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

Am J Hum Genet
Authors
Keywords
Abstract

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.

Year of Publication
2014
Journal
Am J Hum Genet
Volume
94
Issue
6
Pages
870-83
Date Published
2014 Jun 05
ISSN
1537-6605
URL
DOI
10.1016/j.ajhg.2014.05.004
PubMed ID
24906019
PubMed Central ID
PMC4121471
Links
Grant list
U24 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