015239:Arylsulfotransferase / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal; D001835:Body Weight; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D002872:Chromosome Deletion; D058674:Chromosome Duplication / Q000235:genetics*; D033481:Chromosomes, Mammalian / Q000235:genetics; D003071:Cognition; D019465:Craniofacial Abnormalities / Q000235:genetics; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015321:Gene Rearrangement / Q000235:genetics; D006624:Hippocampus / Q000503:physiopathology; D008568:Memory; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D010641:Phenotype; D009435:Synaptic Transmission / Q000235:genetics; D013577:Syndrome; D014886:Weaning
chemical_list: D015239:Arylsulfotransferase; C513291:Sult1a1 protein, mouse