Multibreed genome wide association can improve precision of mapping causative variants underlying milk production in dairy cattle.

Genome wide association studies (GWAS) in most cattle breeds result in large genomic intervals of significant associations making it difficult to identify causal mutations. This is due to the extensive, low-level linkage disequilibrium within a cattle breed. As there is less linkage disequilibrium across breeds, multibreed GWAS may improve precision of causal variant mapping. Here we test this hypothesis in a Holstein and Jersey cattle data set with 17,925 individuals with records for production and functional traits and 632,003 SNP markers. By using a cross validation strategy within the Holstein and Jersey data sets, we were able to identify and confirm a large number of QTL. As expected, the precision of mapping these QTL within the breeds was limited. In the multibreed analysis, we found that many loci were not segregating in both breeds. This was partly an artefact of power of the experiments, with the number of QTL shared between the breeds generally increasing with trait heritability. False discovery rates suggest that the multibreed analysis was less powerful than between breed analyses, in terms of how much genetic variance was explained by the detected QTL. However, the multibreed analysis could more accurately pinpoint the location of the well-described mutations affecting milk production such as DGAT1. Further, the significant SNP in the multibreed analysis were significantly enriched in genes regions, to a considerably greater extent than was observed in the single breed analyses. In addition, we have refined QTL on BTA5 and BTA19 to very small intervals and identified a small number of potential candidate genes in these, as well as in a number of other regions. Where QTL are segregating across breed, multibreed GWAS can refine these to reasonably small genomic intervals. However, such QTL appear to represent only a fraction of the genetic variation. Our results suggest a significant proportion of QTL affecting milk production segregate within rather than across breeds, at least for Holstein and Jersey cattle.

Raven LA ，Cocks BG ，Hayes BJ 《BMC GENOMICS》

Comparing power and precision of within-breed and multibreed genome-wide association studies of production traits using whole-genome sequence data for 5 French and Danish dairy cattle breeds.

The objective of this study was to compare mapping precision and power of within-breed and multibreed genome-wide association studies (GWAS) and to compare the results obtained by the multibreed GWAS with 3 meta-analysis methods. The multibreed GWAS was expected to improve mapping precision compared with a within-breed GWAS because linkage disequilibrium is conserved over shorter distances across breeds than within breeds. The multibreed GWAS was also expected to increase detection power for quantitative trait loci (QTL) segregating across breeds. GWAS were performed for production traits in dairy cattle, using imputed full genome sequences of 16,031 bulls, originating from 6 French and Danish dairy cattle populations. Our results show that a multibreed GWAS can be a valuable tool for the detection and fine mapping of quantitative trait loci. The number of QTL detected with the multibreed GWAS was larger than the number detected by the within-breed GWAS, indicating an increase in power, especially when the 2 Holstein populations were combined. The largest number of QTL was detected when all populations were combined. The analysis combining all breeds was, however, dominated by Holstein, and QTL segregating in other breeds but not in Holstein were sometimes overshadowed by larger QTL segregating in Holstein. Therefore, the GWAS combining all breeds except Holstein was useful to detect such peaks. Combining all breeds except Holstein resulted in smaller QTL intervals on average, but this outcome was not the case when the Holstein populations were included in the analysis. Although no decrease in the average QTL size was observed, mapping precision did improve for several QTL. Out of 3 different multibreed meta-analysis methods, the weighted z-scores model resulted in the most similar results to the full multibreed GWAS and can be useful as an alternative to a full multibreed GWAS. Differences between the multibreed GWAS and the meta-analyses were larger when different breeds were combined than when the 2 Holstein populations were combined.

van den Berg I ，Boichard D ，Lund MS 《-》

Genome-wide association for milk production traits and somatic cell score in different lactation stages of Ayrshire, Holstein, and Jersey dairy cattle.

We performed genome-wide association analyses for milk, fat, and protein yields and somatic cell score based on lactation stages in the first 3 parities of Canadian Ayrshire, Holstein, and Jersey cattle. The genome-wide association analyses were performed considering 3 different lactation stages for each trait and parity: from 5 to 95, from 96 to 215, and from 216 to 305 d in milk. Effects of single nucleotide polymorphisms (SNP) for each lactation stage, trait, parity, and breed were estimated by back-solving the direct breeding values estimated using the genomic best linear unbiased predictor and single-trait random regression test-day models containing only the fixed population average curve and the random genomic curves. To identify important genomic regions related to the analyzed lactation stages, traits, parities and breeds, moving windows (SNP-by-SNP) of 20 adjacent SNP explaining more than 0.30% of total genetic variance were selected for further analyses of candidate genes. A lower number of genomic windows with a relatively higher proportion of the explained genetic variance was found in the Holstein breed compared with the Ayrshire and Jersey breeds. Genomic regions associated with the analyzed traits were located on 12, 8, and 15 chromosomes for the Ayrshire, Holstein, and Jersey breeds, respectively. Especially for the Holstein breed, many of the identified candidate genes supported previous reports in the literature. However, well-known genes with major effects on milk production traits (e.g., diacylglycerol O-acyltransferase 1) showed contrasting results among lactation stages, traits, and parities of different breeds. Therefore, our results suggest evidence of differential sets of candidate genes underlying the phenotypic expression of the analyzed traits across breeds, parities, and lactation stages. Further functional studies are needed to validate our findings in independent populations.

Oliveira HR ，Cant JP ，Brito LF ，Feitosa FLB ，Chud TCS ，Fonseca PAS ，Jamrozik J ，Silva FF ，Lourenco DAL ，Schenkel FS ... -  《-》

Genome-wide association and biological pathway analysis for milk-fat composition in Danish Holstein and Danish Jersey cattle.

The milk fat profile of the Danish Holstein (DH) and Danish Jersey (DJ) show clear differences. Identification of the genomic regions, genes and biological pathways underlying the milk fat biosynthesis will improve the understanding of the biology underlying bovine milk fat production and may provide new possibilities to change the milk fat composition by selective breeding. In this study a genome wide association scan (GWAS) in the DH and DJ was performed for a detailed milk fatty acid (FA) profile using the HD bovine SNP array and subsequently a biological pathway analysis based on the SNP data was performed. The GWAS identified in total 1,233 SNPs (FDR < 0.10) spread over 18 chromosomes for nine different FA traits for the DH breed and 1,122 SNPs (FDR < 0.10) spread over 26 chromosomes for 13 different FA traits were detected for the DJ breed. Of these significant SNPs, 108 SNP markers were significant in both DH and DJ (C14-index, BTA26; C16, BTA14; fat percentage (FP), BTA14). This was supported by an enrichment test. The QTL on BTA14 and BTA26 represented the known candidate genes DGAT and SCD. In addition we suggest ACSS3 to be a good candidate gene for the QTL on BTA5 for C10:0 and C15:0. In addition, genetic correlations between the FA traits within breed showed large similarity across breeds. Furthermore, the biological pathway analysis revealed that fat digestion and absorption (KEGG04975) plays a role for the traits FP, C14:1, C16 index and C16:1. There was a clear similarity between the underlying genetics of FA in the milk between DH and DJ. This was supported by the fact that there was substantial overlap between SNPs for FP, C14 index, C14:1, C16 index and C16:1. In addition genetic correlations between FA showed a similar pattern across DH and DJ. Furthermore the biological pathway analysis suggested that fat digestion and absorption KEGG04975 is important for the traits FP, C14:1, C16 index and C16:1.

Buitenhuis B ，Janss LL ，Poulsen NA ，Larsen LB ，Larsen MK ，Sørensen P ... -  《BMC GENOMICS》

Multibreed genomic prediction using multitrait genomic residual maximum likelihood and multitask Bayesian variable selection.

Genomic prediction is applicable to individuals of different breeds. Empirical results to date, however, show limited benefits in using information on multiple breeds in the context of genomic prediction. We investigated a multitask Bayesian model, presented previously by others, implemented in a Bayesian stochastic search variable selection (BSSVS) model. This model allowed for evidence of quantitative trait loci (QTL) to be accumulated across breeds or for both QTL that segregate across breeds and breed-specific QTL. In both cases, single nucleotide polymorphism effects were estimated with information from a single breed. Other models considered were a single-trait and multitrait genomic residual maximum likelihood (GREML) model, with breeds considered as different traits, and a single-trait BSSVS model. All single-trait models were applied to each of the 2 breeds separately and to the pooled data of both breeds. The data used included a training data set of 6,278 Holstein and 722 Jersey bulls, as well as 374 Jersey validation bulls. All animals had genotypes for 474,773 single nucleotide polymorphisms after editing and phenotypes for milk, fat, and protein yields. Using the same training data, BSSVS consistently outperformed GREML. The multitask BSSVS, however, did not outperform single-trait BSSVS, which used pooled Holstein and Jersey data for training. Thus, the rigorous assumption that the traits are the same in both breeds yielded a slightly better prediction than a model that had to estimate the correlation between the breeds from the data. Adding the Holstein data significantly increased the accuracy of the single-trait GREML and BSSVS in predicting the Jerseys for milk and protein, in line with estimated correlations between the breeds of 0.66 and 0.47 for milk and protein yields, whereas only the BSSVS model significantly improved the accuracy for fat yield with an estimated correlation between breeds of only 0.05. The relatively high genetic correlations for milk and protein yields, and the superiority of the pooling strategy, is likely the result of the observed admixture between both breeds in our data. The Bayesian model was able to detect several QTL in Holsteins, which likely enabled it to outperform GREML. The inability of the multitask Bayesian models to outperform a simple pooling strategy may be explained by the fact that the pooling strategy assumes equal effects in both breeds; furthermore, this assumption may be valid for moderate- to large-sized QTL, which are important for multibreed genomic prediction.

Calus MPL ，Goddard ME ，Wientjes YCJ ，Bowman PJ ，Hayes BJ ... -  《-》