GCRF-BBR: A compendium of structural variation across African cattle breeds

Cattle are a vital component of the economies of low and middle income countries across the globe. They are a source of meat and dairy products, provide leather and other by-products and are often used as working animals. Cattle can be grazed where crops are not easily grown, provide manure as effective fertiliser and can convert forage into high-protein food. Often cattle are the most valuable possession individuals in low and middle income countries own, but are susceptible to a range of infectious diseases, which not only inflict a heavy economic burden on these countries but can also often be transmissible to humans.

Over two-thirds of the global cattle population are in low and middle income countries. Reducing the burden of cattle infectious diseases would consequently have major benefits to these areas. However for many diseases no vaccine or treatment is available. Where they are available, poor veterinary services generally mean the livestock keepers must pay for vaccines and treatments themselves. Consequently these diseases are major barriers to escaping poverty.

Due to the co-evolution of pathogens and cattle there are various examples of cattle breeds that show natural tolerance or resistance to important infectious diseases. Although these breeds are often less productive, making them less attractive to LMIC farmers, if the mechanisms underlying their resistance could be identified and harnessed, then breeds of both higher productivity and tolerance could be developed. Likewise certain breeds have been shown to be better adapted to particular environmental conditions. With certain breeds better able to tolerate extreme temperatures and limited access to feed and water for example.

Structural variants (SVs), large alterations in an animal's genome sequence, have been linked in livestock to adaptation to environments and natural tolerance to important diseases. Despite their potential value, little is currently known about the genome-wide location of SVs in cattle and almost nothing in African cattle breeds. Native African cattle are particularly well adapted to African environments and pathogens, with structural variants expected to underlie many such important traits. Knowledge of the location of structural variants in African cattle breeds will enable researchers to determine their functional consequences and develop better breeding programs. In this project we will develop a database of structural variants focused on African cattle breeds to enable studies of their role in shaping important phenotypes.

There is a range of cattle breeds in Africa that have co-existed with the local environment and pathogens for thousands of years, leading to adaptation and tolerance to local diseases, environments and resources. Notably some cattle breeds tolerate infection with pathogens that cause significant disease in others, while other breeds are drought or temperature tolerant. The exploitation of this valuable resource of natural tolerance has been lacking, but efforts are beginning to characterise the genetic diversity of cattle across these regions. To date the focus has been on using SNPs and short indels to map the locations of genomic loci linked to economically important phenotypes. This is in part due to the difficulty of determining the location of larger alterations from sequencing technologies, in particular in species such as the cow where the reference genome remains incomplete. However, the unique evolutionary history of the cow and current knowledge of the role of SVs in livestock phenotypes suggests larger genomic changes potentially underlie many of these important adaptation events. In this pilot study we propose to address this lack of knowledge on African cattle SVs and start compiling and making available a database of SVs across African breeds. This will enable subsequent studies of the roles of these SVs in important phenotypes, so that they can then be exploited in downstream breeding programs. Due to the relatively poor cow reference genome and limitations of technologies such as array CGH and high-throughput sequencing we propose to use optical mapping to characterise the spectrum of SV across important African breeds. We will then set up a browser interface for users to query and view SVs across breeds at different genomic locations to facilitate the mapping of SVs to phenotypes. The outputs of this project will significantly increase our knowledge base on LMIC cattle diversity and accelerate the potential of exploiting this valuable resource.

This pilot work and portal will enable downstream studies of the role of structural variants in shaping disease tolerance and environmental adaptation in African cattle. We therefore envisage a range of both short term and long term beneficiaries of this program of research.

- Enabling and interpreting genetic association studies

Primary beneficiaries in the short term will be academics investigating the resistance/tolerance of cattle infectious diseases and adaptation to the African environment. A public database of structural variation will both allow for SVs to be tested against key phenotypes but also inform the interpretation of genetic association and population genetic study results by providing candidate functional variants in relevant regions.

- Reduced burden of infectious diseases

The primary long term target beneficiaries of this work are livestock holders in low and middle income countries through enabling the identification and exploitation of genomic regions linked to disease tolerance and environmental adaptation. The annual cost of treating cattle with an acaricide for example (to reduce tick-borne diseases) has been estimated at $6-$36 per animal, with treatment of an infected animal costing approximately $38. The exploitation of functional SVs and development of naturally resistant and productive cattle breeds has the promise of dramatic economic benefits to LMIC farmers and in particular the rural poor.

- Environmental benefits

Current use of insecticides and acaricides have significant impacts on the environment and soil fertility. Reducing their use through understanding alternative mechanisms of reducing disease burden could therefore have substantial longer term environmental benefits. Furthermore exploiting SVs linked to drought tolerance and environmental adaptation could enable the development of less resource intensive, but productive breeds.

- Informing array development and improved genotyping

We expect this work to feed into the ongoing development of African-targeted bovine genotyping arrays/assays that would dramatically improve the ability to undertake GWAS for cattle traits on the continent. Importantly the identification of sites of SVs in LMIC cattle breeds is also expected to substantially improve genotype calling from sequencing data. Unknown structural variation is one of the largest sources of false positive variant calls.

- Training of LMIC researchers

In conjunction with BecA (Biosciences Eastern and Central Africa) we will use this resource in our ongoing training courses for African students and scientists. This will provide the resource for training programs targeted towards understanding the genetic adaptation of African cattle to pathogens and environment and the mechanisms underlying the poor performance of divergent European breeds in an African setting.

- Annotation of Indicine and African Taurine genomes

A major limitation of the current Hereford reference genome is not only its incomplete status but also the extent to which it represents African cattle breeds is unclear. These SVs will be used to inform accurate annotation of a new African taurine reference genome being generated as part of a separate GCRF funded project. This will provide an appropriately tailored and accurate resource for researchers working on these cattle sub-species and will maximise the impact and use of this genomic information. Importantly this resource is also likely to identify issues with the current reference assembly given its incomplete nature and the fact it is likely to contain erroneous rearrangements. Going forward we also expect this dataset to contribute to the generation of a genome graph representation of the cow genome.