AI Article Synopsis
- The study addresses the difficulty of understanding how specific sequences in the genome relate to their functions, especially with limited tools for hypermutation.
- A new platform called helicase-assisted continuous editing (HACE) is introduced, which uses CRISPR-Cas9 to induce mutations over large sections of the genome effectively.
- HACE has been applied to study mutations related to drug resistance and missplicing, and it offers a robust way to explore both coding and noncoding genetic variants to better understand their roles in biological functions.
Article Abstract
Deciphering the context-specific relationship between sequence and function is a major challenge in genomics. Existing tools for inducing locus-specific hypermutation and evolution in the native genome context are limited. Here we present a programmable platform for long-range, locus-specific hypermutation called helicase-assisted continuous editing (HACE). HACE leverages CRISPR-Cas9 to target a processive helicase-deaminase fusion that incurs mutations across large (>1000-base pair) genomic intervals. We applied HACE to identify mutations in mitogen-activated protein kinase kinase 1 (MEK1) that confer kinase inhibitor resistance, to dissect the impact of individual variants in splicing factor 3B subunit 1 (SF3B1)-dependent missplicing, and to evaluate noncoding variants in a stimulation-dependent immune enhancer of CD69. HACE provides a powerful tool for investigating coding and noncoding variants, uncovering combinatorial sequence-to-function relationships, and evolving new biological functions.
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| http://dx.doi.org/10.1126/science.adn5876 | DOI Listing |
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