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Tracing and harnessing the ancestry of RNA-guided nucleases

Objective

The phylogenetic, biochemical and functional diversity of these linked RGNs suggest a common origin that gave rise to the innumerable variations we observe today. However, little is known about these ancestors and the evolutionary paths that led to their modern counterparts. Recently, our team showed that reconstructed ancestors of Cas9 and Cas12a RGNs exhibit flexible substrate recognition and collateral activities distinct from any modern counterpart. This work sets the stage to uncover the evolutionary trajectories that gave rise to all related RGNs and to translate insights into new and improved biomolecular tools. As part of RGNcestry, we assembled four accomplished PIs covering CRISPR/transposon biology and technologies, ancestral sequence reconstruction and structural biology. The ensuing project will test our working hypothesis that ancestral RGNs consistently exhibit flexible properties that allow them to function in roles paralleling their modern counterparts, albeit less effectively due to a lack of specialization. To test this hypothesis and translate the resulting discoveries, we will pursue four objectives:

1. Reconstruct a detailed ancestral tree uniting RuvC-harboring RGNs.
2. Define the properties and functional roles of ancestral RGNs.
3. Explore molecular features and dynamics of ancestral RGNs.
4. Enhance and apply ancestral RGNs.

If successful, our high-risk/high-reward project could reveal how RGNs evolved into the rich diversity observed today and establish a new paradigm for RGN engineering and application spanning genome editing to molecular diagnostics.

Fields of science (EuroSciVoc)

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Keywords

Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)

Programme(s)

Multi-annual funding programmes that define the EU’s priorities for research and innovation.

Topic(s)

Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.

Funding Scheme

Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.

HORIZON-ERC-SYG - HORIZON ERC Synergy Grants

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Call for proposal

Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.

(opens in new window) ERC-2025-SyG

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Host institution

FOUNDATION IMMUNE ENGINEERING FOR GLOBAL CHILD AND ADOLESCENT HEALTH
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 3 563 239,75
Address
COPARTNER REVISION , ST ALBAN-ANLAGE 46
4052 BASEL
Switzerland

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Region
Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt
Activity type
Research Organisations
Links
Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 3 563 239,75

Beneficiaries (4)

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