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

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 eQTL analysis at liveweight locus

Animal genotypes for the 432 Illumina BovineHD BeadChip markers at the chromosome 14 liveweight locus. Animals were genotyped using this panel directly, apart from 29 animals which were genotyped using the Illumina BovineSNP50 and imputed up to the HDChip density using Beagle. These genotypes were used for association analysis with gene expression phenotypes from the lactating mammary tissue biospies. 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

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

Milk Composition Phenotype Data

Milk composition records were measured as part of standard herd testing procedures. Abbreviations used: id = animal identification, sire = sire animal identification, pgsire = parternal sire animal identification, pmgsire = partern fr = friesian, je = jersey, hol = holestein, FxJ = freisian x jersey, FxH = freisian x holestein, JxH = jersey x holestein, fat = fat yield, fat_pct = fat percentage, milk = milk yield, prot = protein, prot_pct = protein percentage, ydlwt = liveweigh

Gene Expression Data

Gene expression data for genes at the chromosome 14 liveweight locus from lactating mammary tissue biopsies. RNAseq read counts have been normalised using variance-stabilisation transformation. Abbreviations used: id = animal identification, sire = sire animal identification, pgsire = parternal sire animal identification, pmgsire = partern fr = friesian, je = jersey, hol = holestein, FxJ = freisian x jersey, FxH = freisian x holestein, JxH = jersey x holestein

ge-phenos-names

Column names for gene expression phenotypes. These are in a separate file per the GCTA input format requirements

Multiple QTL underlie milk phenotypes at the CSF2RB locus

Abstract Background Over many years, artificial selection has substantially improved milk production by cows. However, the genes that underlie milk production quantitative trait loci (QTL) remain relatively poorly characterised. Here, we investigate a previously reported QTL located at the CSF2RB locus on chromosome 5, for several milk production phenotypes, to better understand its underlying genetic and molecular causes. Results Using a population of 29,350 taurine dairy cows, we conducted association analyses for milk yield and composition traits, and identified highly significant QTL for milk yield, milk fat concentration, and milk protein concentration. Strikingly, protein concentration and milk yield appear to show co-located yet genetically distinct QTL. To attempt to understand the molecular mechanisms that might be mediating these effects, gene expression data were used to investigate eQTL for 11 genes in the broader interval. This analysis highlighted genetic impacts on CSF2RB and NCF4 expression that share similar association signatures to those observed for lactation QTL, strongly implicating one or both of these genes as responsible for these effects. Using the same gene expression dataset representing 357 lactating cows, we also identified 38 novel RNA editing sites in the 3′ UTR of CSF2RB transcripts. The extent to which two of these sites were edited also appears to be genetically co-regulated with lactation QTL, highlighting a further layer of regulatory complexity that involves the CSF2RB gene. Conclusions This locus presents a diversity of molecular and lactation QTL, likely representing multiple overlapping effects that, at a minimum, highlight the CSF2RB gene as having a causal role in these processes

HD.milk-animals-29350.grm

GZipped tar file containing the GRM for the 29,350 milk phenotype animals in GCTA binary format. Based on Illumina BovineHD genotypes. Excludes chromosome 5 to enable MLMA-LOCO analyses