Genome-wide mapping and identification of genes controlling resistance to Marek's Disease virus infection in commercial layer chickens

商业蛋鸡马立克氏病病毒感染控制基因的全基因组图谱和鉴定

• 批准号: BB/K006916/1
• 负责人: David Burt
• 金额: $ 81.19万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK006916%2F1
• 关键词: Genome; wide; mapping; identification; genes

Marek's Disease (MD) is caused by a highly contagious virus (MDV), which is a continuing threat to our global poultry industry and food security with estimated losses of £1-2 billion per year. These losses are associated with the cost of the disease, due to increased mortality, escalating vaccination costs and reduced egg production. It is therefore a disease that has an impact on our economy and ability to compete internationally, with additional concerns for animal health and welfare, and our global food security. Although it has been controlled by vaccination for over 40 years, there is growing evidence from researchers that intensive use of vaccines is driving the virus to have an increasing ability to kill poultry, with more aggressive strains of the disease continuing to emerge each year.An alternative means to control this disease is being sought through breeding birds with enhanced resistance to MDV. Such differences were first reported nearly 80 years ago. Subsequently, genes associated with the major histocompatibility complex (MHC), which plays an important role in the immune system, were shown to contribute towards resistance to MDV. Despite this, other genes also have a strong influence on MDV resistance. This has been determined most effectively from studies using inbred strains of chickens that have identical MHC but still show differences in their susceptibility towards MDV.Many chromosomal regions that control MDV resistance have been defined (quantitative trait loci, or QTL) but very few genes have been verified as controlling the host response towards this disease, which is typical for most complex traits. Those which have been identified include growth hormone (GH1), the cytokine SCYC1 and the cell surface marker on lymphocytes LY6E. Identifying genes involved in resistance (or susceptibility) to MDV and resolving their role is crucial to understanding this disease and why it appears to becoming more fatal. This knowledge is important; providing the means to control and reduce this threat to the poultry industry.This proposal is extremely timely in that we now have at our disposal many new research tools which may enable us to identify genes involved in resistance to MD infection. These include QTL data, access to MDV challenge facilities, genomic sequences of chicken lines, a large QTL high resolution mapping population (now in its 6th generation) based on parents differing in their resistance to MDV and a panel of 600K SNPs (single nucleotide polymorphisms - genetic markers) which can be used together to fine map Marek's Disease QTL to high resolution to genomic regions containing around 25 genes. This, in conjunction with high throughput sequencing and bioinformatics approaches, will allow us to not only predict candidate genes for MD resistance but also possible causative mutations within these genes.We also have available to us all the MDV proteins cloned into suitable vectors for testing in 'yeast-2-hybrid' experiments for direct protein/protein binding between viral and host proteins. In this way we will be able to identify genes which bind directly with viral proteins and then go on to test whether mutations within these genes alter any binding interactions.In this proposal we aim to determine the chromosomal regions that play a role in MD resistance in commercial egg-layers, identify genetic variation within candidate genes, explore direct protein binding interactions between host and viral proteins, and examine the functional consequences of genetic variation in these genes.The outcome of this project will be the identification and characterization of valuable genetic markers in commercial egg-layer lines for use in selective breeding programs within the poultry industry, which would result in large economic and health benefits. This comes at a time when there are renewed pressures on the poultry industry as the world population expands and concerns over food security increase.

马立克氏病（MD）是由一种高传染性病毒（MDV）引起的，它对全球家禽业和粮食安全构成持续威胁，估计每年损失10 - 20亿英镑。这些损失与疾病的成本有关，因为死亡率增加，疫苗接种成本上升和产蛋量减少。因此，这是一种对我们的经济和国际竞争能力产生影响的疾病，对动物健康和福利以及我们的全球粮食安全产生了额外的担忧。尽管40多年来一直通过接种疫苗来控制该病，但越来越多的研究人员发现，疫苗的大量使用正在使该病毒对家禽的杀伤力不断增强，每年都有更具攻击性的毒株出现。目前正在寻找一种控制该病的替代方法，即通过饲养对MDV具有增强抵抗力的鸟类。这种差异在近80年前首次被报道。随后，与在免疫系统中起重要作用的主要组织相容性复合体（MHC）相关的基因被证明有助于对MDV的抗性。尽管如此，其他基因也对MDV抗性有很大影响。这已经确定最有效的研究，使用近交系的鸡，具有相同的MHC，但仍然显示出差异，他们对MDV的易感性。许多染色体区域，控制MDV抗性已被定义（数量性状基因座，或QTL），但很少有基因已被验证为控制宿主对这种疾病的反应，这是典型的最复杂的性状。已经鉴定的包括生长激素（GH 1）、细胞因子SCYC 1和淋巴细胞上的细胞表面标记物LY 6 E。鉴定与MDV抗性（或易感性）有关的基因并解决它们的作用对于理解这种疾病以及为什么它似乎变得更加致命至关重要。这些知识很重要;提供方法，以控制和减少这种对家禽业的威胁。这项建议是非常及时的，因为我们现在有许多新的研究工具，可以使我们能够确定与抵抗MD感染有关的基因。这些包括QTL数据，MDV攻击设施的使用，鸡品系的基因组序列，QTL高分辨率作图群体（现在是第6代），基于对MDV抗性不同的亲本和一组600 K SNP（单核苷酸多态性-遗传标记），其可以一起用于将马立克氏病QTL精细定位到含有约25个基因的基因组区域的高分辨率。结合高通量测序和生物信息学方法，这将使我们不仅能够预测MD抗性的候选基因，而且还可以预测这些基因中可能的致病突变。我们还可以将所有MDV蛋白克隆到合适的载体中，用于在“酵母-2-杂交”实验中测试病毒和宿主蛋白之间的直接蛋白质/蛋白质结合。通过这种方式，我们将能够识别与病毒蛋白直接结合的基因，然后继续测试这些基因内的突变是否改变任何结合相互作用。在这个提议中，我们的目标是确定在商品蛋鸡的MD抗性中起作用的染色体区域，识别候选基因内的遗传变异，探索宿主和病毒蛋白之间的直接蛋白结合相互作用，本项目的成果将是鉴定和表征商业蛋鸡品系中有价值的遗传标记，用于家禽业的选择性育种计划，这将产生巨大的经济和健康效益。随着世界人口的增加和对粮食安全的担忧增加，家禽业面临新的压力。

项目成果

Chicken Genome: Current Status and Future Trends from Next Generation Sequencing

鸡基因组：下一代测序的现状和未来趋势

• 作者: David Burt (Author)

Avian Genomics: Current Status and Future Opportunities (Oxford Global 2014)

禽类基因组学：现状和未来机遇（Oxford Global 2014）

• 作者: David Burt (Author)

Poultry Genome: Implications for Immunity, Poultry Productivity and Health

家禽基因组：对免疫、家禽生产力和健康的影响

• 作者: David Burt (Author)

QTLs mapped by selective DNA pooling explain substantial proportion of phenotypic and genetic variation in MD mortality in chicken layer lines

通过选择性 DNA 合并绘制的 QTL 解释了蛋鸡品系 MD 死亡率中表型和遗传变异的很大一部分

• 发表时间: 2018
• 作者: Lipkin E

Avian Genomics: Current Status and Future Opportunities (SBZ)

禽类基因组学：现状和未来机遇 (SBZ)

• 作者: David Burt (Author)