Integrative genomics sheds light on the immunogenetics of tuberculosis in cattle

Mycobacterium bovis causes bovine tuberculosis (bTB), an infectious disease of cattle that represents a zoonotic threat to humans. Research has shown that the peripheral blood (PB) transcriptome is perturbed during bTB disease but the genomic architecture underpinning this transcriptional response remains poorly understood. Here, we analyse PB transcriptomics data from 63 control and 60 confirmed M. bovis infected animals and detect 2,592 differently expressed genes perturbing multiple immune response pathways. Leveraging imputed genome-wide SNP data, we characterise thousands of cis¬-expression quantitative trait loci (eQTLs) and show that the PB transcriptome is substantially impacted by intrapopulation genomic variation during M. bovis infection. Integrating our cis-eQTL data with bTB susceptibility GWAS summary statistics, we perform a transcriptome-wide association study and identify 132 functionally relevant genes (including RGS10, GBP4, TREML2, and RELT) and provide important new omics data for understanding the host response to mycobacterial infections that cause tuberculosis in mammals. Peripheral blood RNA-seq was extracted from a cohort of control and bovine tuberculosis (bTB) reactor animals to conduct a differential expression, expression quantitative trait loci and transcriptome wide association study to identify differentially expressed genes between the two groups, to characterise genomic variants associated with variability in mRNA transcript abundance and to identify genes with expression patterns correlated with bTB infection

牛分枝杆菌（Mycobacterium bovis）可引发牛结核病（bTB），这是一种可对人类构成人畜共患病威胁的牛类传染病。已有研究证实，牛结核病感染期间宿主外周血（PB）转录组会出现紊乱，但支撑该转录应答的基因组结构仍有待深入解析。本研究对63例健康对照动物与60例确诊牛分枝杆菌感染动物的外周血转录组学数据进行分析，共检测到2592个差异表达基因，这些基因可扰动多条免疫应答通路。本研究利用填充后的全基因组单核苷酸多态性（SNP）数据，对数千个顺式表达数量性状位点（eQTLs）开展特征解析，并证明牛分枝杆菌感染期间，种群内基因组变异可对宿主外周血转录组造成显著影响。本研究将顺式eQTL数据与牛结核病易感全基因组关联研究（GWAS）汇总统计量相结合，开展转录组全基因组关联分析，最终鉴定出132个功能相关基因（包括RGS10、GBP4、TREML2及RELT），为解析宿主对引发哺乳动物结核病的分枝杆菌感染的应答机制提供了重要的新型组学数据。本研究从健康对照与牛结核病（bTB）反应阳性动物队列中提取外周血RNA测序（RNA-seq）数据，旨在开展差异表达分析、表达数量性状位点分析及转录组全基因组关联研究，以鉴定两组间的差异表达基因、表征与mRNA转录本丰度变异相关的基因组变异，并筛选出表达模式与牛结核病感染相关的基因。