M N Loviglio ¹, M Leleu ^2 3, K Männik ^1 4, M Passeggeri ⁵, G Giannuzzi ¹, I van der Werf ¹, S M Waszak ^2 3 6, M Zazhytska ¹, I Roberts-Caldeira ⁵, N Gheldof ¹, E Migliavacca ^1 2, A A Alfaiz ^1 2, L Hippolyte ⁵, A M Maillard ⁵, 2p15 Consortium; 16p11.2 Consortium; A Van Dijck ⁷, R F Kooy ⁷, D Sanlaville ⁸, J A Rosenfeld ^9 10, L G Shaffer ¹¹, J Andrieux ¹², C Marshall ¹³, S W Scherer ^14 15, Y Shen ^16 17 18, J F Gusella ^19 20, U Thorsteinsdottir ²¹, G Thorleifsson ²¹, E T Dermitzakis ^2 22, B Deplancke ^2 3, J S Beckmann ^2 5 23, J Rougemont ^2 3, S Jacquemont ⁵, A Reymond 

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.