Wilkinson S, Bishop S C, Allen A R, McBride S H, Skuce R A, Bermingham M, Woolliams J A, Glass E J
The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush EH25 9RG, Edinburgh, UK.
Agri-Food and Biosciences Institute, Stormont, Belfast, Northern Ireland, BT4 3SD, UK.
BMC Genomics. 2017 Jun 24;18(1):477. doi: 10.1186/s12864-017-3836-x.
Susceptibility to Mycobacterium bovis infection in cattle is governed in part by host genetics. However, cattle diagnosed as infected with M. bovis display varying signs of pathology. The variation in host response to infection could represent a continuum since time of exposure or distinct outcomes due to differing pathogen handling. The relationships between host genetics and variation in host response and pathological sequelae following M. bovis infection were explored by genotyping 1966 Holstein-Friesian dairy cows at 538,231 SNPs with three distinct phenotypes. These were: single intradermal cervical comparative tuberculin (SICCT) test positives with visible lesions (VLs), SICCT-positives with undetected visible lesions (NVLs) and matched controls SICCT-negative on multiple occasions.
Regional heritability mapping identified three loci associated with the NVL phenotype on chromosomes 17, 22 and 23, distinct to the region on chromosome 13 associated with the VL phenotype. The region on chromosome 23 was at genome-wide significance and candidate genes overlapping the mapped window included members of the bovine leukocyte antigen class IIb region, a complex known for its role in immunity and disease resistance. Chromosome heritability analysis attributed variance to six and thirteen chromosomes for the VL and NVL phenotypes, respectively, and four of these chromosomes were found to explain a proportion of the phenotypic variation for both the VL and NVL phenotype. By grouping the M. bovis outcomes (VLs and NVLs) variance was attributed to nine chromosomes. When contrasting the two M. bovis infection outcomes (VLs vs NVLs) nine chromosomes were found to harbour heritable variation. Regardless of the case phenotype under investigation, chromosome heritability did not exceed 8% indicating that the genetic control of bTB resistance consists of variants of small to moderate effect situated across many chromosomes of the bovine genome.
These findings suggest the host genetics of M. bovis infection outcomes is governed by distinct and overlapping genetic variants. Thus, variation in the pathology of M. bovis infected cattle may be partly genetically determined and indicative of different host responses or pathogen handling. There may be at least three distinct outcomes following M. bovis exposure in dairy cattle: resistance to infection, infection resulting in pathology or no detectable pathology.
牛对牛分枝杆菌感染的易感性部分受宿主遗传学控制。然而，被诊断感染牛分枝杆菌的牛表现出不同的病理症状。宿主对感染反应的差异可能代表自接触病原体以来的连续变化，也可能是由于病原体处理方式不同导致的不同结果。通过对1966头荷斯坦 - 弗里生奶牛进行基因分型，检测538,231个单核苷酸多态性（SNP），并观察三种不同表型，探讨了宿主遗传学与牛分枝杆菌感染后宿主反应变异及病理后遗症之间的关系。这三种表型分别为：单次皮内颈侧比较结核菌素（SICCT）试验阳性且有可见病变（VL）、SICCT阳性但无可见病变（NVL）以及多次SICCT试验均为阴性的匹配对照。
区域遗传力图谱分析确定了与NVL表型相关的三个基因座，分别位于17号、22号和23号染色体上，与位于13号染色体上与VL表型相关的区域不同。23号染色体上的区域达到全基因组显著性水平，与定位窗口重叠的候选基因包括牛白细胞抗原IIb类区域的成员，该复合体以其在免疫和抗病中的作用而闻名。染色体遗传力分析分别将VL和NVL表型的方差归因于6条和13条染色体，其中4条染色体被发现可解释VL和NVL表型的部分表型变异。通过将牛分枝杆菌感染结果（VL和NVL）分组，方差归因于9条染色体。当对比两种牛分枝杆菌感染结果（VL与NVL）时，发现9条染色体存在遗传变异。无论研究的病例表型如何，染色体遗传力均不超过8%。这表明牛结核病抗性的遗传控制由位于牛基因组许多染色体上的小到中等效应的变异组成。
这些发现表明，牛分枝杆菌感染结果的宿主遗传学受不同且重叠的遗传变异控制。因此，牛分枝杆菌感染牛的病理学变异可能部分由遗传决定，表明不同的宿主反应或病原体处理方式。奶牛接触牛分枝杆菌后可能至少有三种不同结果：对感染有抗性、感染导致病理学变化或无可检测到的病理学变化。
