An analysis of effects of heterozygosity in dairy cattle for bovine tuberculosis resistance

Abstract

SummaryGenetic selection of cattle more resistant to bovine tuberculosis (bTB) may offer a complementary control strategy. Hypothesising underlying non‐additive genetic variation, we present an approach using genome‐wide high density markers to identify genomic loci with dominance effects on bTB resistance and to test previously published regions with heterozygote advantage in bTB. Our data comprised 1151 Holstein–Friesian cows from Northern Ireland, confirmed bTB cases and controls, genotyped with the 700K Illumina BeadChip. Genome‐wide markers were tested for associations between heterozygosity and bTB status using marker‐based relationships. Results were tested for robustness against genetic structure, and the genotypic frequencies of a significant locus were tested for departures from Hardy‐Weinberg equilibrium. Genomic regions identified in our study and in previous publications were tested for dominance effects. Genotypic effects were estimated through ASReml mixed models. A SNP (rs43032684) on chromosome 6 was significant at the chromosome‐wide level, explaining 1.7% of the phenotypic variance. In the controls, there were fewer heterozygotes for rs43032684 (P < 0.01) with the genotypic values suggesting that heterozygosity confers a heterozygote disadvantage. The region surrounding rs43032684 had a significant dominance effect (P < 0.01). SNP rs43032684 resides within a pseudogene with a parental gene involved in macrophage response to infection and within a copy‐number‐variation region previously associated with nematode resistance. No dominance effect was found for the region on chromosome 11, as indicated by a previous candidate region bTB study. These findings require further validation with large‐scale data.

Variance components for bovine tuberculosis infection and multi-breed genome-wide association analysis using imputed whole genome sequence data

“…Nonetheless, consistency is lacking in genomic studies on bTB infection in the regions of the genome putatively associated with bTB infection. For example, putative quantitative trait loci (QTL) pertaining to bTB infection in Holstein cattle have been reported on BTA1 [10], BTA2 [5], BTA6 [11], BTA13 [5], BTA22 [12], and BTA23 [7,10]. Even when the same autosome was documented in two studies for association with bTB [7, 10], the QTL identified to harbor putative single nucleotide polymorphisms (SNP) by Richardson et al [7] were 28 Mb downstream of the QTL identified on the same autosome by Raphaka et al [10].…”

Exploring the Risk Posed by Animals with an Inconclusive Reaction to the Bovine Tuberculosis Skin Test in England and Wales

“…Amos et al (2013) investigated a possible effect of a particular TB genotype, which was noted to be prevalent in non-reactor animals. Increases in skin thickness were lower in animals with the "22" genotype [21], although a subsequent study investigating the same genomic region in a larger dataset did not find any evidence to support these findings [22]. It was also observed that the difference in skin thickness between the bovine tuberculin site and avian tuberculin site was reduced in animals pre-exposed to Mycobacterium avium [23].…”

Integrative genomics of the mammalian alveolar macrophage response to intracellular mycobacteria

“…bovis infection resistance in domestic cattle (Raphaka et al 2017;Tsairidou et al 2018a;Tsairidou et al 2018b;Ring et al 2019).…”

“…In parallel to functional genomics studies of bTB, increasingly powerful genome-wide association studies (GWAS) have been performed in Irish and UK cattle populations using estimated breeding values (EBVs; estimate of genetic merit of an animal derived from a statistical model) for several M. bovis infection resistance traits with heritabilities ranging from 0.04 to 0.37, depending on the phenotype used (Finlay et al 2012;Bermingham et al 2014;Richardson et al 2016;Raphaka et al 2017;Wilkinson et al 2017;Tsairidou et al 2018b;Ring et al 2019). These GWAS have used medium-and high-density single-nucleotide polymorphism (SNP) arrays and, more recently, imputed whole-genome sequence (WGS) data sets for a large multi-breed GWAS on 7,346 bulls, which identified 64 quantitative trait loci (QTLs) associated with resistance to M. bovis infection (Ring et al 2019); the association study was based on phenotypic data from 781,270 individuals.…”