Award details

Effect and interaction of mutation and recombination in the dynamics of genetic variation in modern chickens

Reference	BB/T005408/1
Principal Investigator / Supervisor	Dr Andreas Kranis
Co-Investigators / Co-Supervisors	Professor Michael Watson
Institution	University of Edinburgh
Department	The Roslin Institute
Funding type	Research
Value (£)	345,321
Status	Current
Type	Research Grant
Start date	30/04/2020
End date	29/10/2023
Duration	42 months

Abstract

The question of what determines the observed levels of genetic variation is central to quantitative genetics, yet it remains unresolved. According to theory, directional selection reduces this variation, yet observations from populations selected over a long time suggest that variation is largely maintained. This project aims to precisely estimate the effect of the forces generating (mutation), and modifying (recombination) genetic variation using a dataset comprising hundreds of thousands of chickens from a commercial breeding programme that are sequenced or genotyped. As in birds, there is evidence that mutation and recombination rates are higher than in mammals, focusing on these forces can help to explain how they counterbalance the effect of directional selection of reducing genetic variation. The overarching goal of the project is to reconcile the observed high levels of genetic variation with the theoretical expectations. To that effect, we will establish the rate and the variance explained by mutation as the force that creates new genetic variation using fully connected trios of sequenced animals spanning five generations on average. We will then phase all genotyped animals to estimate the recombination rate with high precision and pinpoint to the genetic architecture of its control. We will use recombination profiles to track haplotypes over fifteen generations to investigate and monitor how their preservation is related to changes in genetic variation. Finally, we will estimate the effect of selection on genetic variation and focus on specific genomic regions to monitor the changes in diversity with the ultimate objective to update theoretical expectations on where selection limits may lay. This project has clear potential in producing a step change in addressing fundamental questions in genetics and its outcomes can be applied across animals and plants to improve the resilience and sustainability of their genetic improvement programmes

Summary

Resolving how genetic variation is maintained in closed populations under directional selection is one of the fundamental, yet still open questions in quantitative genetics. Addressing this question has also vital implications for the sustainability of genetic improvement programmes that underpin global staple food production systems. Considerable research effort has focused on studying how selection reduces genetic variation and how its footprint can be identified in the genome. Little effort has been placed to study how genetic variation is de-novo created and shuffled across generations. The reason is that until now, it was not feasible to track mutation, the evolutionary force creating new genetic variation, on the large-scale that analysis required, due to technological and economic constraints. The only option available to geneticists was to rely on low precision estimates for the mutation rate, since they mostly arose from small scale studies in experimental populations. These parameters then would be used in models aiming to describe the dynamics of genetic variation, which were based on many theoretical assumptions due to lack of data on the observed rate of mutation. The uncertainty of the parameters used, combined with our limited understanding of the interplay of forces on genetic variation, reduce the power of our current models to capture the underlying processes and therefore, explain why "there is still no clear resolution on the evolutionary forces responsible for the maintenance of variation", as one of the gold standard textbooks in Quantitative Genetics (Lynch and Walsh, 2018) emphatically states. The main hypothesis of this proposal is that the rate of creation and shuffling of genetic variation can counterbalance the effects of selection, genetic drift and inbreeding in finite closed populations, such as the elite breeding populations. Our goal is to take a data-driven approach to quantify with unprecedented accuracy the mutation and recombination processes that could explain how genetic variation appears to be maintained in closed populations that are under intense directional selection. To achieve this aim, we will use a unique genomic repository consisting of hundreds of thousands of birds (either sequenced in high-depth or genotyped with SNP arrays) extending over 25 generations with full pedigree and phenotypic information to study how genetic variation is maintained over time. This dataset gives us the required power to precisely estimate important parameters, such as how many mutational events occur per generation, where they tend to occur across the genome, and how the new genetic variation due to mutation balances its removal. As our data extend over many generations, we will have the power to track both mutations and chromosomal segments through the pedigree in order to remove false positive observations that can inflate estimates. Our study will also focus on quantifying recombination, as the force shuffling genetic variation, and we will explore its interplay with mutation. Finally, we will apply our more precise estimates to update theoretical expectations on where selection limits may lay and thus we will aim to reconcile theoretical predictions and observations. Beyond the potential to address the key question of how genetic variation is maintained, our findings could be directly applicable across animal and plant breeding organisations to improve the resilience and sustainability of their genetic improvement programmes.

Impact Summary

This research underpins a variety of stakeholders in academic, commercial and public sector as outlined below. 1. The UK and international academic community. Scientists from both across and within disciplines such as: 1.1 Quantitative genetics and animal and plant breeding 1.2 Wider genetics and genomics community, including evolutionary, conservation and human genetics, genome biology, poultry science 1.3 Bioinformatics, Data Science and Computational Biology 2. Animal breeding companies and societies, and levy boards such as HolsteinUK, EFFAB 3. The entire broiler supply chain including multipliers, farmers, processors, retailers and consumers 4. Other livestock and plant supply chains, e.g. ducks, turkeys, salmon, dairy 6. Policy makers, including regulators, domestic and international development agencies (e.g. FAO) 7. Third sector such as organisations and charities for preserving endangered species 8. General Public Our research will drive future innovation and societal impact, by delivering benefits, including: 1. Field-advancing knowledge. This proposal aims to address previously intractable questions on the fundamental mechanisms involved in the maintenance of genetic diversity. We expect its outcomes, were to be successful, to precisely estimate and predict how frequent mutation and recombination are, where in the genome these are more likely to occur and how much they contribute to the maintenance of genetic diversity in chickens. 2. Applied research. Our approach could revolutionise breeding. With the improved understanding of the forces involved in the creation and shuffling of genetic diversity, it would be possible to refine control of gene flow to secure diversity without compromising genetic progress in order to balance short and long term benefits. 3.UK company productivity. This project has the potential to bring operational changes in breeding programmes and improve their efficiency. Thus, thiswill enable UK based breeding companies, such as Aviagen and Cherry Valley Farms to maintain their world leading position by strengthening their R&D investment and opening up new opportunities in the knowledge economy. 4. Initiate collaborations and strengthen the UK science base. We will strive to set a collaborative platform between breeding companies in different species and a UK-based research center that has pioneered the adoption of genomics in livestock. Successful outcomes of this project can drive a culture of open innovation and forge investment from the private sector and increase R&D capabilities in the UK, maintaining its scientific reputation and increased capability for sustainable agricultural production. 5. Sustainability and resilience of food supply chains. By better managing and exploiting their genetic resources, breeders will be able to accelerate genetic progress and tailor their products to meet the diverse requirements of their customers emanating from different environmental, market and societal conditions and adapt to ever changing conditions. Consequently, the downstream actors of the supply chain will directly benefit from higher quality products, which cost less, have smaller environmental footprint and are overall better suited to their individual requirements. Most importantly, the optimal utilisation of genetic resources in short-term selection will enhance the long-term sustainability of the supply chain. 6. Evidence based policy. Equipped with insights on management of diversity, policymakers can make informed decision influencing regulations. 7. Broader societal benefits including food security and environmental preservation, e.g. review protocols for conservation programmes to reflect the insights on the dynamics of diversity. 8. Training. The PDRA will be trained in a cutting edge area of research, while interacting with other scientists in a world-leading research environment.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	Animal Health
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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