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.
Lingua originale | English |
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pagine (da-a) | 836-849 |
Numero di pagine | 14 |
Rivista | Molecular Psychiatry |
Volume | 22 |
DOI | |
Stato di pubblicazione | Pubblicato - 2017 |
Keywords
- Adolescent
- Adult
- Aged
- Autism Spectrum Disorder
- Autistic Disorder
- Body Mass Index
- Cellular and Molecular Neuroscience
- Child
- Child, Preschool
- Chromatin
- Chromosome Deletion
- Chromosome Duplication
- Chromosome Mapping
- Chromosomes, Human, Pair 16
- DNA Copy Number Variations
- Female
- Humans
- In Situ Hybridization, Fluorescence
- Infant
- Intellectual Disability
- Male
- Megalencephaly
- Microcephaly
- Middle Aged
- Molecular Biology
- Obesity
- Phenotype
- Psychiatry and Mental Health