Towards lice-resistant salmon: functional genetics and genome editing to enhance disease resistance in aquaculture

Farmed salmon is a major source of high quality protein and fatty acids essential for human health. Salmon aquaculture is worth approximately £1Bn to the UK economy, and supports many rural and coastal communities. However, sea lice are a major perennial problem for salmon aquaculture worldwide. These parasites attach to the skin of salmon and feed on tissue, mucus and blood. Infected fish show impaired growth and increased occurrence of secondary infections. They cause significant negative impacts on salmonid health and welfare, while lice prevention and treatment costs are a large economic burden for salmon farming, over £800M per annum.

Encouragingly there is substantial genetic variation in resistance to sea lice both within and across salmonid species. While the commonly farmed Atlantic salmon are generally susceptible to infection, other salmonid species such as coho salmon are fully resistant. Improving the innate genetic resistance of the farmed salmon to sea lice is an environmentally friendly, but underexploited approach to lice control. Incremental improvements have been achieved via selective breeding of Atlantic salmon, but their long generation interval slows progress. Genome editing raises the possibility of rapidly increasing the resistance of salmon via precise targeted changes to their genomes; the key is knowing which specific genes to target. This project focusses on understanding the genetic mechanisms underlying resistance to sea lice, and identifying gene targets for genome editing to develop lice-resistant Atlantic salmon.

To identify target lice resistance genes for editing, several different approaches will be taken, each exploiting the latest genomic technologies. Firstly, whole genome sequences will be obtained from a large population of farmed salmon on which sea lice counts following challenge have been collected. These will be used to map individual genes that contribute to variation in resistance in the commercial Atlantic salmon population.

Secondly, it is known that the mechanisms underlying resistance to sea lice are due to a successful localised immune response close to the attachment site of the louse. Therefore, a detailed gene expression comparison of the immune response of Atlantic and coho salmon in the first four days following a lice challenge will be undertaken, using single cell sequencing approaches to highlight different responses in distinct cell populations at louse attachment sites. This will be complemented by profiling of the gene expression of the lice, and identification of potential immunomodulatory proteins and their targets in the host.

Thirdly, genome editing approaches will be used to assess the impact of perturbing candidate resistance genes on response to sea lice both in cell culture and in the fish themselves. The former will be used to assess the cellular response to proteins secreted from the sea lice, and the consequences of knocking out each of the target genes on that response. This will lead to a final set of target genes for editing in salmon embryos, after which the edited fish will be challenged with sea lice. The resistance of the edited fish compared to full sibling control fish will then be assessed.

The scientific programme of the project will be complemented by co-development of a strategy for the breeding and dissemination of edited lice resistant salmon, together with industrial partner Benchmark PLC. Furthermore, public and stakeholder engagement events are planned to communicate the research plans and outcomes, with a particular focus on the benefits and risks of genome editing in aquaculture.

A successful outcome of lice resistant salmon would have major animal welfare and economic impacts via prevention of outbreaks, and removal of the need for chemical treatments. It would also provide a high profile example of the power of genome editing technology to understand biology and to improve food security and animal health.

Improving genetic resistance of farmed salmon stocks is a promising but underutilised component of preventing the economic and animal welfare burden caused by sea lice. While selective breeding incrementally increases host resistance, it is restricted to utilising genomic variants segregating in the broodstock. Genome editing approaches offer new opportunities to create de novo resistance alleles, or to introgress resistance alleles from closely related species. Therefore, understanding and harnessing within and across species variation in sea lice resistance in salmonids is a key goal.

While Atlantic salmon are susceptible to lice, certain Pacific salmon such as coho are highly resistant. This resistance is mediated by a localised epithelial hyperplasia coupled with immune cell infiltration in the first few days after louse attachment. This project focusses on understanding and exploiting the functional mechanisms underpinning this response. Harnessing large scale disease challenge and pedigree data provided by the industrial partner Benchmark, the team will map and characterise genes underpinning host resistance in Atlantic salmon. This will be coupled by a detailed temporal profiling of the localised host response using single cell RNA sequencing of attachment sites in resistant and susceptible fish, within and across species. Putative targets for immunomodulation by the parasite will also be identified using a yeast-two-hybrid approach with known louse secretory proteins.

The high-throughput genomic data will provide a list of putative key resistance genes and pathways for further filtering using CRISPR editing in a primary cell culture model system. This will culminate in high priority targets for in vivo editing, followed by assessment of the relative resistance to sea lice in edited salmon versus unedited controls. A successful outcome of an edited Atlantic salmon with resistance to sea lice has potential to transform global aquaculture.