A new technique to model certain copy-number variants (CNVs) in the genome, using the CRISPR/Cas9 genome editing system, could facilitate the study of genomic disorders and opening a potential new approach to targeted treatments for those disorders.
Copy-number variants – an abnormal number of copies of DNA sections—are widespread in the human genome. Relatively small duplications and deletions of error-prone areas of the genome are now known to underlie human disease, particularly neurodevelopmental and psychiatric disorders.
A research team led by Michael E. Talkowski, Ph.D., of Massachusetts General Hospital, and including Jackson Laboratory for Genomic Medicine Scientific Director and Professor Charles Lee, Ph.D., studied a particular kind of CNV: errors created by non-allelic homologous recombination (NAHR). The resulting CNVs can result in dosage errors for many genes in the segment flanked by these segmental duplication (SD) sequences and lead to recurrent microdeletion and microduplication syndromes in humans, but the very structure of those SDs has made modeling NAHR a challenge.
Using CRISPR/Cas9, the researchers developed what they call “single-guide CRISPR/Cas targeting of repetitive elements” or SCORE, to model reciprocal genomic disorders. As proof of concept, they generated reciprocal CNVs of DNA regions at chromosome 16p11.2 (which are associated with autism-spectrum disorders, intellectual disability and neuropsychiatric disorders) and chromosome 15q13.3. They demonstrated that the method is reproducible, accurate and flexible, and shows promise for developing induced pluripotent stem cells for in vitro study and, ultimately, targeted treatments of diseases caused by reciprocal CNVs.
Tai et al.: Engineering microdeletions and microduplications by targeting segmental duplications with CRISPR. Nature Neuroscience, Feb. 1, 2016, http://dx.doi.org/10.1038/nn.4235