The influence of selective breeding on MHC diversity.

Individuals differ in susceptibility to disease and much of the variation is genetic in origin. The collection of all the genes in an individual is known as the genome. Many different regions of the genome influence susceptibility to disease. One of the most important genetic regions is the major histocompatibility complex (MHC). This region contains genes that determine how the immune system recognises and responds to disease-causing foreign organisms.

Animal breeders want to identify genetically resistant animals and use these individuals to produce offspring with enhanced resistance to disease. This is difficult but could become easier if we could use the MHC. Evolution has produced a wide range of different genetic variants at the MHC and we want to manage this diversity to optimise disease resistance in livestock populations.

The purpose of this proposal is to identify the selective forces that maintain variation at the MHC using infection with parasitic roundworms in sheep as our test system. Parasitic roundworms are an important disease of livestock. The infection and disease process in sheep is one of the best understood of all diseases. We already know that the MHC plays an important role in resistance to roundworms and this system is therefore ideal to study how MHC variation influences resistance to disease.

We plan to quantify the selective forces that maintain the high variation at the MHC. We will use a population of sheep that has been selected for high levels of resistance to roundworm infections. We will compare the resistance to roundworms of individuals with different MHC genes using advanced statistical programs that remove all background variation and test whether the differences between individuals with different MHC alleles could have arisen by chance. We have already tested a Scottish population and know that there are two different effects involved. There are differences among genes. In addition most individuals have two different genes but some inherit two identical copies. Individuals with two different genes are more resistant than individuals with two identical copies of the same gene. We want to extend this analysis. We predict that some individuals with two different copies (say A and B) will be more resistant than individuals with another set of two genes (say C and D). In particular, an individual with a pair of similar genes will recognise fewer parasite molecules than an individual with a pair of dissimilar genes. Individuals that recognise more parasite molecules will more resistant to infection.

We then plan to examine the influence on MHC diversity of the selective breeding for disease resistance and production traits. There are many different ways to measure diversity but we plan to use a recently developed method that uses a mathematical formula to aggregate many different measures into a single diversity profile. We predict that overall, there will be no marked loss of MHC diversity as a consequence of selection for resistance to nematodes as well as increased meat and wool production. As individuals with two different alleles are more resistant, selection is expected to maintain diversity. In particular, we expect the frequency of heterozygotes to be maintained and we expect selection to increase diversity by favouring divergent alleles.

Finally we will mathematically model the process of selection to reproduce the effect of selection on MHC diversity. Once we understand how selection affects MHC diversity and how MHC diversity affects disease resistance we can create selection schemes to optimise the contribution of the MHC for resistance to disease.

Livestock industries are starting to use genomic breeding values (GEBV) to identify superior animals. Directional selection then increases the frequency of the genes that contribute to the GEBV. However, some polymorphisms are balanced and here directional selection could paradoxically increase disease susceptibility.

The most important genetic region contributing to disease resistance is the Major Histocompatibility Complex; this is the most variable region of the genome and this variation is maintained by balancing selection. However, we do not fully understand how balancing selection on the MHC works.

We have compared different forms of balancing selection by mathematical modelling and our preliminary results suggest that divergent allele advantage is the main driver of MHC polymorphism. The divergent allele hypothesis makes specific predictions about the behaviour of MHC alleles in response to selection for disease resistance. In particular, heterozygosity should be maintained although the frequency of individual alleles may change.

We propose to examine a flock of sheep that has been successfully selected for increased resistance to nematode infection. This flock of sheep contains 500 breeding ewes and has been selected for reduced faecal egg count over 25 years. We have access to DNA from the founder and current lamb populations and propose to test whether MHC genotype frequencies have changed in agreement with the divergent allele or alternative hypotheses.

Once we understand how selection maintains MHC diversity we will develop breeding schemes based that utilise MHC variation in a sustainable way to improve resistance to disease. These breeding schemes will utilise GEBV and incorporate all polymorphisms known to increase economically important traits including disease resistance and fertility. By replicating the selective forces that maintain MHC variation, we expect to increase disease resistance in a sustainable and effective way.

Sheep are an important source of food and contribute to global food security. Sheep suffer from a variety of diseases and profitable and humane farming demands the control of disease. Selective breeding for disease resistance offers a cost-effective and sustainable method to reduce the impact of disease. While this research will be conducted in sheep bred for resistance to nematodes, the use of mathematical models will extend the relevance to diseases of other livestock species, particularly cattle, goats, pigs, chicken and fish.

One constraint on selective breeding is the concern that selection for resistance to any given set of diseases may increase susceptibility to other diseases. Diversity at the MHC is key to this argument. Our research is therefore essential to understanding the basis of resistance/resilience to pests and diseases in farmed animal species.

The response to deliberate selection is governed by the same rules that determine the response to natural selection, although the selection objective and the selection intensity may differ. The MHC is the most polymorphic region in the mammalian genome. Therefore natural selection for disease resistance clearly maintains genetic variation at the MHC. Once we understand how natural selection achieves this we will develop breeding schemes that maximise the impact of the MHC on disease resistance. This research will develop novel tools for defining disease biomarkers and phenotypes to inform breeding strategies for subclinical diseases and increased disease resistance.

Farmers will benefit from healthier and more productive livestock while consumers will benefit from cheaper and safer food. In addition, industry will benefit from a healthier livestock sector and from the sale of genetic tests based on MHC and similar markers of superior resistance. We expect that selective breeding will be based on genomic breeding values and this research will allow the MHC to be incorporated into these schemes.