Abstract
Clinical mastitis (CM) is an inflammatory disease occurring in the mammary glands of lactating cows. CM is under genetic control, and a prominent CM resistance QTL located on chromosome 6 was reported in various dairy cattle breeds. Nevertheless, the biological mechanism underpinning this QTL has been lacking. Herein, we mapped, fine-mapped, and discovered the putative causal variant underlying this CM resistance QTL in the Dutch dairy cattle population. We identified a ~12 kb multi-allelic copy number variant (CNV), that is in perfect linkage disequilibrium with a lead SNP, as a promising candidate variant. By implementing a fine-mapping and through expression QTL mapping, we showed that the group-specific component gene (GC), a gene encoding a vitamin D binding protein, is an excellent candidate causal gene for the QTL. The multiplicated alleles are associated with increased GC expression and low CM resistance. Ample evidence from functional genomics data supports the presence of an enhancer within this CNV, which would exert cis-regulatory effect on GC. We observed that strong positive selection swept the region near the CNV, and haplotypes associated with the multiplicated allele were strongly selected for. Moreover, the multiplicated allele showed pleiotropic effects for increased milk yield and reduced fertility, hinting that a shared underlying biology for these effects may revolve around the vitamin D pathway. These findings together suggest a putative causal variant of a CM resistance QTL, where a cis-regulatory element located within a CNV can alter gene expression and affect multiple economically important traits.
Highlights
Clinical mastitis (CM) is an inflammation in the mammary glands
We revealed a multi-allelic copy number variant (CNV) harbouring a strong enhancer targeting group-specific component (GC), as the likely causative variant
Our findings revealed that the candidate causal gene GC is likely regulated by an enhancer located in the GC CNV
Summary
Clinical mastitis (CM) is an inflammation in the mammary glands. This condition is often seen in dairy cattle and the repercussions of CM include production loss, use of antibiotics, and compromised animal welfare [1]. The proposed candidate SNPs showed antagonistic allele effects for milk yield (MY) (the high CM resistance allele was linked to low MY, and vice versa [7,13,16]), and one study concluded that a single pleiotropic variant regulates both of the traits [17] This locus harbours QTL for many traits including body conformation, fertility, and longevity [11,15,18,19,20,21,22], implying pleiotropy, which remains to be investigated. Our findings show that (1) the CM resistance QTL on BTA 6 is
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