Aetiopathogenesis and genomic architecture of resistance to claw horn disruption lesions in dairy cattle

Maintaining good foot health is one of the most critical challenges the dairy industry faces today. This is because poor foot health leads to reduced mobility of the animal and causes lameness. The latter is a debilitating and painful condition, and is described as one of the clearest indicators of compromised welfare in dairy cattle and one of the most important factors for the involuntary replacement of animals. No other common condition is associated with such visible signs of pain and, as such, cow lameness damages the public's perception of the industry. Recent studies have suggested that nearly half the dairy cows in the UK face reduced mobility and lameness issues at some point in their life, costing the dairy sector approximately £250 million annually.

Painful foot lesions account for more than 90% of reduced cow mobility and lameness cases. These lesions broadly fall under two categories: infectious diseases such as digital dermatitis and interdigital phlegmon, and non-infectious claw horn disruption lesions (CHDL) such as sole haemorrhages, sole ulcers and white line disease. CHDL are the most prevalent conditions associated with impaired mobility and pain in dairy cattle in the UK and worldwide. In a recent study by our group, 44% of cows developed CHDL during 12 months of monitoring (26%, 12% and 19% for sole haemorrhages, sole ulcers and white line disease, respectively).

Despite the importance of CHDL, the reasons leading to their development have not yet been fully described. The anatomic structure of the foot, animal hormonal and immune profiles, inflammation around calving, animal metabolism, and management practices have been thought to contribute. There are also genetic differences between individual animal susceptibility to CHDL development. In this project, all these factors will be studied together using a large number of animals (3,000 Holstein cows) raised in four UK commercial farms. As a result, the project will (i) determine and quantify the impact of different factors affecting the development of CHDL, (ii) identify and quantify the genetic background of animal resistance to the development of CHDL and (iii) develop practical breeding strategies and tools to reduce the incidence of CHDL while maintaining improvement in other important animal traits (fertility, resistance to other diseases and productivity). To achieve its objectives, the project will draw on complementary expertise in animal science, veterinary medicine, genetics, biotechnology, bioinformatics, molecular pathology, immunology, microscopy and epidemiology.

Animals recruited for this project will be pregnant cows. The farms where these animals are raised have already been identified and have agreed to participate. Animals will be closely monitored by a qualified veterinarian from 60 days before calving through to the first half of the ensuing lactation. Systematic recording of CHDL, the thickness of the digital cushion (a protective anatomical structure of the foot), hormonal levels in blood, specific proteins in blood and tissues indicative of inflammation, acid levels in blood indicative of altered metabolism, and cow activity and resting patterns will take place, generating a unique database of relevant information. Individual cattle genomic profiles will be generated and analysed together with cow measurements to assess the environmental and genetic impact on CHDL. Using advanced sequencing technologies will try to understand the underlying molecular mechanisms that lead to the development of foot lesions. Finally, simulation studies will be designed to evaluate different breeding strategies and tools with the aim to breed resistance to CHDL into the dairy cattle population.

Outcomes of this project may improve considerably animal health and welfare by underpinning the development of efficient management practices, new breeding tools and novel pharmaceutical interventions.

The project will (i) determine and evaluate factors affecting the development of claw horn disruption lesions (CHDL) in dairy cattle; (ii) identify genomic markers (SNPs) and regions associated with animal resistance to CHDL development; (iii) identify and characterise causal genes and regulatory regions underlying pathways and networks associated with CHDL; (iv) develop and evaluate breeding tools and strategies for enhanced animal resistance to CHDL while at the same time improving other important dairy cattle traits. The study will involve 3,000 pedigree Holstein cows. Animals will be repeatedly examined by a qualified veterinarian for CHDL. In addition, mobility and foot conformation scores, digital cushion thickness, body condition score, claw temperature and backfat thickness will be recorded along with environmental temperature and animal activity and resting patterns. Blood levels of hormones, immuno-modulating cytokines, non-esterified fatty acids and beta-hydroxybutyric acid will also be measured. Statistical analysis of all these data, using mixed models, will reveal the impact of foot structure and anatomy, periparturient hormonal profile and inflammatory status, fat mobilisation and metabolic stress, and environmental and management conditions on CHDL. Interactions among factors will be also assessed. All animals will have genome-wide genotypes generated to identify SNPs and genomic regions associated with CHDL. Additive and dominance effects of significant SNPs and genomic heritabilities will be derived. Whole-genome sequencing and RNA-sequencing results on a subset of animals with extreme phenotypes and genotypes will be combined with pathways analyses and functional interpretation to reveal the underlying molecular mechanisms of CHDL development. All results will inform simulation studies to assess breeding strategies and tools (including a trait-specific SNP array) to enable breeding for resistance to CHDL development.

Compromised foot health leads to pain, reduced cow mobility and lameness, and constitutes a major welfare issue in dairy cattle. Painful lesions such as those disrupting the claw horn of the foot account for 90% of cases, represent the primary reason for veterinary interventions and lead to involuntary culling of affected animals, thereby posing serious threats to the sustainability and profitability of dairy farms. Many consider that lameness is currently the most significant welfare issue affecting dairy cattle in the UK because of the level of discomfort caused, the number of animals affected and the average duration of clinical episodes. Furthermore, studies have shown a significant adverse effect of lameness on milk yield both before and after a cow is diagnosed as lame that can last up to nine months. The total current cost to the UK dairy sector is estimated at £250 million or higher annually.

This project proposes a holistic approach to identify the key factors leading to the development of claw horn disruption lesions (CHDL). The project will develop a unique veterinary database and will combine complementary scientific expertise in order to develop a thorough understanding of the aetiopathogenesis of CHDL, while also developing practical knowledge and tools that can be used in genetic improvement programmes. Envisaged benefits from the outcomes are expected to apply at multiple levels:

1. Early identification of animals prone to development of CHDL will assist selection and replacement strategies, and minimise animal suffering.

2. Dairy farmers will directly benefit from reduced incidence of CHDL leading to decreased cost of involuntary culling. More animals will then be available for selection to improve productivity and other important traits. Fewer foot health problems will also signify enhanced animal welfare.

3. The dairy industry will benefit from advances and optimisation of genetic improvement programmes brought about by outcomes of the project. Currently, the economic benefits of genetic improvement in the UK exceed £100 million/year; about half of this is being realised by improvements in cow health and longevity. Project results will enhance animal health and welfare, and underpin the sustainability of the sector.

4. Improved health and welfare of the milking cows will enhance the public profile of dairy products and, eventually, the image of the sector and acceptability by consumers.

5. Benefits in the dairy industry will permeate the entire food producing animal sector, where outcomes from this project could be used as models for other relevant activities.

6. Environmental benefits are expected to accrue because of the reduced number of on-farm replacements necessary to replace cows culled due to poor foot health. On-farm replacements currently account for nearly one third of the methane produced by dairy cattle.

7. Policy makers and government could use outcomes and evidence from this project in the formulation and regulation of actions aiming at enhancing animal welfare and the social acceptability and environmental image of the livestock sector.

8. Identification of key mechanisms involved in the pathogenesis of CHDL may lead to specific targeting of inflammatory mechanisms to improve foot health and be of interest to the pharmaceutical industry.

9. Scientific benefits in the form of publications, presentations and collaborations are anticipated. Staff involved in the project will receive training and develop scientific and professional skills in laboratory, computational and numerical analyses.

10. The UK economy as a whole will benefit through the links between the scientific partners in the project and industry, ensuring quick uptake and implementation of the research results, contributing to enhanced farm output, health and living standards.

This is a 3-year grant but benefits from the outcomes are expected to continue long after the completion of the project.