Genomic Selection for Bovine Tuberculosis Resistance

Lead Research Organisation: SRUC
Department Name: Research

Abstract

The bacterium, Mycobacterium bovis, has a major economic, trade, health and welfare impact on the cattle industry worldwide as well as posing a risk to humans, other domesticated, feral and wild animal populations. This pathogen causes the chronic respiratory disease, bovine tuberculosis (bTB), which remains an increasing problem in cattle herds in the UK and Republic of Ireland despite over sixty years of costly eradication programmes. These programmes included the slaughter of animals which are positive for a skin test which indicates that the animal has become infected. Alternative control strategies are urgently needed. Previous studies have suggested that cattle differ genetically in their risk of bTB, opening up the possibility of genetic selection for decreased risk of bTB. Breeding livestock for more favourable traits is becoming faster and more accurate through advances in genomic resources and information, including new genotyping tools such as high density single nucleotide polymorphism (SNP) chips. These 'chips' consist of thousands of SNP markers which can relate variation across the genome to variation seen in traits. In our previous BBSRC CEDFAS grant using bTB cases (defined as skin test and lesion positive) and herd-matched Holstein-Friesian controls from Northern Ireland, we could account for ca. 25% of the observed variation in bTB status using chips comprising over 700,000 SNPs. We now propose to build on this information and combine it with datasets derived from other cattle populations in the UK and Republic of Ireland (for which we have obtained reciprocal permission in principle) to develop robust genomic predictors of bTB risk. These could then be directly applied by the cattle industry to select for bTB resistance.

First we will enhance the power of our original study by genotyping a further set of cattle which are skin test positive but lesion negative. This will also enable us to clarify the genetic relationship between this phenotype and our more strict definition of a bTB case. We will then conduct a meta-analysis combining this enriched dataset with that from other sources, and use this large dataset to develop genomic predictors of bTB risk. The results will provide a direct tool to the dairy industry, enabling it to select for increased bTB resistance without a continuing requirement to collect bTB phenotypes from cattle in currently infected herds. In addition, we will ensure that selection for bTB resistance is not detrimental to production traits by determining the genetic relationship of bTB resistance with milk production and other economically important traits in the UK breeding goal.

We also want to find the actual SNPs that lead to the genetic differences we detect in bTB resistance. To do this, we propose to take advantage of the fact that it has now become feasible to sequence whole genomes of individual animals; this usually reveals many novel SNPs. Furthermore, genetic changes due to insertions and deletions (indels and copy number variants) in the DNA sequence are also increasingly associated with variation in traits and may underpin disease resistance as well. In order to investigate this type of variation and also identify SNPs closer to the actual causative SNPs, we propose to resequence animals with the most extreme bTB risk, as determined by the genomic predictors developed in the earlier part of the grant. This information, i.e. identification of the actual DNA changes associated with increased resistance, would improve the accuracy of the genomic predictors across generations and potentially have utility in other breeds. These results will also enable us to explore the underlying basis for resistance to M. bovis infection, which could advance our ability to design further control strategies for this intractable disease.

Technical Summary

Bovine tuberculosis (bTB) is a chronic respiratory disease caused by the pathogen, Mycobacterium bovis. Despite many years of statutory testing and slaughter, bTB still has major impacts on the health and welfare of UK cattle and the livestock economy. Substantial evidence now exists that the risk of a herd contracting this disease is variable and has a strong genetic component. We propose to build on our recent results from a genome wide association study (GWAS) in which we genotyped ca. 1200 cases and controls for 750,000 SNPs in the major UK dairy breed, the Holstein. We identified a marker-based heritability of 0.24 and chromosome wide significance for specific loci associated with bTB resistance. We now plan to provide accurate genomic predictors for bTB risk which can be directly applied by the dairy industry by combining our current data with additional datasets in a meta-analysis. We will exploit our unique biobank of DNA samples collected from bTB phenotyped cattle from high prevalence herds, to explore whether skin test positive, lesion negative animals have similar or distinct genotypes to our previous case definition of skin test positive, lesion positive animals. Further datasets available from collaborators consist of Holstein sires with estimated breeding values for bTB risk, and another case/control study. These have been genotyped at lower density compared to our samples. The meta-analysis of 5 distinct datasets will enable us to develop enhanced genomic predictors of bTB resistance calibrated by cross-validation, an essential requirement for GWAS studies. Predictors for complex traits in livestock based on whole genome sequencing are now on the horizon; we plan to whole genome sequence selected high and low bTB risk sires to provide novel information that could lead to further accuracy of the predictors as well as identifying novel SNPs closer to the causal loci, potentially identifying putative candidate genes for bTB resistance in cattle.

Planned Impact

The goal of this proposed project is to help tackle the seemingly intractable problem of bovine tuberculosis (bTB) in the UK, caused by infection with the bacterium Mycobacterium bovis. This disease has shown a year on year increases in incidence, in cattle herds in both the UK and Republic of Ireland (ROI), especially over the last decade. We aim to take a novel approach to help combat the issue, by providing essential science-led information to the dairy industry, enabling it to utilise advanced genomic breeding tools for selecting for increased resistance to bTB. The major output from this project will be an enhancement of the health, welfare and productivity of UK cattle, adding to food security and contributing toward evidence based policy-making at a national and international level. This leads to both economic and societal impacts, as bTB is a costly and controversial problem for the UK government. It has major economic impacts on the UK livestock industry, especially as the UK does not enjoy bTB-free status, unlike the rest of the EU. Furthermore, the impact of bTB on the farmers dealing with this problem is immensely distressing, with many farms being under statutory restrictions on animal movement for considerable periods of time. Thus, any measures to lessen the disease impact will be beneficial at many levels. Our project will provide information and tools directly applicable to the dairy industry through DairyCo who are supportive and will facilitate the necessary technology transfer. The information provided will enable farmers to avoid using highly bTB susceptible sires and cows, and choose bulls which are expected by genomic prediction to be more bTB resistant. Uptake may be expected to be regional and dependent on individual circumstances, in that use by breeders may well be greatest in high bTB prevalence areas such as Northern Ireland, Wales and South West of England. Utilising accurate genomic predictors would be expected to also have a positive feed-back in that as ever-more resistant bulls are employed in a herd, the overall level of infection should be reduced, resulting in greater herd protection. Furthermore genomic selection for bTB resistance can be used as a complementary control measure alongside other strategies, and could have a positive benefit to other control efforts. Adoption of genomic predictors for bTB resistance would move towards providing a green and sustainable solution to the issue, and thus make major contributions to environmental sustainability, protection and impact reduction. Our proposal should also be seen as public-friendly as it should reduce the emphasis on badger controls and reduce the impacts of the hugely costly test and slaughter schemes. The project also has other benefits. It would have impact on the UK academic community by enhancing the knowledge economy, particularly for those engaged in animal health and agricultural/food production research. The project has potentially even greater benefit to the worldwide farming fraternity as our information will be invaluable in other countries where bTB is rife. It will provide information that could be applicable directly to Holstein-Friesian cattle herds globally, as well as potentially to other breeds of cattle. State-of-the-art technologies will be employed to tackle an important health trait and thus it will represent a proof-of-principle that could be applied to other infectious diseases of livestock. Furthermore, the project will provide training in the latest genomic technologies, and the PDRA employed on the project will become a highly skilled researcher. In summary, this is a proposed project with many direct and indirect benefits. The potential returns on investment for the research should be very high.
 
Description We have found that breeding values using national data can be used to create deregressed proofs that can act as a phenotype for genomic breeding values. These gEBVs are readily accepted by the industry and have been received with high expectations. At subsequent KE events, farmers and industry influencers see the availability of TB Advantage as a great step forward in the control of TB. Furthermore, adding genotyped cows from TB affected herds adds to the accuracy of prediction
Exploitation Route The great thing about this project is its close proximity to industry through the connection with EGENES. All outputs that can be will be applied almost straight away due to the route to market through gEBVs and the involvement of EGENES in the project. Farmers can then select for increased TB resistance straight away - in fact that has been available to them since Jan 18th 2016 and this project is expected to improve the accuracy of predictions leading to even greater impact.
Sectors Agriculture, Food and Drink,Government, Democracy and Justice

URL https://dairy.ahdb.org.uk/technical-information/breeding-genetics/tb-advantage/#.XGKvGzP7SUk
 
Description Outputs from the activity of the scientists involved in the project were discussed at a closed workshop organised by Professor Mike Coffey which included industry partners and government vets and others involved in TB research for Defra. Around 30 stakeholders from the research team, AHDB Dairy, BBSRC, HCC, Defra, APHA, Teagasc and DARDNI attended a 2 days closed workshop held in Cardiff to discuss the genetic and genomic improvement of TB resistance in UK dairy cattle. This led to government support to the release of gEBVs to industry in January 2016, funded and driven by AHDB Dairy delivered by EGENES from work conducted by SRUC and Roslin. This project provided some of the underlying confidence required by government to 'sanction' the release of gEBVs and furthermore to agree to continued supply of data. A follow up workshop was held in Belfast in November 2016 and Birmingham November 2017. A member of the project team (Professor Mike Coffey) was invited to a closed meeting with Michael Gove on the governments TB policy in January 2018 and in February 2018 the government announced a review of the 25 strategy on TB eradication to allow the inclusion of genetic selection for TB resistance. AHDB Dairy have won a significant award from Innovate UK (£360,000) to genotype 10,000 cows in the TB area and 2000 bulls with TB Advantage proofs to improve the accuracy of genomic predictions.
First Year Of Impact 2016
Sector Agriculture, Food and Drink,Government, Democracy and Justice
Impact Types Societal,Economic

 
Description Input to the Godfray review committe on the Defra 25 year TB eradication strategy
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
Impact The review was specifically targeted at new tests and genetics of resistance. Professor Mike Coffey attended a meeting at Defra which included around 20 heads of schools and departments involved in TB research and strategy definition plus Michael Gove. At that meeting the review was announced and we subsequently contributed 4 documents on genetics of TB resistance. We also had a teleconference with the committee to clarify some of the points made in our submission. The uptake of TB Advantage has been good by farmers and having the government review mention it a few times certainly increases its profile and enhances its impact. as with all genetic improvements, it will take time to measure the impact.
URL https://www.gov.uk/government/news/review-of-governments-bovine-tb-strategy-published
 
Description Dairy Co (now AHDB) grant for bovine tuberculosis genetic evaluations
Amount £100,000 (GBP)
Organisation Agricultural and Horticulture Development Board 
Sector Public
Country United Kingdom
Start 01/2014 
End 12/2015
 
Title Integration of national TB testing data with cattle pedigree and performance data 
Description Nationally collected TB testing results have been integrated into the national genetic evaluation systems for dairy cattle such that the genetics of TB resistance/tolerance in the national herd can be studied as part of the BBSRC Animal health Club research project 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact Given the system has been developed to integrate with national genetic evaluation systems when the research is completed it is likely to ease the implementation of results for the UK dairy industry - with relevant permissions. 
 
Title Update of TB Advantage to include cow genotytpes in the reference population 
Description AHDB were awarded ~£350,000 to genotype 10,000 cows and 1000 bulls in the TB affected area to add to the reference population for calculation of SNP effects. This also allows us to consider using the 1-step approach which provides greater prediction accuracy. 
Type Of Material Improvements to research infrastructure 
Year Produced 2019 
Provided To Others? No  
Impact accuracy of prediction for TB resistance rises from about 40% to about 54% (depending on the information content for the animal). This has been considered by the EGENES technical advisory group (TAG) and will be rolled out to farmers later in 2019 after AHDB knowledge exchange officers have publicised it. 
 
Title TB Project Genotyping Results 
Description Raw SNP data and ancillary files from genome wide association studies on bovine tuberculosis BBSRC funded projects: CEDFAS initiative grants BB/E018386/1 and BB/E018335/1 and 2; Animal Health Research Club grant BB/L004054/1; Institute Strategic Programme Grants (ISP3 Innate Immunity & Endemic Disease) [BB/J004227/1], (ISP1 Analysis and Prediction in Complex Animal Systems) [BB/J004235/1] and (ISP2 Control of Infectious Diseases) [BB/P013740/1]. Abstract Holstein-Friesian raw SNP data. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Dataset related to publication: 5. Wilkinson, S., Bishop, S.C. Allen, A.R., McBride, S.H., Skuce, R.A., Bermingham, M., Woolliams, J.A. and Glass, E.J. (2017) Fine-mapping host genetic variation underlying outcomes to Mycobacterium bovis infection in dairy cows. BMC Genomics, 18: 477. Dataset linked to Bermingham et al, 2014, Genome-wide association study identifies novel loci associated with resistance to bovine tuberculosis. Heredity, 112, 543-551. 
URL https://www.research.ed.ac.uk/portal/en/datasets/liz-glass-tb-project-genotyping-results(7aa9bca3-a0...
 
Description Collaboration relating to genetics of bovine tuberculosis 
Organisation Agri-Food and Biosciences Institute
Country United Kingdom 
Sector Public 
PI Contribution Secured two rounds of grant funding from BBSRC. Expertise in genome wide association studies.
Collaborator Contribution Epidemiology of bovine TB and data and samples from cases and controls to genotype and analyse.
Impact Multi-disciplinary: AFBI: epidemiology; bovine TB expertise; data analysis; surveillance Roslin: genetics; GWAS; genotyping; immunogenetics; innate immunity; host-pathogen interactions Outputs: See BB/E018335/1 and BB/E018335/2; BB/L004054/1; BB/L004119/1 Publications: Bermingham ML, Handel IG, Glass EJ, Woolliams JA, de Clare Bronsvoort BM, McBride SH..Bishop SC. (2015). Hui and Walter's latent-class model extended to estimate diagnostic test properties from surveillance data: a latent model for latent data. Scientific reports, pp. 11861 Bermingham ML, Bishop SC, Woolliams JA, Pong-Wong R, Allen AR, McBride SH..Glass EJ. (2014). Genome-wide association study identifies novel loci associated with resistance to bovine tuberculosis. Heredity, 112 (5), pp. 543-51 Tsairidou, S. Woolliams, J.A., Allen, A.R., Skuce, R.A., McBride, S.H., Wright, D.M., Bermingham, M.L., Pong-Wong, R., Matika, O., McDowell, S.W., Glass, E.J., Bishop, S.C. Genomic prediction for tuberculosis resistance in dairy cattle (2014) PLoS ONE, 9, e96728. doi:10.1371 Tsairidou S, Woolliams JA, Allen AR, Skuce RA, McBride SH, Wright DM..Bishop SC. (2014). Genomic prediction for tuberculosis resistance in dairy cattle. PloS one, 9 (5), pp. e96728
Start Year 2006
 
Description Data transfer from DARDNI (DEARA) 
Organisation Department of Agriculture and Rural Development (DARDNI)
Country United Kingdom 
Sector Public 
PI Contribution We engaged with this department to agree file transfer formats and protocols for NI TB data pertinent to the calculation of TB Advantage EBVs. It is anticipated that these additional data will allow new bulls to get TB Advantage EBVs and will add to the accuracy of existing bulls with daughters in both GB and NI. Our team has been merging these animal records into the routine calculation of TB Advantage by EGENES
Collaborator Contribution The other partners (AFBI) were supportive of the process and assisted in shaping the proposition to DARDNI at the annual workshops
Impact The outcome is that we now have additional data from cows in NI that have bTB records. The data has been received, stored, validated, merged, cleaned, salvaged and the processes all automated by EGENES. The next steps expected over the new few months is to quantify the impact of additional data on TB Advantage and then release new EBVs. This will include higher accuracy EBVs for bulls with existing EBVs and EBVs for bulls with daughters only in NI. Subsequently, an assessment of the impact of additional data on the accuracy of genomic predictions will be made.
Start Year 2016
 
Description UK and Ireland TB resistance workshop 
Organisation Department For Environment, Food And Rural Affairs (DEFRA)
Country United Kingdom 
Sector Public 
PI Contribution We have produced breeding values (TB Advantage) that are now being used by the industry. The production of those gEBVs was through another project funded by AHDB Dairy but the outcomes have been used in this project to identify bulls for sequencing and for GWAS analyses. These gEBVs have been warmly received by industry and have been accepted by Defra as a useful addition to the toolbox for tackling TB
Collaborator Contribution Defra have agreed to fund APHA (internally) to provide continuous BCMS and TB data to allow us to continue producing gEBVs for the next 4 years at least.
Impact The outcomes are a closer relationship between the project and government on a genetic component to the national TB eradication plan
Start Year 2016
 
Description UK and Ireland TB resistance workshop 
Organisation Department of Agriculture and Rural Development (DARDNI)
Country United Kingdom 
Sector Public 
PI Contribution as before for Defra
Collaborator Contribution DARDNI keep records similar to BCMS and APHA. Currently, these data do not contribute to UK EBVs for TB resistance but following the workshop, we are now discussing how to get Northern Ireland data into the UK system of evaluations.
Impact None yet but it is expected to yield results in 2016.
Start Year 2016
 
Description UK and Ireland TB resistance workshop 
Organisation Government of Scotland
Country United Kingdom 
Sector Public 
PI Contribution We produce national genetic and genomic evaluations that rely on all UK data on cattle. Some of those animals originate in Scotland or end up in Scotland. Whilst there is no TB in Scotland, the availability of UK wide gEBVs for this trait provides selection options for Scottish Farmers
Collaborator Contribution TB evaluations rely on all UK data and Scottish data for CTS is held by BCMS. SG approval is needed to utilise these data and was given for continued use of the data for the purpose of national evaluations for TB resistance.
Impact The main outcome of SG involvement formally is that we now have approval for all devolved administrations for the use of national data in TB evaluations
Start Year 2016
 
Description UK and Ireland TB resistance workshop 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution as before for Defra
Collaborator Contribution as before for Defra
Impact HCC were one of the original funders to previous work that showed UK national data could be used for TB genetic evaluations (along with Defra). That work directly resulted in our ability to create the impacts we have through this project.
Start Year 2008
 
Description UK and Ireland TB resistance workshop 
Organisation Teagasc
Department Teagasc Food Research Centre
Country Ireland 
Sector Academic/University 
PI Contribution as for Defra but including the exchange of TB genetic evaluations for comparison with similar breeding values produced on Irish data. This creates sanity checking of results across country and provides confidence in use and outcomes.
Collaborator Contribution Teagasc contributed to the workshop by presenting results from Ireland and subsequently by exchanging genotypes with EGENES to add sires to the UK reference population for TB.
Impact A direct outcome is that the UK reference population increased by around 90 bulls (increase of about 5%) but these bulls were very informative. Increased interaction with Ireland on TB research has resulted.
Start Year 2015
 
Description Bovine TB Resistance & Genetics Workshop; Belfast November 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Following the success of the Workshop that the team ran in November 2015 in Cardiff, this was the second 2 day workshop on genetic improvement for bovine tuberculosis (bTB)resistance. The aim of the workshop was to discuss the genetics of bTB and breeding for bTB resistance between academic researchers, industry and government officials. attendees came from England, Northern Ireland and the Republic of Ireland and included representatitives from DEFRA, DAERA, AFBI, BBSRC and the Knowledge Transfer Network. The first day of the workshop discussed the current situation in England, Wales and Northern Ireland as well as Ireland; scientific advances in the genetics of bTB in dairy cattle as well as genetic evaluations for bTB resistance in UK and Ireland. The plan to sequence high and low risk sires for bTB resistance was presented. A new topic was discussed that of infectivity and the potential to combine selection for infectivity and susceptibility. The uptake of bTB resistance EBVs through AHDB as "TB Advantage" index was discussed. Future research priorities, including the potential impact of selection on economics and health and welfare of cattle in the dairy industry, potential for EBVs for bTB for beef breeds, interaction with other traits including Johne's disease and sharing of data were also discussed. The workshop further fostered dialogue between government officials, academics and industry on tackling bTB and was found to be useful and informative by all.
Year(s) Of Engagement Activity 2016
 
Description Bovine TB Resistance & Genetics Workshop; Cardiff November 2015 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact The project team organised a 2 day workshop on bTB resistance held in 18-19 November 2015, Cardiff, UK. The aim of the workshop was to discuss the genetics of bTB and breeding for bTB resistance between not just academic researchers, but also importantly industry and government officials. Attendees included academics from United Kingdom, Northern Ireland and the Republic of Ireland and DEFRA, AFBI and representatives from the Welsh Government, BBSRC. The first day of the workshop involved a series of presentations from academics detailing the latest research results on the genetics of bTB resistance and officials describing the current situation on bTB prevalence across parts of the UK and ROI. The second day of the workshop started with presentations on the publications of EBVs for bTB resistance followed by a round-table discussion on bTB issues. Overall, it was shown that a genetic strategy to reduce bTB prevalence is a feasible option and this message was well received and supported. Concerns on the impact of breeding for bTB resistance on response to the tuberculin skin test were discussed. In addition, there were discussions on future directions of research on bTB genetics. The workshop fostered dialogue between government officials, academics and industry on tackling bTB and was found to be useful and informative by all.
Year(s) Of Engagement Activity 2015
 
Description Magazine article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact I wrote an article on selection for TB resistance for Country Life.
Year(s) Of Engagement Activity 2015
URL http://www.countrylife.co.uk/publication/country-life/country-life-march-18-2015
 
Description New phenotypes for new traits 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact I presented a talk to farmers, vets, industry stakeholders, industry influencers at the AHDB DIG conference held at Nottingham on Feb 1/2. I included TB Advantage and the benefits to industry and society.
Year(s) Of Engagement Activity 2016
 
Description Presentation at the Edinburgh Alliance for Complex Trait Genetics meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The presentation took place on March 9, 2016, and focused on the new genetic and genomic evaluation system for bovine Tuberculosis. The event was attended by approx. 100 Edinburgh-based scientists and international visitors at the time.
Year(s) Of Engagement Activity 2016
 
Description Radio interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I was interviewed by Radio 4 Farming Today programme on the impending release of TB Advantage and the benefits of selection for TB resistance.
Year(s) Of Engagement Activity 2015
 
Description Visit to Defra 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact I attended a meeting with a Defra official to update on a number of issues relating to the current grant and how to extend the reach of the project. We discussed a new proposal to AHDB to extend TB Advantage as applied in dairy cattle to beef. We also discussed a proposition we had previously made to Defra on how the results of this project might be greater through targeted genotyping of specific bulls and through more widespread genotyping of cows from herds with high prevalence of bTB.
Year(s) Of Engagement Activity 2017
 
Description Wellcome Trust Board of Governors and Executive Board 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact The Wellcome Trust's Board of Governors and Executive Board visited Edinburgh University including the Roslin Institute on 19/20 September. The Post-doc on this grant, Samantha Wilkinson, Smaragda Tsairidou and Adrian Mwonge presented a joint poster on their work on various aspects of bovine TB host genetics, epidemiology and the detection test characteristics.
Year(s) Of Engagement Activity 2016
 
Description visit to Defra 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact a workshop with Defra officials to inform on the results of the DairyCo project and how that fits into the BBSRC project of genomics of TB.

As a result, we now have access to UK BCMS and TB data every 6 months and are in active dialogue with government officials on the use of national government data for research purposes and importantly for impact.
Year(s) Of Engagement Activity 2014