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- Wheat is the most cultivated cereal in the world, with a planted area exceeding 220 million hectares, and is a staple food for 40% of the world's population. Since the 1980s, wheat demand has doubled. Consequently, wheat is at the epicentre of food security, particularly with the ongoing Russia-Ukraine conflict. Take-all disease, caused by the soil fungus Gaeumannomyces graminis var. tritici (Ggt), is one of the most damaging root diseases of wheat worldwide. In the UK half of the wheat crop is affected by take-all annually, with average yield losses of 5-20% and complete failure under severe take-all conditions1,2. A moderate case of take-all, causing a yield reduction of 15% would cost the UK approximately £427.7m per year (see accompanying summary report from IP Pragmatics). Although there are fungicides for take-all these do not provide consistent control of the disease. In addition, chemical control measures can lead to adverse environmental impacts so there is an urgent need for more sustainable and effective approaches. Novel genetic methods could provide a solution. Genetic resistance to take-all in wheat has been identified as a priority by UK plant breeders, AHDB and arable farmers to deliver an environmentally sustainable strategy for disease control and to increase wheat productivity. Conventional breeding strategies are not possible as genetic resistance to take-all is restricted to oats. Oat roots naturally produce an antifungal compound known as avenacin A-1 that provides protection against take-all3. The genes for the biosynthesis of this compound are organised in a cluster on a chromosome of the oat genome. We have recently characterised the genes encoding the complete avenacin pathway4. We have also demonstrated that the avenacin pathway can be reconstituted when the genes are introduced into tobacco4, showing that it is possible to transfer this pathway into other plant species. Furthermore, in previous work funded by BBSRC responsive mode grant BB/K005952/1 we have demonstrated assembly of parts of the pathway in wheat. In this sFoF project, we intend to complete the grand challenge of introducing the entire avenacin pathway into bread wheat and evaluate the consequences of this for take-all resistance. To achieve this we will: 1) Establish a comprehensive metabolite analysis platform to enable systematic detection of all avenacin pathway intermediates, end products and potential modified variants thereof. 2) Transform the full set of genes necessary for avenacin biosynthesis into wheat. 3) Characterise the transformed wheat lines at the molecular, metabolic and phenotypic levels and evaluate them for take-all resistance Demonstration of take-all resistance through genetic modification would represent a major breakthrough that could impact on wheat production worldwide. It is timely as the UK Government passes the Precision Breeding Bill and Argentinian Biotech, Bioceres releases the first GM wheat, HB4, for large scale cultivation5. A priority during the project will be to intensify engagement with stakeholders to define a long-term strategy for the deployment of GM take-all resistant wheat in the UK and the world through our partnership with CIMMYT6. We have developed a programme to achieve this objective (see Development Plan), which will be delivered in consultation with our Steering Group: plant breeder Dr Richard Summers, RAGT; US ag biotech expert Professor Dick Flavell, CSO, Ceres; and Professor Joyce Tait, University of Edinburgh, a social scientist with extensive experience in GM technologies and other areas directly relevant to the project.