Genome-wide association analysis reveals QTL and candidate mutations involved in white spotting in cattle

International audienceAbstractBackgroundWhite spotting of the coat is a characteristic trait of various domestic species including cattle and other mammals. It is a hallmark of Holstein–Friesian cattle, and several previous studies have detected genetic loci with major effects for white spotting in animals with Holstein–Friesian ancestry. Here, our aim was to better understand the underlying genetic and molecular mechanisms of white spotting, by conducting the largest mapping study for this trait in cattle, to date.ResultsUsing imputed whole-genome sequence data, we conducted a genome-wide association analysis in 2973 mixed-breed cows and bulls. Highly significant quantitative trait loci (QTL) were found on chromosomes 6 and 22, highlighting the well-established coat color genes KIT and MITF as likely responsible for these effects. These results are in broad agreement with previous studies, although we also report a third significant QTL on chromosome 2 that appears to be novel. This signal maps immediately adjacent to the PAX3 gene, which encodes a known transcription factor that controls MITF expression and is the causal locus for white spotting in horses. More detailed examination of these loci revealed a candidate causal mutation in PAX3 (p.Thr424Met), and another candidate mutation (rs209784468) within a conserved element in intron 2 of MITF transcripts expressed in the skin. These analyses also revealed a mechanistic ambiguity at the chromosome 6 locus, where highly dispersed association signals suggested multiple or multiallelic QTL involving KIT and/or other genes in this region.ConclusionsOur findings extend those of previous studies that reported KIT as a likely causal gene for white spotting, and report novel associations between candidate causal mutations in both the MITF and PAX3 genes. The sizes of the effects of these QTL are substantial, and could be used to select animals with darker, or conversely whiter, coats depending on the desired characteristics

Data from: Functional confirmation of PLAG1 as the candidate causative gene underlying major pleiotropic effects on body weight and milk characteristics

A major pleiotropic quantitative trait locus (QTL) located at ~25Mbp on bovine chromosome 14 affects a myriad of growth and developmental traits in Bos taurus and indicus breeds. These QTL have been attributed to two functional variants in the bidirectional promoter of PLAG1 and CHCHD7, and although PLAG1 is a good candidate for mediating these effects, its role remains uncertain given these variants are also associated with expression of five additional genes at the broader locus. In the current study, we conducted expression QTL (eQTL) mapping of this region using a large, high depth mammary RNAseq dataset representing 375 lactating cows. Here we show that of the seven previously implicated genes, only PLAG1 and LYN are differentially expressed by QTL genotype, and only PLAG1 bears the same association signature of the growth and body weight QTLs. For the first time, we also report significant association of PLAG1 genotype with milk production traits, including milk fat, volume, and protein yield. Collectively, these data confirm PLAG1 as the causative gene underlying this diverse range of physiological QTLs, and indicate new effects for the locus on lactation phenotypes

Animal Genotypes for milk production analysis at liveweight locus

Animal genotypes for the 432 Illumina BovineHD BeadChip markers at the chromosome 14 liveweight locus. Animals were genotyped either using this panel directly, or were genotyped using the Illumina BovineSNP50 and imputed to the HDChip markers using Beagle. These genotypes were used for association analysis with milk production phenotypes generated as part of standard herd test procedures. PLINK was used to recode the genotypes to 0,1,2 to represent the number of alternative allele copies for each marker. anml_id = anonymised animal identificatio

imputed-seq-genotypes-Chr1.153640000-154640000.vcf

Imputed genotypes for variants within 1Mbp of the Chr1:153.96 LC QTL, for 357 animals

imputed-seq-genotypes-12k-Chr16.67270000-68270000.vcf

Imputed genotypes for variants within 1Mbp of the Chr16:67.77 LC QTL, for 12,000 animals

validation_results_LC

The association statistics for the 22 LC QTL peaks in the 18k animal validation set

imputed-seq-genotypes-Chr26.22460000-23460000.vcf

Imputed genotypes for variants within 1Mbp of the Chr26:22.96 LY QTL, for 357 animals