Table_10_Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed.xls

African animal trypanosomiasis (AAT) is caused by a protozoan parasite that affects the health of livestock. Livestock production in Ethiopia is severely hampered by AAT and various controlling measures were not successful to eradicate the disease. AAT affects the indigenous breeds in varying degrees. However, the Sheko breed shows better trypanotolerance than other breeds. The tolerance attributes of Sheko are believed to be associated with its taurine genetic background but the genetic controls of these tolerance attributes of Sheko are not well understood. In order to investigate the level of taurine background in the genome, we compare the genome of Sheko with that of 11 other African breeds. We find that Sheko has an admixed genome composed of taurine and indicine ancestries. We apply three methods: (i) The integrated haplotype score (iHS), (ii) the standardized log ratio of integrated site specific extended haplotype homozygosity between populations (Rsb), and (iii) the composite likelihood ratio (CLR) method to discover selective sweeps in the Sheko genome. We identify 99 genomic regions harboring 364 signature genes in Sheko. Out of the signature genes, 15 genes are selected based on their biological importance described in the literature. We also identify 13 overrepresented pathways and 10 master regulators in Sheko using the TRANSPATH database in the geneXplain platform. Most of the pathways are related with oxidative stress responses indicating a possible selection response against the induction of oxidative stress following trypanosomiasis infection in Sheko. Furthermore, we present for the first time the importance of master regulators involved in trypanotolerance not only for the Sheko breed but also in the context of cattle genomics. Our finding shows that the master regulator Caspase is a key protease which plays a major role for the emergence of adaptive immunity in harmony with the other master regulators. These results suggest that designing and implementing genetic intervention strategies is necessary to improve the performance of susceptible animals. Moreover, the master regulatory analysis suggests potential candidate therapeutic targets for the development of new drugs for trypanosomiasis treatment.

非洲动物锥虫病（African animal trypanosomiasis, AAT）是由一种影响家畜健康的原生动物寄生虫引发的疾病。埃塞俄比亚的家畜养殖业因AAT遭受严重制约，且多种防控手段均未能成功根除该疾病。AAT会以不同程度侵害本土牛品种，但绍科（Sheko）牛品种展现出比其他品种更优的锥虫耐受性（trypanotolerance）。学界普遍认为绍科牛的耐受性特性与其普通牛（taurine）遗传背景相关，但目前对其耐受性特性的遗传调控机制仍不甚明晰。为探究其基因组中的普通牛血统占比，本研究将绍科牛的基因组与另外11个非洲牛品种的基因组进行比对，发现绍科牛拥有由普通牛和瘤牛（indicine）血统构成的混合基因组。本研究采用三种方法探究绍科牛基因组中的选择性清除信号：（1）整合单倍型得分法（integrated haplotype score, iHS）；（2）种群间整合位点特异性扩展单倍型纯合度的标准化对数比值法（standardized log ratio of integrated site specific extended haplotype homozygosity between populations, Rsb）；（3）复合似然比法（composite likelihood ratio, CLR）。本研究在绍科牛基因组中鉴定出99个基因组区域，共包含364个特征基因。研究人员依据文献中记载的生物学重要性，从上述特征基因中筛选出15个基因。本研究还借助geneXplain平台中的TRANSPATH数据库，在绍科牛中鉴定出13条富集通路与10个主调控因子（master regulators）。大部分富集通路均与氧化应激反应相关，这表明绍科牛可能在锥虫感染后针对氧化应激的诱导产生了选择应答。此外，本研究首次证实了参与锥虫耐受性调控的主调控因子不仅对绍科牛品种具有重要意义，同时也为牛基因组学研究提供了新的视角。本研究结果显示，主调控因子半胱天冬酶（Caspase）作为一种关键蛋白酶，与其他主调控因子协同作用，在适应性免疫的形成过程中发挥核心作用。上述研究结果表明，设计并实施遗传干预策略以提升易感家畜的生产性能是十分必要的。此外，主调控因子分析结果还为开发治疗锥虫病的新型药物提供了潜在的候选治疗靶点。