The influence of selective breeding on MHC diversity.

个体对疾病的易感性各不相同，许多变异源于遗传。个体所有基因的集合称为基因组。基因组的许多不同区域影响对疾病的易感性。一个最重要的遗传区域是主要组织相容性复合体（MHC）。这个区域包含决定免疫系统如何识别和应对致病外来生物的基因。动物育种者想要鉴定出具有遗传抗性的动物，并利用这些个体来生产具有更强抗病能力的后代。这很困难，但如果我们能利用MHC，就会变得更容易。进化已经在MHC上产生了广泛的不同的遗传变异，我们希望管理这种多样性，以优化牲畜种群的抗病能力。本提案的目的是利用绵羊寄生蛔虫感染作为我们的测试系统，确定维持MHC变异的选择力。寄生蛔虫是家畜的一种重要疾病。绵羊的感染和发病过程是所有疾病中最容易理解的。我们已经知道MHC在对蛔虫的抵抗力中起着重要作用，因此这个系统是研究MHC变异如何影响对疾病抵抗力的理想选择。我们计划量化维持MHC高变异的选择力。我们将选用一群对蛔虫感染具有高度抗性的绵羊。我们将使用先进的统计程序来比较具有不同MHC基因的个体对蛔虫的抗性，该程序可以消除所有背景变异，并测试具有不同MHC等位基因的个体之间的差异是否可能偶然产生。我们已经对苏格兰人口进行了测试，知道有两种不同的影响。基因之间存在差异。此外，大多数人有两个不同的基因，但有些人遗传了两个相同的拷贝。拥有两个不同基因的个体比拥有两个相同基因副本的个体更有抵抗力。我们想扩展这个分析。我们预测，一些拥有两个不同拷贝的个体（比如A和B）将比拥有另一组两个基因（比如C和D）的个体更具抵抗力。特别是，具有一对相似基因的个体将比具有一对不同基因的个体识别更少的寄生虫分子。识别出更多寄生虫分子的个体将更能抵抗感染。然后，我们计划研究抗病和生产性状的选择性育种对MHC多样性的影响。有许多不同的方法来测量多样性，但我们计划使用最近开发的一种方法，该方法使用数学公式将许多不同的测量方法汇总到单一的多样性概况中。我们预测，总体而言，不会因为选择抗线虫以及增加肉类和羊毛产量而导致MHC多样性的显著丧失。由于具有两种不同等位基因的个体具有更强的抗性，因此选择有望保持多样性。特别是，我们期望杂合子的频率保持不变，我们期望选择通过偏爱不同的等位基因来增加多样性。最后，我们将对选择过程进行数学建模，以再现选择对MHC多样性的影响。一旦我们了解了选择如何影响MHC多样性以及MHC多样性如何影响抗病性，我们就可以创建选择方案来优化MHC对抗病性的贡献。

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.