Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes
June 1, 2017
... ontamination. qPCR experiments were performed in triplicate using SYBR-Green (Roche, Basel, Switzerland) as reporter. The reaction mixtures were prepared in 384-well plates using a Freedom Evo robot (Tecan, Männedorf, Switzerland) and run in an ABI 7900HT sequence detection system (Applied Biosystems) using the following conditions: 50°C for 2 min, 95°C for 10 min, followed by 45 cycles of 95
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.
Loviglio, MN; Leleu, M; Männik, K; Passeggeri, M; Giannuzzi, G; van der Werf, I; Waszak, SM; Zazhytska, M; Roberts-Caldeira, I; Gheldof, N; Migliavacca, E; Alfaiz, AA; Hippolyte, L; Maillard, AM; , ; , ; Van Dijck, A; Kooy, RF; Sanlaville, D; Rosenfeld, JA; Shaffer, LG; Andrieux, J; Marshall, C; Scherer, SW; Shen, Y; Gusella, JF; Thorsteinsdottir, U; Thorleifsson, G; Dermitzakis, ET; Deplancke, B; Beckmann, JS; Rougemont, J; Jacquemont, S; Reymond, A;
Journal: Mol. Psychiatry Pages: 836-849
Original article (27240531)