Engineering microdeletions and microduplications by targeting segmental duplications with CRISPR
Tai, Derek J. C.
Seabra, Catarina M.
MetadataShow full item record
CitationTai, D. J. C., A. Ragavendran, P. Manavalan, A. Stortchevoi, C. M. Seabra, S. Erdin, R. L. Collins, et al. 2016. “Engineering microdeletions and microduplications by targeting segmental duplications with CRISPR.” Nature neuroscience 19 (3): 517-522. doi:10.1038/nn.4235. http://dx.doi.org/10.1038/nn.4235.
AbstractRecurrent, 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 significant challenge for modeling these syndromes; however, the capability to efficiently generate reciprocal copy number variants (CNVs) that mimic NAHR would represent an invaluable 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 RNAseq reliably clusters transcriptional signatures from human subjects with in vivo CNV 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:29002620