Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Dominant

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2014

Species-specific name: Also known as Variant Red, Holstein dominant red; Haplotype HDR

Species-specific symbol: VR (Variant Red); HDR (Holstein Dominant Red)

History: This dominant trait was first reported by Leduc (2006) who, in the words of Dorshorst et al. (2015) reported that "In 1980, a female Holstein calf (HOCANF3541221, SURINAM SHEIK ROSABEL-RED) was born in Canada that displayed the typical red Holstein coat color phenotype . . . , but from parents that were not thought to carry either of the MC1R alleles associated with red color based on pedigree."

Inheritance: Dreger and Schmutz (2010) reported that "The variant red phenotype in Holstein cattle is indistinguishable from the traditional e/e recessive red phenotype caused by a mutation in melanocortin 1 receptor [OMIA 001199-9913], but is inherited as a dominant trait in relation to black".

Dorshorst et al. (2015) propose "that the Dominant Red locus is designated DR with two alleles, the derivative allele DR^DR and the ancestral or wild-type allele DR^+".

Mapping: Dreger and Schmutz (2010) excluded linkage of this trait with polymorphisms in some of the common coat-colour genes, namely melanocortin 1 receptor (MC1R), agouti signalling protein (ASIP), attractin (ATRN) and melatonin receptor 1A (MTNR1A). However, linkage with microsatellites near, and SNPs within the 5' UTR of, another comparative candidate coat-colour gene (beta-defensin 103; DEFB103), located on chromosome BTA27, was detected.

Using SNP-chip genotypes of Holsteins from the shared national resource maintained by the Council on Dairy Cattle Breeding (CDCB; Reynoldsburg, Ohio), Lawlor et al. (2013) identified a haplotype at 8-12 Mb on chromosome BTA3 that co-segregates with this trait. While this results appears to contradict the earlier linkage result, it is known that there are many defensin genes/pseudogenes scattered throughout the bovine genome, and it is possible that the earlier results actually involved a defensin-like sequence on BTA3.

Using "31 cases and 36 control relatives", each genotyped with the Illumina BovineSNP50 chip, Capitan et al. (2014)/Bourneuf et al. (2017) confirmed and detaileded the location of this trait to a 4.6Mb region on chromosome BTA3: 7,906,099-12,475,989.

Dorshorst et al. (2015) used linkage mapping and GWAS to also confirm the BTA3 map location.

Molecular basis: By comparing whole-genome sequence of a small number of Holsteins having the trait, with sequence data from hundreds of control animals, Capitan et al. (2014) confirmed the mapping results of Lawlor et al. (2014) and identified the causal mutation as a de novo variant BTA3 g.C9479761T, which corresponds to a missense mutation p.R160C in the COPA gene that encodes coatomer protein complex, subunit alpha.

By whole-genome sequencing of a Dominant Red heterozygote, Dorshorst et al. (2015) confirmed this causal mutation (c.478C>T; p.Arg160Cys).

The results of Capitan et al. (2014) were formally published by Bourneuf et al. (2017).

Associated gene: