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Peer-reviewedCC BYBioinformatics (Oxford, England)

CRISPR-HAWK: haplotype- and variant-aware guide design toolkit for CRISPR-Cas.

  • Alisa Kumbara1
  • Manuel Tognon2
  • Giulia Carone2
  • Arianna Fontanesi2
  • Nicola Bombieri1
  • Rosalba Giugno2
  • Luca Pinello3,4,5
5 affiliations
  1. 1Department of Engineering for Innovation Medicine, University of Verona, Verona, VR 37134, Italy.
  2. 2Department of Computer Science, University of Verona, Verona, VR 37134, Italy.
  3. 3Molecular Pathology Unit, Center for Computational and Integrative Biology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, United States.
  4. 4Department of Pathology, Harvard Medical School, Boston, MA 02115, United States.
  5. 5Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States.
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Abstract

Motivation

Current CRISPR guide RNA design tools rely on reference genomes, overlooking how genetic variation impacts editing outcomes. As genome editing advances toward clinical applications, incorporating population diversity becomes essential for ensuring therapeutic efficacy across diverse populations.Results

We present CRISPR-HAWK, a framework integrating individual- and population-scale variants and haplotypes into gRNA design. Analyzing therapeutic targets across 79 648 genomes reveals that genetic variants substantially alter guide performance. For the clinically approved sickle cell disease therapeutic guide targeting BCL11A, we identify haplotypes that completely abolish predicted cutting activity. Across seven therapeutic loci, 82.5% of guides contain variants modifying on-target activity. Variants also create novel protospacer adjacent motif sites generating individual-specific guides invisible to reference-based design. These findings demonstrate that variant-aware selection is critical for equitable genome editing.Availability

CRISPR-HAWK is available at https://github.com/pinellolab/CRISPR-HAWK and https://github.com/InfOmics/CRISPR-HAWK.

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Cite

BibTeXRIS
BibTeX
@article{kumbara2026crisprhawk,
  title = {{CRISPR-HAWK: haplotype- and variant-aware guide design toolkit for CRISPR-Cas.}},
  author = {Alisa Kumbara and Manuel Tognon and Giulia Carone and Arianna Fontanesi and Nicola Bombieri and Rosalba Giugno and Luca Pinello},
  journal = {Bioinformatics (Oxford, England)},
  year = {2026},
  month = oct,
  doi = {10.1093/bioinformatics/btag708},
  url = {https://europepmc.org/article/MED/42872486},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - CRISPR-HAWK: haplotype- and variant-aware guide design toolkit for CRISPR-Cas.
AU  - Alisa Kumbara
AU  - Manuel Tognon
AU  - Giulia Carone
AU  - Arianna Fontanesi
AU  - Nicola Bombieri
AU  - Rosalba Giugno
AU  - Luca Pinello
PY  - 2026
DA  - 2026/10/01
JO  - Bioinformatics (Oxford, England)
DO  - 10.1093/bioinformatics/btag708
UR  - https://europepmc.org/article/MED/42872486
AB  - Motivation  Current CRISPR guide RNA design tools rely on reference genomes, overlooking how genetic variation impacts editing outcomes. As genome editing advances toward clinical applications, incorporating population diversity becomes essential for ensuring therapeutic efficacy across diverse populations.Results  We present CRISPR-HAWK, a framework integrating individual- and population-scale variants and haplotypes into gRNA design. Analyzing therapeutic targets across 79 648 genomes reveals that genetic variants substantially alter guide performance. For the clinically approved sickle cell disease therapeutic guide targeting BCL11A, we identify haplotypes that completely abolish predicted cutting activity. Across seven therapeutic loci, 82.5% of guides contain variants modifying on-target activity. Variants also create novel protospacer adjacent motif sites generating individual-specific guides invisible to reference-based design. These findings demonstrate that variant-aware selection is critical for equitable genome editing.Availability  CRISPR-HAWK is available at https://github.com/pinellolab/CRISPR-HAWK and https://github.com/InfOmics/CRISPR-HAWK.
SN  - 1367-4803
SN  - 1367-4811
ER  -