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Am J Hum Genet DOI:10.1016/j.ajhg.2014.05.004

Transcriptional consequences of 16p11.2 deletion and duplication in mouse cortex and multiplex autism families.

Publication TypeJournal Article
Year of Publication2014
AuthorsBlumenthal, I, Ragavendran, A, Erdin, S, Klei, L, Sugathan, A, Guide, JR, Manavalan, P, Zhou, JQ, Wheeler, VC, Levin, JZ, Ernst, C, Roeder, K, Devlin, B, Gusella, JF, Talkowski, ME
JournalAm J Hum Genet
Date Published2014 Jun 05
KeywordsAnimals, Autistic Disorder, Cerebral Cortex, Child, Chromosome Deletion, Chromosome Duplication, Chromosomes, Human, Pair 16, DNA Copy Number Variations, Female, Genome-Wide Association Study, Genotype, Humans, Intellectual Disability, Male, Mice, Pedigree, Phenotype, Sequence Analysis, RNA, Transcription, Genetic

Reciprocal copy-number variation (CNV) of a 593 kb region of 16p11.2 is a common genetic cause of autism spectrum disorder (ASD), yet it is not completely penetrant and can manifest in a wide array of phenotypes. To explore its molecular consequences, we performed RNA sequencing of cerebral cortex from mouse models with CNV of the syntenic 7qF3 region and lymphoblast lines from 34 members of 7 multiplex ASD-affected families harboring the 16p11.2 CNV. Expression of all genes in the CNV region correlated well with their DNA copy number, with no evidence of dosage compensation. We observed effects on gene expression outside the CNV region, including apparent positional effects in cis and in trans at genomic segments with evidence of physical interaction in Hi-C chromosome conformation data. One of the most significant positional effects was telomeric to the 16p11.2 CNV and includes the previously described "distal" 16p11.2 microdeletion. Overall, 16p11.2 CNV was associated with altered expression of genes and networks that converge on multiple hypotheses of ASD pathogenesis, including synaptic function (e.g., NRXN1, NRXN3), chromatin modification (e.g., CHD8, EHMT1, MECP2), transcriptional regulation (e.g., TCF4, SATB2), and intellectual disability (e.g., FMR1, CEP290). However, there were differences between tissues and species, with the strongest effects being consistently within the CNV region itself. Our analyses suggest that through a combination of indirect regulatory effects and direct effects on nuclear architecture, alteration of 16p11.2 genes disrupts expression networks that involve other genes and pathways known to contribute to ASD, suggesting an overlap in mechanisms of pathogenesis.


Alternate JournalAm. J. Hum. Genet.
PubMed ID24906019
PubMed Central IDPMC4121471
Grant ListU24 MH081810 / MH / NIMH NIH HHS / United States
R37 MH057881 / MH / NIMH NIH HHS / United States
R00 MH095867 / MH / NIMH NIH HHS / United States
K99 MH095867 / MH / NIMH NIH HHS / United States
1U24MH081810 / MH / NIMH NIH HHS / United States
MH095867 / MH / NIMH NIH HHS / United States