Candidate genes associated with the heritable humoral response to Mycobacterium avium ssp. paratuberculosis in dairy cows have factors in common with gastrointestinal diseases in humans

Abstract

Infection of cattle with bovine paratuberculosis (i.e., Johne's disease) is caused by Mycobacterium avium ssp. paratuberculosis (MAP) and results in a chronic incurable gastroenteritis. This disease, which has economic ramifications for the cattle industry, is increasing in detected prevalence globally; subclinically infected animals can silently shed the bacterium into the environment for years, exposing contemporaries and hampering disease-control programs. The objective of the present study was to first quantify the genetic parameters for humoral response to MAP in dairy cattle. This was followed by a genome-based association analysis and subsequent downstream bioinformatic analyses from imputed whole genome sequence SNP data. After edits, ELISA test records were available on 136,767 cows; analyses were also undertaken on a subset of 33,818 of these animals from herds with at least 5 MAP ELISApositive cows, with at least 1 of those positive cows being homebred. Variance components were estimated using univariate animal and sire linear mixed models. The heritability calculated from the animal model for humoral response to MAP using alternative phenotype definitions varied from 0.02 (standard error = 0.003) to 0.05 (standard error = 0.008). The genome-based associations were undertaken within a mixed model framework using weighted deregressed estimated breeding values as a dependent variable on 1,883 phenotyped animals that were ≥87.5% Holstein-Friesian. Putative susceptibility quantitative trait loci (QTL) were identified on Bos taurus autosome 1,

Systematic Assessment of Mycobacterium avium Subspecies Paratuberculosis Infections from 1911–2019: A Growth Analysis of Association with Human Autoimmune Diseases

“…Research into MAP virulence is rooted in the desire to understand pathophysiological effects of MAP in different life forms and to establish clinical and subclinical biomarkers of MAP infections and diseases. These researches seek to determine molecular resistance, susceptibility gene markers or factors that drive the establishment of MAP infections in hosts [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ]. Growth related to MAP disease resistance research underscored the inclination towards selection of animal breeding stocks that are capable of high productivity in the event of MAP infections on-farm to minimize husbandry failures and economic losses.…”

Identification of the ABCC4, IER3, and CBFA2T2 candidate genes for resistance to paratuberculosis from sequence-based GWAS in Holstein and Normande dairy cattle

“…Individual diagnostic tests for paratuberculosis are known to lack sensitivity and specificity, and these characteristics have been put forward as explanations for the low heritability of MAP-related traits that has been reported in the literature. Since the study of Settles et al in 2009 [9] to the most recent publication in 2019, 13 GWAS analyses have been conducted for traits linked with bovine paratuberculosis [6][7][8][9][10][11][12][13][14][15][16][17][18]. These studies examined various numbers of animals and SNPs, and all succeeded in identifying genomic regions associated with MAP resistance/susceptibility.…”

“…Several previous GWAS analyses have reported QTL on BTA23 that are associated with resistance to MAP, in the vicinity of the MHC [7-9, 16, 18], while only one previous study, a meta-analysis conducted in US Holsteins based on 50 K SNP genotypes, found QTL at ~ 70 Mbp on BTA12 and ~ 65 Mbp on BTA13 [8]. McGovern et al [18], who performed a GWAS on imputed whole-genome sequences, identified two SNPs associated with the humoral response to MAP on BTA13, at 62,037,755 bp and 66,373,805 bp, i.e. on either side of but quite far from the QTL we detected (63,497,960-63,506,532 bp) and outside its confidence interval.…”

“…As recently reviewed by Brito et al [6], various studies have shown the role of host genetics in resistance to MAP and have estimated heritability values for this trait between 0.03 and 0.27. In addition, numerous genomewide association studies (GWAS) have been conducted using genotyping of single-nucleotide polymorphisms (SNPs) at low [7], medium [8][9][10][11][12][13][14], or high [6,15,16] densities as well as whole-genome sequences [17,18] imputed from data of the 1000 Bull Genomes project [19]. These GWAS analyses have led to the identification of quantitative trait loci (QTL) associated with resistance/susceptibility to MAP on all Bos taurus (BTA) autosomes, with the most frequently identified QTL located on BTA1, 6, 7, and 23.…”

Structure and Emerging Functions of LRCH Proteins in Leukocyte Biology

“…Pigs with SNPs in LRCH3 are more susceptible to infections with Escherichia coli (E. coli) and cows with SNPs in LRCH3 have a higher susceptibility to Mycobacterium avium ssp. paratuberculosis infection (Jacobsen et al, 2010;McGovern et al, 2019). Furthermore, gene amplifications of LRCH2 and LRCH3 are associated with tumorigenesis of low grade gliomas and melanomas, respectively (Liu et al, 2019;Williams et al, 2020).…”