Functional Annotation of the Sheep Genome

Animals and humans are made up of many different kinds of organs and cells, each of which requires the actions of a subset of the genes in the genome. We currently know the function of only a subset of the genes in the genome. Much of what we know comes from studies of rodents but their biology is quite different to humans and their small size compromises their use. In the current study we will examine how individual genes are used in every tissue and cell of the sheep. From that information, we will be able to identify sets of genes that are always used together, and infer the function of genes of unknown function from the company they keep. That information will, in turn, allow us to interpret studies of the genetics and genomics of large animals, including humans (this study could not be done on a human). This will, in turn, inform the rational breeding of livestock for improved performance and welfare through selection for disease resistance. It will also give us a better understanding of the basic biology of humans that can be translated in better lifelong health.

The current proposal seeks to establish a gene expression atlas for the domestic sheep, based upon a comprehensive transcriptomic analysis of hundreds of cell and tissue samples using RNAseq, genome-scale 5' RACE (CAGE) and high throughput sequencing. We will use that information to annotate the genome of sheep and other ruminants. We will also use the atlas to identify novel candidate genes underlying complex traits in large animals, including humans, to infer gene function and orthology relationships across species and to gain insights into evolution of the mammalian transcriptome, to assess the prevalence and significance of expressed genetic variation and allelic imbalance in gene expression, to examine in detail the expression of genes involved in immune function and to examine the role of promoter evolution and functional site turnover as a major driver of species divergence. We will develop web tools to provide an online resource for the livestock and health science research community.

Who will benefit from our research?
The scientific community will provide expression-based annotations of the sheep genome that can be translated across to other ruminants and large animals (including humans). The biomedical research community will benefit from a resource that could provide a rational base for connection of genotype and phenotype in humans, especially in interpretation of genome-wide association studies. In the animal health sector, the information will also underpin sustainable improvements in production and resistance against infectious diseases, many of which (e.g. salmonella, influenza) are zoonotic. Thus our proposal will bridge fundamental and applied science; a One Biology:One Health agenda within two BBSRC grand challenges; Food Security and Basic Bioscience Underpinning Health. The further development of genome editing in livestock in the sheep model also falls within the province of synthetic biology and has the potential to produce novel livestock breeds with improved performance and reduce environmental footprint.
Small ruminants are a major livestock species in developing countries, and a focus of international efforts at improvement, especially for disease resistance. In the long term, the research will benefit the poorest farmers.
How will they benefit from this research?
We will contribute data that will be publicly available in appropriate international databases for the wider research community to access and exploit. We interact directly with many breeding companies to develop tools that utilise genomic evaluation in breeding strategies. Our project will thus provide added value to the international efforts to generate and maintain genomic information.
What will be done to ensure that the benefits from this research arise?
Scientific community: This project is a key component of the UK contribution to International Genome Projects and will contribute critically to the Sheep Genome Consortium and to ruminant and mammalian functional genomics. Primary data will be made available through multiple web sites and databases, notably ENSEMBL. We will also present the results and publicise the resources at key scientific meetings (ISAG, PAG, BSAS) and will particularly seek to engage a wide spectrum of researchers from the fields of genetic and genomics,agriculture, immunology and veterinary pathology and to emphasise the cross-disciplinarity of the research.
Industry: We will engage with livestock, animal health and biomedical industries through the University's commercialisation arm Edinburgh Research and Innovation. Roslin has 3 permanent business development staff who have helped to host multiple events over the past three years specifically showcasing the institute's work to industry partners.
Public: We (will) provide information about our research through our web sites (with project-specific information), talks and discussion groups and direct interaction with the media. The Roslin Institute encourages clear and open communication and has a policy of promoting Public Engagement by means of interaction with the media, presentations, publications, exhibitions and schools activities. Roslin provides support for staff and students wishing to undertake such activities. The Roslin Institute's Scientific Administrator oversees both internal and external communication of the research performed at the institute.
Track record: We have an excellent track record for translating the outcomes of our research and Roslin was considered an exemplar of good practice in KEC evaluation during the most recent ISPG review. We hold regular Industry Open Days, and have more than 40 existing industry partnerships. The individual PIs have existing collaborations with multiple companies including Genus, Pfizer, AMGEN, Affymetrix, Merck, Novartis, Aviagen and several SMEs. Our major partner, the breeding company Genus, has provided a letter of support.