Transcriptional Consequences of 16p11.2 Deletion and Duplication in Mouse Cortex and Multiplex Autism Families

被引:98
作者
Blumenthal, Ian [1 ,2 ]
Ragavendran, Ashok [1 ,2 ]
Erdin, Serkan [1 ,2 ]
Klei, Lambertus [3 ]
Sugathan, Aarathi [1 ,2 ]
Guide, Jolene R. [1 ,2 ]
Manavalan, Poornima [1 ,2 ]
Zhou, Julian Q. [6 ]
Wheeler, Vanessa C. [1 ,2 ]
Levin, Joshua Z. [4 ]
Ernst, Carl [5 ]
Roeder, Kathryn [6 ]
Devlin, Bernie [3 ]
Gusella, James F. [1 ,2 ,4 ,7 ,8 ,9 ,10 ,11 ]
Talkowski, Michael E. [1 ,2 ,4 ,7 ,8 ,9 ,10 ,11 ]
机构
[1] Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA
[2] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA
[3] Univ Pittsburgh, Dept Psychiat, Sch Med, Pittsburgh, PA 15213 USA
[4] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02141 USA
[5] McGill Univ, Dept Psychiat, Douglas Hosp, Res Inst, Verdun, PQ H4H 1R3, Canada
[6] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA
[7] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02141 USA
[8] Massachusetts Gen Hosp, Dept Genet, Boston, MA 02141 USA
[9] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02141 USA
[10] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02141 USA
[11] Harvard Univ, Sch Med, Boston, MA 02141 USA
关键词
LONG-RANGE INTERACTIONS; COPY NUMBER VARIATION; DE-NOVO MUTATIONS; ENRICHMENT ANALYSIS; FUNCTIONAL IMPACT; SPECTRUM; REVEALS; MODELS; KNOWLEDGEBASE; MICRODELETION;
D O I
10.1016/j.ajhg.2014.05.004
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:870 / 883
页数:14
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