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BackgroundWhole-genome sequence (WGS) data could contain information on genetic variants at or in high linkage disequilibrium with causative mutations that underlie the genetic variation of polygenic traits. Thus far, genomic prediction accuracy has shown limited increase when using such information in dairy cattle studies, in which one or few breeds with limited diversity predominate. The objective of our study was to evaluate the accuracy of genomic prediction in a multi-breed Australian sheep population of relatively less related target individuals, when using information on imputed WGS genotypes.MethodsBetween 9626 and 26,657 animals with phenotypes were available for nine economically important sheep production traits and all had WGS imputed genotypes. About 30% of the data were used to discover predictive single nucleotide polymorphism (SNPs) based on a genome-wide association study (GWAS) and the remaining data were used for training and validation of genomic prediction. Prediction accuracy using selected variants from imputed sequence data was compared to that using a standard array of 50k SNP genotypes, thereby comparing genomic best linear prediction (GBLUP) and Bayesian methods (BayesR/BayesRC). Accuracy of genomic prediction was evaluated in two independent populations that were each lowly related to the training set, one being purebred Merino and the other crossbred Border Leicester x Merino sheep.ResultsA substantial improvement in prediction accuracy was observed when selected sequence variants were fitted alongside 50k genotypes as a separate variance component in GBLUP (2GBLUP) or in Bayesian analysis as a separate category of SNPs (BayesRC). From an average accuracy of 0.27 in both validation sets for the 50k array, the average absolute increase in accuracy across traits with 2GBLUP was 0.083 and 0.073 for purebred and crossbred animals, respectively, whereas with BayesRC it was 0.102 and 0.087. The average gain in accuracy was smaller when selected sequence variants were treated in the same category as 50k SNPs. Very little improvement over 50k prediction was observed when using all WGS variants.ConclusionsAccuracy of genomic prediction in diverse sheep populations increased substantially by using variants selected from whole-genome sequence data based on an independent multi-breed GWAS, when compared to genomic prediction using standard 50K genotypes.

The objective of this study was to compare the accuracies of genomic prediction for milk yield, fat yield, and protein yield from Philippine dairy buffaloes using genomic best linear unbiased prediction (GBLUP) and single-step GBLUP (ssGBLUP) with the accuracies based on pedigree BLUP (pBLUP). To also assess the bias of the prediction, the regression coefficient (slope) of the adjusted phenotypes on the predicted breeding values (BVs) was also calculated. Two data sets were analyzed. The GENO data consisting of all female buffaloes that have both phenotypes and genotypes (n = 904 with 1,773,305-days lactation records) were analyzed using pBLUP and GBLUP. The ALL data, consisting of the GENO data plus females with phenotypes but not genotyped (n = 1,975 with 3,821,305-days lactation records), were analyzed using pBLUP and ssGBLUP. Animals were genotyped with the Affymetrix 90k buffalo genotyping array. After quality control, 60,827 single-nucleotide polymorphisms were used for downward analysis. A pedigree file containing 2,642 animals was used for pBLUP and ssGBLUP. Accuracy of prediction was calculated as the correlation between the predicted BVs of the test set and adjusted phenotypes, which were corrected for fixed effects, divided by the square root of the heritability of the trait, corrected for the number of lactations used in the test set. To assess the bias of the prediction, the regression coefficient (slope) of the adjusted phenotypes on the predicted BVs was also calculated. Results showed that genomic methods (GBLUP and ssGBLUP) provide more accurate predictions compared to pBLUP. Average GBLUP and ssGBLUP accuracies were 0.24 and 0.29, respectively, whereas average pBLUP accuracies (for GENO and ALL data) were 0.21 and 0.22, respectively. Slopes of the two genomic methods were also closer to one, indicating lesser bias, compared to pBLUP. Average GBLUP and ssGBLUP slopes were 0.89 and 0.84, respectively, whereas the average pBLUP (for GENO and ALL data) slopes were 0.80 and 0.54, respectively.

Background Imputation to whole-genome sequence is now possible in large sheep populations. It is therefore of interest to use this data in genome-wide association studies (GWAS) to investigate putative causal variants and genes that underpin economically important traits. Merino wool is globally sought after for luxury fabrics, but some key wool quality attributes are unfavourably correlated with the characteristic skin wrinkle of Merinos. In turn, skin wrinkle is strongly linked to susceptibility to “fly strike” (Cutaneous myiasis), which is a major welfare issue. Here, we use whole-genome sequence data in a multi-trait GWAS to identify pleiotropic putative causal variants and genes associated with changes in key wool traits and skin wrinkle. Results A stepwise conditional multi-trait GWAS (CM-GWAS) identified putative causal variants and related genes from 178 independent quantitative trait loci (QTL) of 16 wool and skin wrinkle traits, measured on up to 7218 Merino sheep with 31 million imputed whole-genome sequence (WGS) genotypes. Novel candidate gene findings included the MAT1A gene that encodes an enzyme involved in the sulphur metabolism pathway critical to production of wool proteins, and the ESRP1 gene. We also discovered a significant wrinkle variant upstream of the HAS2 gene, which in dogs is associated with the exaggerated skin folds in the Shar-Pei breed. Conclusions The wool and skin wrinkle traits studied here appear to be highly polygenic with many putative candidate variants showing considerable pleiotropy. Our CM-GWAS identified many highly plausible candidate genes for wool traits as well as breech wrinkle and breech area wool cover.

The objective of this study was to investigate the accuracy of genomic prediction of body weight and eating quality traits in a numerically small sheep population (Dorper sheep). Prediction was based on a large multi-breed/admixed reference population and using (a) 50k or 500k single nucleotide polymorphism (SNP) genotypes, (b) imputed whole-genome sequencing data (~31 million), (c) selected SNPs from whole genome sequence data and (d) 50k SNP genotypes plus selected SNPs from whole-genome sequence data. Furthermore, the impact of using a breed-adjusted genomic relationship matrix on accuracy of genomic breeding value was assessed. The selection of genetic variants was based on an association study performed on imputed whole-genome sequence data in an independent population, which was chosen either randomly from the base population or according to higher genetic proximity to the target population. Genomic prediction was based on genomic best linear unbiased prediction (GBLUP), and the accuracy of genomic prediction was assessed according to the correlation between genomic breeding value and corrected phenotypes divided by the square root of trait heritability. The accuracy of genomic prediction was between 0.20 and 0.30 across different traits based on common 50k SNP genotypes, which improved on average by 0.06 (absolute value) on average based on using prioritized genetic markers from whole-genome sequence data. Using prioritized genetic markers from a genetically more related GWAS population resulted in slightly higher prediction accuracy (0.02 absolute value) compared to genetic markers derived from a random GWAS population. Using high-density SNP genotypes or imputed whole-genome sequence data in GBLUP showed almost no improvement in genomic prediction accuracy however, accounting for different marker allele frequencies in reference population according to a breed-adjusted GRM resulted to on average 0.024 (absolute value) increase in accuracy of genomic prediction.

Background In this study, we assessed the accuracy of genomic prediction for carcass weight (CWT), marbling score (MS), eye muscle area (EMA) and back fat thickness (BFT) in Hanwoo cattle when using genomic best linear unbiased prediction (GBLUP), weighted GBLUP (wGBLUP), and a BayesR model. For these models, we investigated the potential gain from using pre-selected single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) on imputed sequence data and from gene expression information. We used data on 13,717 animals with carcass phenotypes and imputed sequence genotypes that were split in an independent GWAS discovery set of varying size and a remaining set for validation of prediction. Expression data were used from a Hanwoo gene expression experiment based on 45 animals. Results Using a larger number of animals in the reference set increased the accuracy of genomic prediction whereas a larger independent GWAS discovery dataset improved identification of predictive SNPs. Using pre-selected SNPs from GWAS in GBLUP improved accuracy of prediction by 0.02 for EMA and up to 0.05 for BFT, CWT, and MS, compared to a 50 k standard SNP array that gave accuracies of 0.50, 0.47, 0.58, and 0.47, respectively. Accuracy of prediction of BFT and CWT increased when BayesR was applied with the 50 k SNP array (0.02 and 0.03, respectively) and was further improved by combining the 50 k array with the top-SNPs (0.06 and 0.04, respectively). By contrast, using BayesR resulted in limited improvement for EMA and MS. wGBLUP did not improve accuracy but increased prediction bias. Based on the RNA-seq experiment, we identified informative expression quantitative trait loci, which, when used in GBLUP, improved the accuracy of prediction slightly, i.e. between 0.01 and 0.02. SNPs that were located in genes, the expression of which was associated with differences in trait phenotype, did not contribute to a higher prediction accuracy. Conclusions Our results show that, in Hanwoo beef cattle, when SNPs are pre-selected from GWAS on imputed sequence data, the accuracy of prediction improves only slightly whereas the contribution of SNPs that are selected based on gene expression is not significant. The benefit of statistical models to prioritize selected SNPs for estimating genomic breeding values is trait-specific and depends on the genetic architecture of each trait.

International audience; AbstractBackgroundThis study aimed at (1) comparing the accuracies of genomic prediction for parasite resistance in sheep based on whole-genome sequence (WGS) data to those based on 50k and high-density (HD) single nucleotide polymorphism (SNP) panels; (2) investigating whether the use of variants within quantitative trait loci (QTL) regions that were selected from regional heritability mapping (RHM) in an independent dataset improved the accuracy more than variants selected from genome-wide association studies (GWAS); and (3) comparing the prediction accuracies between variants selected from WGS data to variants selected from the HD SNP panel.ResultsThe accuracy of genomic prediction improved marginally from 0.16 ± 0.02 and 0.18 ± 0.01 when using all the variants from 50k and HD genotypes, respectively, to 0.19 ± 0.01 when using all the variants from WGS data. Fitting a GRM from the selected variants alongside a GRM from the 50k SNP genotypes improved the prediction accuracy substantially compared to fitting the 50k SNP genotypes alone. The gain in prediction accuracy was slightly more pronounced when variants were selected from WGS data compared to when variants were selected from the HD panel. When sequence variants that passed the GWAS -log10(pvalue)\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$- log_{10} (p\,value)$$\end{document} threshold of 3 across the entire genome were selected, the prediction accuracy improved by 5% (up to 0.21 ± 0.01), whereas when selection was limited to sequence variants that passed the same GWAS -log10(pvalue)\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$- log_{10} (p\,value)$$\end{document} threshold of 3 in regions identified by RHM, the accuracy improved by 9% (up to 0.25 ± 0.01).ConclusionsOur results show that through careful selection of sequence variants from the QTL regions, the accuracy of genomic prediction for parasite resistance in sheep can be improved. These findings have important implications for genomic prediction in sheep.

The objectives of this study were to estimate the additive and dominance variance component of several weight and ultrasound scanned body composition traits in purebred and combined cross-bred sheep populations based on single nucleotide polymorphism (SNP) marker genotypes and then to investigate the effect of fitting additive and dominance effects on accuracy of genomic evaluation. Additive and dominance variance components were estimated in a mixed model equation based on "average information restricted maximum likelihood" using additive and dominance (co)variances between animals calculated from 48,599 SNP marker genotypes. Genomic prediction was based on genomic best linear unbiased prediction (GBLUP), and the accuracy of prediction was assessed based on a random 10-fold cross-validation. Across different weight and scanned body composition traits, dominance variance ranged from 0.0% to 7.3% of the phenotypic variance in the purebred population and from 7.1% to 19.2% in the combined cross-bred population. In the combined cross-bred population, the range of dominance variance decreased to 3.1% and 9.9% after accounting for heterosis effects. Accounting for dominance effects significantly improved the likelihood of the fitting model in the combined cross-bred population. This study showed a substantial dominance genetic variance for weight and ultrasound scanned body composition traits particularly in cross-bred population; however, improvement in the accuracy of genomic breeding values was small and statistically not significant. Dominance variance estimates in combined cross-bred population could be overestimated if heterosis is not fitted in the model.

Reference populations for genomic selection usually involve selected individuals,which may result in biased prediction of estimated genomic breeding values (GEBV). In a simulation study, bias and accuracy of GEBV were explored for various genetic models with individuals selectively genotyped in a typical nucleus breeding program. We compared the performance of three existing methods, that is,Best Linear Unbiased Prediction of breeding values using pedigree‐based relationships (PBLUP), genomic relationships for genotyped animals only (GBLUP) and aSingle‐Step approach (SSGBLUP) using both. For a scenario with no‐selection and random mating (RR), prediction was unbiased. However, lower accuracy and bias were observed for scenarios with selection and random mating (SR) or selection and positive assortative mating (SA). As expected, bias disappeared when all individuals were genotyped and used in GBLUP. SSGBLUP showed higher accuracy compared to GBLUP, and bias of prediction was negligible with SR. However, PBLUP and SSGBLUP still showed bias in SA due to high inbreeding. SSGBLUP and PBLUP were unbiased provided that inbreeding was accounted for in the relationship matrices.Selective genotyping based on extreme phenotypic contrasts increased the prediction accuracy, but prediction was biased when using GBLUP. SSGBLUP could correct the biasedness while gaining higher accuracy than GBLUP. In a typical animal breeding program, where it is too expensive to genotype all animals, it would be appropriate to genotype phenotypically contrasting selection candidates and use a Single‐Step approach to obtain accurate and unbiased prediction of GEBV. Refereed/Peer-reviewed

Reference populations for genomic selection (GS) usually involve highly selected individuals, which may result in biased prediction of estimated genomic breeding values (GEBV). In the present study, bias and accuracy of GEBV were explored for various genetic models and prediction methods when using selected individuals for a reference. Data were simulated for an animal breeding program to compare Best Linear Unbiased Prediction of breeding values using pedigree based relationships (PBLUP), genomic relationships for genotyped animals only (GBLUP) and a Single Step approach (SSGBLUP), where information on genotyped individuals was used to infer a matrix H with relationships among all available genotyped and non-genotyped individuals that were linked through pedigree. In SSGBLUP, various weights (α=0.95, 0.80, 0.50) for the genomic relationship matrix (G) relative to the numerator relationship matrix (A) were applied to construct H and in another version (SSGBLUP_F), inbreeding was accounted for while computing A-1. With GBLUP, accuracy of GEBV prediction increased linearly with an increase in the number of animals selected in reference. For the scenario with no-selection and random mating (RR) prediction was unbiased. For GBLUP, lower accuracy and bias observed in the scenarios with selection and random mating (SR) or selection and positive assortative mating (SA), in which prediction bias increased when a smaller and highly selected proportion genotyped. Bias disappeared when all individuals were genotyped. SSGBLUP_F showed higher accuracy compared to GBLUP and bias of prediction was negligible even with selective genotyping. However, PBLUP and SSGBLUP showed bias in SA owing to not fully accounting for allele frequency changes because of selection of quantitative trait loci (QTL) with larger effects and also due to high inbreeding rate. In genetic models with fewer QTL but each with larger effect, predictions were less accurate and more biased for selection scenarios. Results suggest that prediction accuracy and bias is affected by the genetic architecture of the trait. Selective genotyping lead to significant bias in GEBV prediction. SSGBLUP with appropriate scaling of A and G matrices can provide accurate and less biased prediction but scaling requires careful consideration in populations under selection and with high levels of inbreeding.

Background The application of genomic selection to sheep breeding could lead to substantial increases in profitability of wool production due to the availability of accurate breeding values from single nucleotide polymorphism (SNP) data. Several key traits determine the value of wool and influence a sheep’s susceptibility to fleece rot and fly strike. Our aim was to predict genomic estimated breeding values (GEBV) and to compare three methods of combining information across traits to map polymorphisms that affect these traits. Methods GEBV for 5726 Merino and Merino crossbred sheep were calculated using BayesR and genomic best linear unbiased prediction (GBLUP) with real and imputed 510,174 SNPs for 22 traits (at yearling and adult ages) including wool production and quality, and breech conformation traits that are associated with susceptibility to fly strike. Accuracies of these GEBV were assessed using fivefold cross-validation. We also devised and compared three approximate multi-trait analyses to map pleiotropic quantitative trait loci (QTL): a multi-trait genome-wide association study and two multi-trait methods that use the output from BayesR analyses. One BayesR method used local GEBV for each trait, while the other used the posterior probabilities that a SNP had an effect on each trait. Results BayesR and GBLUP resulted in similar average GEBV accuracies across traits (~0.22). BayesR accuracies were highest for wool yield and fibre diameter (>0.40) and lowest for skin quality and dag score (

International audience; AbstractBackground Genomic prediction using high-density (HD) marker genotypes is expected to lead to higher prediction accuracy, particularly for more heterogeneous multi-breed and crossbred populations such as those in sheep and beef cattle, due to providing stronger linkage disequilibrium between single nucleotide polymorphisms and quantitative trait loci controlling a trait. The objective of this study was to evaluate a possible improvement in genomic prediction accuracy of production traits in Australian sheep breeds based on HD genotypes (600k, both observed and imputed) compared to prediction based on 50k marker genotypes. In particular, we compared improvement in prediction accuracy of animals that are more distantly related to the reference population and across sheep breeds.MethodsGenomic best linear unbiased prediction (GBLUP) and a Bayesian approach (BayesR) were used as prediction methods using whole or subsets of a large multi-breed/crossbred sheep reference set. Empirical prediction accuracy was evaluated for purebred Merino, Border Leicester, Poll Dorset and White Suffolk sire breeds according to the Pearson correlation coefficient between genomic estimated breeding values and breeding values estimated based on a progeny test in a separate dataset.ResultsResults showed a small absolute improvement (0.0 to 8.0% and on average 2.2% across all traits) in prediction accuracy of purebred animals from HD genotypes when prediction was based on the whole dataset. Greater improvement in prediction accuracy (1.0 to 12.0% and on average 5.2%) was observed for animals that were genetically lowly related to the reference set while it ranged from 0.0 to 5.0% for across-breed prediction. On average, no significant advantage was observed with BayesR compared to GBLUP.

International audience; Background The accuracy of genomic prediction depends largely on the number of animals with phenotypes and genotypes. In some industries, such as sheep and beef cattle, data are often available from a mixture of breeds, multiple strains within a breed or from crossbred animals. The objective of this study was to compare the accuracy of genomic prediction for several economically important traits in sheep when using data from purebreds, crossbreds or a combination of those in a reference population.MethodsThe reference populations were purebred Merinos, crossbreds of Border Leicester (BL), Poll Dorset (PD) or White Suffolk (WS) with Merinos and combinations of purebred and crossbred animals. Genomic breeding values (GBV) were calculated based on genomic best linear unbiased prediction (GBLUP), using a genomic relationship matrix calculated based on 48 599 Ovine SNP (single nucleotide polymorphisms) genotypes. The accuracy of GBV was assessed in a group of purebred industry sires based on the correlation coefficient between GBV and accurate estimated breeding values based on progeny records.ResultsThe accuracy of GBV for Merino sires increased with a larger purebred Merino reference population, but decreased when a large purebred Merino reference population was augmented with records from crossbred animals. The GBV accuracy for BL, PD and WS breeds based on crossbred data was the same or tended to decrease when more purebred Merinos were added to the crossbred reference population. The prediction accuracy for a particular breed was close to zero when the reference population did not contain any haplotypes of the target breed, except for some low accuracies that were obtained when predicting PD from WS and vice versa.ConclusionsThis study demonstrates that crossbred animals can be used for genomic prediction of purebred animals using 50 k SNP marker density and GBLUP, but crossbred data provided lower accuracy than purebred data. Including data from distant breeds in a reference population had a neutral to slightly negative effect on the accuracy of genomic prediction. Accounting for differences in marker allele frequencies between breeds had only a small effect on the accuracy of genomic prediction from crossbred or combined crossbred and purebred reference populations.