Chromatin loops and CNVs: the complex spatial organization of the 16p11.2 locus. M. N. Loviglio1, M. Leleu2, N. Ghedolf1, E. Migliavacca1, K. Männik1, J. S. Beckmann3, 4, S. Jacquemont3, J. Rougemont2, A. Reymond1 1) Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, Switzerland; 2) EPFL, Lausanne, Switzerland; 3) Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; 4) Swiss Institute of Bioinformatics, Lausanne, Switzerland.

   Hemizygosity of the 16p11.2 ~600kb BP4-BP5 region (29.5 to 30.1Mb) is one of the most frequent known genetic etiologies of autism spectrum disorder (ASD). It is also associated with a highly penetrant form of obesity and a significant increase in head circumference. Mirror phenotypes are observed in carriers of the reciprocal duplication, who present a high risk of being underweight, microcephalic and/or schizophrenic. The distal 16p11.2 220kb BP2-BP3 deletion is similarly associated with obesity and neuropsychiatric disorders. We assessed possible chromatin interplays between these regions via long-range acting regulatory elements using high-resolution Chromosome Conformation Capture Sequencing (4C-seq) technology. We compared the three dimensional organization at the 16p11.2 locus between normal copy number and 600kb deletion or duplication state using the promoters of the SH2B1, MVP, KCTD13, ALDOA, TBX6 and MAPK3 genes as viewpoints. The analysis of normal copy number samples highlights complex chromatin looping between genes located in the 600kb and 220kb regions. In particular, blocks of regulators in chromosomal kontext of the 5 viewpoints from the 600kb interval encompass the genes CD19, LAT, RABEP2, TUFM and SH2B1, whose polymorphisms and mutations were previously associated with BMI, serum leptin, maladaptive behaviors and obesity. This interaction was reciprocally confirmed using SH2B1 as a viewpoint. To gauge whether the presence of a genomic rearrangement alters any of the identified chromatin interactions along chromosome 16, we compared interaction profile signals of deletions and duplications of the 600kb BP4-BP5 region and of controls. Considering all viewpoints we identified 342 and 378 regions whose looping intensities are significantly modified in deleted and duplicated samples, respectively. In parallel, we profiled the transcriptome of lymphoblastoid cell lines of 50 600kb BP4-BP5 deletion, 32 reciprocal duplication and 29 control individuals and identified 1188 differentially expressed (DE) genes using a numerical variable to reflect a dosage effect. 27 of the 74 DE genes (36.5%) mapping on chromosome 16 show concomitant significant changes in chromatin interaction. Our results show that relevant chromatin conformation changes may arise from copy number variants. They suggest a link between the observed chromatin perturbations and gene expression and a possible contribution of the chromosome conformation to the disease phenotype.

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