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

Lead Research Organisation: University of Liverpool
Department Name: Institute of Infection and Global Health

Abstract

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Technical Summary

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.

Planned Impact

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.

Publications

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Barden M (2023) Genetic parameters of sole lesion recovery in Holstein cows. in Journal of dairy science

 
Description Individual cow phenotypic, genotypic and pedigree data were collected on approximately. 2,500 cows in four herds. Multiple records were collected at different time-points in the cows' life and at the end the database included more than 10,000 phenotypic records. All animals were genotyped with a genome-wide DNA array. After imputation, 80,000 informative Single Nucleotide Polymorphism markers were retained in each genotype.

Data were analysed to examine the genomic background of claw horn disruption lesions (CHDL) development and severity, as well as of digital cushion thickness, a foot structure trait.

Analyses conducted have attested to the presence of considerable genetic variation in the studied CHDL traits. Depending on the lesion and time-point of measurement, trait heritability estimates ranged from 0.06 to 0.21 for susceptibility, 0.04-0.26 for severity, and around 0.24 for recovery. The range and magnitude of these estimates are as expected for health-related traits. The low to moderate heritability values reflect substantial environmental variance, which is expected in the commercial dairy cattle population. Nevertheless, genetic variance, reflecting inherent differences among individual animals, was present and significant suggesting that there is potential to identify and select breeding animals with an enhanced capacity to withstand and/or successfully cope with CHDL. This was corroborated by the examination of estimated Genomic Breeding Values of individual cows and their sires that illustrated the differences between desirable (resistant) and undesirable (susceptible) animal genotypes. All these results were published in the scientific literature.

Heritability of digital cushion thickness was between 0.12 and 0.31, and its estimated genetic correlation with lesion severity was moderate and significant (between -0.21 and -0.25) suggesting that no or milder lesions may be expected for animal with genetically thick and robust digital cushion. This result has also been published.

In addition, the current genetic evaluation for foot health, termed by the industry as the lameness advantage index, was analysed jointly with project data, and found to be associated with CHDL. Therefore, this index is recommended to be considered in herds aiming to reduce lameness. These results were published.

Genomic association analyses also took place to examine the association of genomic markers and regions with CHDL phenotypes. In general, these analyses revealed a largely complex, polygenic architecture of the studied traits. Nevertheless, there were certain markers and genomic regions with potentially larger effects on CHDL than others. Mapping results on the most recent bovine reference genome suggested that some of these regions harbour annotated genes known to be associated with the cows' innate immune function, inflammation, energy metabolism, and nervous system. Relevant results have been published in the scientific literature.
A subset of cows have had serum biomarkers for fat mobilisation (bhb and NEFAs) and hormonal profiles (relaxin and insulin) measured from stored serum samples. The inflammatory status, using serum concentrations of Interleukin 1-alpha, Interlukin-6 and Interleukin-10, has also been assessed in these cows. Blood Lipopolysaccharide has also been assayed. Analysis of this dataset together with measurements of foot structure and anatomy is ongoing and will lead to an improved understanding of CHDL aetiopathogenesis.
Furthermore, whole-genome sequencing, total RNA-seq and reduced representation bisulfite sequencing were performed on blood and foot biopsy samples on a subset of 24 animals with extreme phenotypes and genotypes, i.e., totally healthy vs. severely affected individuals. Twenty-five differentially expressed genes associated with CHDL were identified including genes involved in immune and keratin pathways. These results provide deep insights into the genetic architecture underlying CHDL and inform genetic improvement of CHDL resistance in dairy cattle. Results have been published.
Moreover, 30 differentially expressed long-non coding RNAs and 9896 differentially methylated genes associated with CHDL were identified providing further insights.
Interestingly, 5 of the differentially expressed genes were also differentially methylated in CHDL cases and controls.

Finally, simulation studies were conducted to assess breeding strategies to include results in genetic improvement programmes. Different scenarios were examined, with emphasis on CHDL in selective breeding ranging from 0 to 75% of the breeding goal. A useful balance of emphasis of 75% on cow productivity and 25% on CHDL resistance was revealed where the overall benefit is maximised
Exploitation Route Improvement of cows resistance to lameness through genetic selection. Findings regarding aetiopathogenesis are communicated to veterinarians and foot trimmers and could improve current practices and lameness control.
Sectors Agriculture, Food and Drink

 
Description Results regarding lameness genetics are being communicated to farmers and foot trimmers. We expect that this will lead to an increased interest in lameness genetics. Our follow up project (Utilising foot trimmers' records to inform genetic evaluations of resistance to lameness causing foot lesions in dairy cattle.) could further improve the accuracy of the UK lameness genetic evaluations.
Sector Agriculture, Food and Drink
Impact Types Societal,Economic

 
Description Deciphering the role of host-pathogen-microbiome interactions in the development of bovine digital dermatitis
Amount £128,264 (GBP)
Funding ID 2599436 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2021 
End 09/2025
 
Description Integrating clinical, data-driven and in-vitro approaches to the study of host-pathogen interactions in bovine digital dermatitis
Amount £434,929 (GBP)
Funding ID BB/X008762/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2023 
End 03/2026
 
Description Utilising foot trimmers' records to inform genetic evaluations of resistance to lameness causing foot lesions in dairy cattle.
Amount £56,254 (GBP)
Organisation Agricultural and Horticulture Development Board 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2021 
End 03/2022
 
Title Lameness phenotypes 
Description Over an eight-month period, 2,353 Holstein cows were enrolled on four dairy farms in the United Kingdom. Animals were assessed at four timepoints: prepartum (average: 56 days prepartum); freshly calved (average: 5 days postpartum), early lactation (average: 84 days postpartum) and late lactation (average:182 days postpartum). At each timepoint feet were inspected by a trained veterinarian and all lesions present were recorded and scored by severity. These animals were also genotyped with the use of a bovine 50k SNP chip. At the same time-points ultrasound images of animals claws were collected and stored. These images have now been analysed and several important measurements have been added to our database (thickness of the digital cushion at two locations, sole thickness). This database consisting of detailed and accurate phenotypic records regarding lameness causing foot lesions and genotypes is unique worldwide and will eventually be made available to the scientific community (project/ data collection ongoing). 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? No  
Impact Will eventually lead in an improved understanding of the aetiopathogenesis and genetic architecture of resistance to lameness causing foot lesions. Will be made available to the scientific community. 
 
Description Can we breed our way out of lameness? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A series of face to face meetings with farmers and foot trimmers. New findings on lameness genetics were communicated. Participants were also informed about the new project funded by AHDB and BBSRC (Utilising foot trimmers' records to inform genetic evaluations of resistance to lameness causing foot lesions in dairy cattle).
Year(s) Of Engagement Activity 2022
 
Description Controlling digital dermatitis in dairy herds; current thinking and latest research findings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk for dairy farmers, vets and dairy consultants (Total Dairy). Communication of recent research findings.
Year(s) Of Engagement Activity 2021
 
Description Keynote presentation at World Buiatrics Congress 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Two keynote presentations on cattle lameness that communicated our research findings to an international audience of cattle veterinarians.
Year(s) Of Engagement Activity 2022
 
Description Talk and workshop delivered to Spanish foot trimmers and veterinarians. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Research findings were communicated to foot trimmers and cattle veterinarians in Spain.
Year(s) Of Engagement Activity 2023
 
Description Update of undergraduate and post graduate teaching 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Project PI (Prof Oikonomou) is responsible for cattle lameness teaching at the University of Liverpool (undergraduate and postgraduate teaching). Lectures and teaching material have been updated and improved as a result of this ongoing research project.
Year(s) Of Engagement Activity 2020,2021
 
Description Webinar for foot trimmers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Relevant research findings were communicated to professional foot trimmers. Importantly foot trimmers were made aware of the University of Liverpool's effort to create a national database with foot trimmer records. UK based foot trimmers learned about how they can contribute their data to this project.
Year(s) Of Engagement Activity 2021
URL https://youtu.be/3uM8oLQAJZY