Securing and developing the IPD-MHC database to enhance research into livestock diseases

The Immuno Polymorphism Database (IPD) (https://www.ebi.ac.uk/ipd/) is a set of specialist databases that contain curated sequence datasets of polymorphic immune genes. Developed and maintained by the Anthony Nolan, these databases help save the lives of people with blood cancer by matching donors major histocompatibility complex (MHC; (also known as HLA in humans) to prevent rejection. One of these databases is IPD-MHC, a repository of non-human MHC genes that includes the major farmed animals species; cattle, sheep, pigs, trout and salmon. All these species exhibit high degrees of variation within their MHC genes. This diversity differentially influences how the adaptive and innate immune systems respond to pathogens and vaccines. Therefore a greater understanding of this diversity and the tools to analyse it offer a significant advance to our broad capability to examine immune function in these fundamental food producing species.
Since the first release in 2003, IPD-MHC has become the central source of curated and annotated comparative MHC data and nomenclature globally. The website now receives nearly 250 visitors every day and over 500 sequences were submitted in 2013 from all over the world. However, this success has created problems. The database and website have never been specifically funded. IPD-MHC has existed as an 'in kind' project that the research community and bioinformaticians at Antony Nolan have considered important enough to create and continue. The demands that the level of traffic has created mean that this model is no longer sustainable. Indeed, there is already a chronic lack of development and this data repository is in danger of becoming redundant.
This proposal will support a dedicated IPD-MHC bioinformatician located at Anthony Nolan to work alongside the other IPD bioinformaticians. Their role will be to unify the individual species websites, incorporate the extensive chicken MHC data as a key farmed animal and create one streamlined data submission processes. Once this is in place, the capability of IPD-MHC will be significantly enhanced to accept a greater range of data and an expanded suite of analysis tools will be imbedded to allow advanced analysis for non-bioinformaticians. IPD-MHC still has overwhelming support from the research community, Anthony Nolan and the offer of free infrastructure from the European Bioinformatics Institute. This project is aimed at securing this central resource and expertise in the UK, to benefit this important UK research community and reach out to the rest of the world as part of the global food security agenda.

The unusual complexity and importance of the MHC led to the research community driving the creation of a curated database and bioinformatics resource dedicated to comparative major histocompatibility complex (MHC) sequences; IPD-MHC. The MHC is a highly variable region of all vertebrate genomes that encodes genes that dictate how an individual's immune system responds to challenge, influence reproduction and is linked with production in livestock. Since 2003 the considerable expansion and success of IPD-MHC has been sustained solely by 'in kind' contributions from curators, nomenclature committees, bioinformaticians and infrastructure resources.
Advances in sequencing technology and the growth in comparative immunology, especially for livestock species as part of national and international food security agendas, has created a demand for IPD-MHC that can only be met by providing a dedicated bioinformatician. Through the long term relationship between Anthony Nolan and the European Bioinformatics Institute (EBI), the infrastructure and access to the EBI suite of analysis tools will still be provided 'in kind'. However, the modernisation of IPD-MHC to be compatible with recent EBI upgrades is urgent, and the tools for submitting and curating sequences must be made to reflect current sequencing technologies and community needs. These upgrades require a bioinformatician to work exclusively on this project. With these upgrades, the opportunity will exist to significantly expand the analytical capabilities of IPD-MHC to be of maximum use to the MHC community. By developing current and bespoke bioinformatic analysis tools available through one portal, this project will ultimately provide a uniquely high quality sequence resource that includes the capability to interrogate MHC data for non-bioinformaticians. As current traffic is nearly 200 unique hits per day, the demand for this UK based resource can only increase, nationally and globally.

A majority of the data in IPD-MHC is accessible through other publically accessible databases, such as GenBank and DDBJ. The key and hence the demand for IPD-MHC is that it adds significant value and impact to this data by having species specific teams of experts to ensure the quality and naming system is correct. This level of curation is essential for highly variable immune genes; low quality/wrongly named data can fragment research fields, cause confusion and lower the impact of research. This is evidenced by the numerous comparable resources for different human genes, many of which are also within the IPD framework.
Currently IPD-MHC is the central accurate repository for MHC data globally. The improvements and extensions this proposal will maintain this status and enhance its impact considerably. It should also be noted that this is a free web based resource and the data will be available to all researchers and interested parties with the widest of definitions.
The fundamental nature of the MHC combined with the farmed and companion species within IPD-MHC, means that researchers in many fields will be interested in this data. This will be enhanced by the capability to analyse MHC sequences knowing they are accurate and that the analysis tools have been tailored appropriately. As the importance of MHC and our analytical ability continues to increase, IPD-MHC will become a more valuable tool not only for academics, but also for veterinarians and livestock breeding companies. These groups will be able to understand MHC in the precise context of their species and associate phenotypic data. As the lPD-MHC capabilities increase, it is hoped that allele frequencies and other information directly applicable to livestock breeding companies and potentially farmers will also be available.
The accurate information that IPD-MHC provides can also be adopted by other sequence projects and resources. Public repositories contain MHC data that is incorrectly named or misinterpreted due to the highly polymorphic nature of these genomic regions. This has also caused the current genome assemblies of IPD-MHC species to contain inaccurate or very low confidence MHC assemblies. By targeting the MHC and taking on these quality and assembly challenges IPD-MHC will have the opportunity to feed back to other databases and repositories to improve quality. The impact of this will be very broad as academic and commercial genotyping strategies, livestock diversity measures and genome wide association studies are based on the current genome builds. Outputs from such studies, as well as more unbiased transcriptomic and proteomic studies, are interpreted using public sequence databases. Accurate data underlying these studies can therefore have a wide impact across academia and industry by improving the analysis accuracy. Confirming that the MHC is or isn't associated with important traits is equally as important.
A BBSRC supported bioinformatician within Anthony Nolan working with the EBI would become a highly skilled asset and possess skills now broadly identified as lacking in the UK. Future impact from this position would also be achieved by raising the profile of The Pirbright Institute and the BBSRC an area currently dominated by other funding streams and pharmaceutical companies.
As part of improving food security this research will have a beneficial impact on UK society in general and ultimately the rest of the world. Any effect on reducing the burden of disease will have a major beneficial effect on social welfare, wealth creation through the development of livestock industries and the removal of barriers to trade. As such, this project directly addresses BBSRC strategic priority areas in Food Security and therefore contributes to meeting its targets. This project also facilitates data sharing within the animal genetics community, and several other bioscience areas, to facilitate global research.