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How CRISPR/Cas9 Finds Off-Targets

  • Full or part time
  • Application Deadline
    Sunday, December 01, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

In recent years, the application of CRISPR/Cas9 technology has revolutionised genome editing in biological research. Cas9 is a programmable endonuclease routinely used to generate sequence deletions, insertions and even to regulate gene expression from bacteria to mammals1. Most importantly, it offers vast potential for novel, gene-editing-based therapeutic applications. However, spurious off-target edits represent an important barrier towards therapeutic applications2. The molecular mechanism by which Cas9 binds and cleaves off-targets remains largely unknown. Lack of such knowledge is a significant problem because it hinders the development of new and improved CRISPR/Cas9 systems with high accuracy and efficiency.

The objective of this project is to elucidate the molecular mechanism by which Cas9 discriminates between on- and off-targets and to develop new Cas9 variants with accurate gene-editing . We have recently developed an optical tweezers assay to image off-target activity with single-molecule resolution3. The student involved in this project will combine such cutting-edge experiments at single molecule resolution with more traditional assays touching on multiple fields (e.g., biochemistry, structural and cellular biology and bioinformatics). Understanding how Cas9 finds on- and off-targets at the molecular level will help to engineer new and improved gene-editing tools for therapeutic applications.

To Apply: Please visit our website (https://lms.mrc.ac.uk/study-here/phd-studentships/lms-3-5yr-studentships/) to download an application form.

Funding Notes

This project is one of multiple available projects potentially funded by the MRC. If successful the studentship would cover all tuition fee payments and includes a tax-free stipend amounting to £21,000pa (paid in monthly installments directly to the student) for 3.5 years.

Whilst this funding is available to students worldwide, due to the higher tuition fee rate of overseas students competition is higher and so only exceptional OS applicants will be considered.

References

Jinek, M. et al. (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337:816-821.

Tsai, S. Q. et al. (2017) CIRCLE-seq: a highly sensitive in vitro screen for genome-wide CRISPR-Cas9 nuclease off-targets. Nat Methods 14:607-614.

Newton, M. D. et al. (2019) DNA stretching induces Cas9 off-target activity. Nat Struct Mol Biol 26:185-192.

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