Fine mapping of a QTL on bovine chromosome 6 using imputed full sequence data suggests a key role for the group-specific component (GC) gene in clinical mastitis and milk production

Abstract

BackgroundClinical mastitis is an inflammation of the mammary gland and causes significant costs to dairy production. It is unfavourably genetically correlated to milk production, and, thus, knowledge of the mechanisms that underlie these traits would be valuable to improve both of them simultaneously through breeding. A quantitative trait locus (QTL) that affects both clinical mastitis and milk production has recently been fine-mapped to around 89 Mb on bovine chromosome 6 (BTA6), but identification of the gene that underlies this QTL was not possible due to the strong linkage disequilibrium between single nucleotide polymorphisms (SNPs) within this region. Our aim was to identify the gene and, if possible, the causal polymorphism(s) responsible for this QTL through association analysis of high-density SNPs and imputed full sequence data in combination with analyses of transcript and protein levels of the identified candidate gene.ResultsAssociations between SNPs and the studied traits were strongest for SNPs that were located within and immediately upstream of the group-specific component (GC) gene. This gene encodes the vitamin D-binding protein (DBP) and has multiple roles in immune defense and milk production. A 12-kb duplication that was identified downstream of this gene covered its last exon and segregated with the QTL allele that is associated with increased mastitis susceptibility and milk production. However, analyses of GC mRNA levels on the available samples revealed no differences in expression between animals having or lacking this duplication. Moreover, we detected no differences in the concentrations of DBP and its ligand vitamin D between the animals with different GC genotypes that were available for this study.ConclusionsOur results suggest GC as the gene that underlies the QTL for clinical mastitis and milk production. However, since only healthy animals were sampled for transcription and expression analyses, we could not draw any final conclusion on the absence of quantitative differences between animals with different genotypes. Future studies should investigate GC RNA expression and protein levels in cows with different genotypes during an infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12711-016-0257-2) contains supplementary material, which is available to authorized users.

GWAS and Fine-Mapping of Livability and Six Disease Traits in Holstein Cattle

“…The region around 7,048,452 bp on BTA 16 for ketosis was also previously associated with fat metabolism. The region around 88,868,886 bp on BTA 6 associated with mastitis is close to the GC gene with many reported QTLs associated with mastitis [17–20]. This region was also associated with cow livability in this study with QTLs involved with the length of productive life [21].…”

“…Interestingly, the GC gene was also detected to have tissue-specific expression in the liver for mastitis (Table 4). This is corroborated by a study on cattle infected with mastitis to possess limited DBP concentration [17]. Vitamin D plays a key part in maintaining serum levels of calcium when it is secreted into the milk [39].…”

“…Additionally, we identified an associated variant for livability at 88,687,845 - 88,739,292 bp on BTA6 was close to the gene GC , which was specifically expressed in tissues such as the liver (Table 4). This gene has been previously studied in an association analysis that investigated the role of GC on milk production [17]. It found that the gene expression of GC in cattle is predominantly expressed in the liver.…”

Validating genome‐wide associated signals for clinical mastitis in German Holstein cattle

“…Other strong candidate genes in the same region are immunoglobulin J chain ( JCHAIN , also known as IGJ ) and GC, vitamin D‐binding protein ( GC , previously known as DBP ) (Olsen et al . ) with distances of 300 and 626 kb up‐ and downstream respectively. SNP rs41257403 on BTA19 is close to the forkhead box K2 ( FOXK2 ) gene (2.67 kb downstream), which has an essential role in the transcriptional regulation of IL2 (Li et al .…”

Prioritizing single-nucleotide polymorphisms and variants associated with clinical mastitis

“…More recently, imputed sequence variants have been rigorously used for association studies, and udder conformation traits including mastitis were identified in noncoding regions of the genome 15. This region underlying the peaks of associations with bovine clinical mastitis has certain traits specific for vitamin D components across all eutherians including humans 16. Conversely, strong linkage disequilibrium (LD), especially in these regions, affects the subregions underlying the peaks of associations with the disease.…”