Engineering microdeletions and microduplications by targeting segmental duplications with CRISPR.
Document Type
Article
Publication Date
3-2016
JAX Source
Nat Neurosci 2016 Mar; 19(3):517-22.
Volume
19
Issue
3
First Page
517
Last Page
522
ISSN
1546-1726
PMID
26829649
Grant
CA034196, HG007497
Abstract
Recurrent, reciprocal genomic disorders resulting from non-allelic homologous recombination (NAHR) between near-identical segmental duplications (SDs) are a major cause of human disease, often producing phenotypically distinct syndromes. The genomic architecture of flanking SDs presents a challenge for modeling these syndromes; however, the capability to efficiently generate reciprocal copy number variants (CNVs) that mimic NAHR would represent a valuable modeling tool. We describe here a CRISPR/Cas9 genome engineering method, single-guide CRISPR/Cas targeting of repetitive elements (SCORE), to model reciprocal genomic disorders and demonstrate its capabilities by generating reciprocal CNVs of 16p11.2 and 15q13.3, including alteration of one copy-equivalent of the SDs that mediate NAHR in vivo. The method is reproducible, and RNA sequencing reliably clusters transcriptional signatures from human subjects with in vivo CNVs and their corresponding in vitro models. This new approach will provide broad applicability for the study of genomic disorders and, with further development, may also permit efficient correction of these defects. Nat Neurosci 2016 Mar; 19(3):517-22.
Recommended Citation
Tai D,
Ragavendran A,
Manavalan P,
Stortchevoi A,
Seabra C,
Erdin S,
Collins R,
Blumenthal I,
Chen X,
Shen Y,
Sahin M,
Zhang C,
Lee C,
Gusella J,
Talkowski M.
Engineering microdeletions and microduplications by targeting segmental duplications with CRISPR. Nat Neurosci 2016 Mar; 19(3):517-22.