Improving Genomic Prediction Accuracy in the Chinese Holstein Population by Combining with the Nordic Holstein Reference Population.

The size of the reference population is critical in order to improve the accuracy of genomic prediction. Indeed, improving genomic prediction accuracy by combining multinational reference populations has proven to be effective. In this study, we investigated the improvement of genomic prediction accuracy in seven complex traits (i.e., milk yield; fat yield; protein yield; somatic cell count; body conformation; feet and legs; and mammary system conformation) by combining the Chinese and Nordic Holstein reference populations. The estimated genetic correlations between the Chinese and Nordic Holstein populations are high with respect to protein yield, fat yield, and milk yield-whereby these correlations range from 0.621 to 0.720-and are moderate with respect to somatic cell count (0.449), but low for the three conformation traits (which range from 0.144 to 0.236). When utilizing the joint reference data and a two-trait GBLUP model, the genomic prediction accuracy in the Chinese Holsteins improves considerably with respect to the traits with moderate-to-high genetic correlations, whereas the improvement in Nordic Holsteins is small. When compared with the single population analysis, using the joint reference population for genomic prediction in younger animals, results in a 2.3 to 8.1 percent improvement in accuracy. Meanwhile, 10 replications of five-fold cross-validation were also implemented in order to evaluate the performance of joint genomic prediction, thereby resulting in a 1.6 to 5.2 percent increase in accuracy. With respect to joint genomic prediction, the bias was found to be quite low. However, for traits with low genetic correlations, the joint reference data do not improve the prediction accuracy substantially for either population.

Genetic parameters of semen quality traits and genetic correlations with service sire nonreturn rate in Nordic Holstein bulls.

Despite the importance of the quality of semen used in artificial insemination to the reproductive success of dairy herds, few studies have estimated the extent of genetic variability in semen quality traits. Even fewer studies have quantified the correlation between semen quality traits and male fertility. In this study, records of 100,058 ejaculates collected from 2,885 Nordic Holstein bulls were used to estimate genetic parameters for semen quality traits, including pre- and postcryopreservation semen concentration, sperm motility and viability, ejaculate volume, and number of doses per ejaculate. Additionally, summary data on nonreturn rate (NRR) obtained from insemination of some of the bulls (n = 2,142) to cows in different parities (heifers and parities 1-3 or more) were used to estimate correlations between the semen quality traits and service sire NRR. In the study, low to moderate heritability (0.06-0.45) was estimated for semen quality traits, indicating the possibility of improving these traits through selective breeding. The study also showed moderate to high genetic and phenotypic correlations between service sire NRR and some of the semen quality traits, including sperm viability pre- and postcryopreservation, motility postcryopreservation, and sperm concentration precryopreservation, indicating the predictive values of these traits for service sire NRR. The positive moderate to high genetic correlations between semen quality and service sire NRR traits also indicated that selection for semen quality traits might be favorable for improving service sire NRR.

Genomic prediction using a reference population of multiple pure breeds and admixed individuals.

BACKGROUND: In dairy cattle populations in which crossbreeding has been used, animals show some level of diversity in their origins. In rotational crossbreeding, for instance, crossbred dams are mated with purebred sires from different pure breeds, and the genetic composition of crossbred animals is an admixture of the breeds included in the rotation. How to use the data of such individuals in genomic evaluations is still an open question. In this study, we aimed at providing methodologies for the use of data from crossbred individuals with an admixed genetic background together with data from multiple pure breeds, for the purpose of genomic evaluations for both purebred and crossbred animals. A three-breed rotational crossbreeding system was mimicked using simulations based on animals genotyped with the 50 K single nucleotide polymorphism (SNP) chip. RESULTS: For purebred populations, within-breed genomic predictions generally led to higher accuracies than those from multi-breed predictions using combined data of pure breeds. Adding admixed population's (MIX) data to the combined pure breed data considering MIX as a different breed led to higher accuracies. When prediction models were able to account for breed origin of alleles, accuracies were generally higher than those from combining all available data, depending on the correlation of quantitative trait loci (QTL) effects between the breeds. Accuracies varied when using SNP effects from any of the pure breeds to predict the breeding values of MIX. Using those breed-specific SNP effects that were estimated separately in each pure breed, while accounting for breed origin of alleles for the selection candidates of MIX, generally improved the accuracies. Models that are able to accommodate MIX data with the breed origin of alleles approach generally led to higher accuracies than models without breed origin of alleles, depending on the correlation of QTL effects between the breeds. CONCLUSIONS: Combining all available data, pure breeds' and admixed population's data, in a multi-breed reference population is beneficial for the estimation of breeding values for pure breeds with a small reference population. For MIX, such an approach can lead to higher accuracies than considering breed origin of alleles for the selection candidates, and using breed-specific SNP effects estimated separately in each pure breed. Including MIX data in the reference population of multiple breeds by considering the breed origin of alleles, accuracies can be further improved. Our findings are relevant for breeding programs in which crossbreeding is systematically applied, and also for populations that involve different subpopulations and between which exchange of genetic material is routine practice.

Genomic selection in American mink (Neovison vison) using a single-step genomic best linear unbiased prediction model for size and quality traits graded on live mink.

Genomic selection relies on single-nucleotide polymorphisms (SNPs), which are often collected using medium-density SNP arrays. In mink, no such array is available; instead, genotyping by sequencing (GBS) can be used to generate marker information. Here, we evaluated the effect of genomic selection for mink using GBS. We compared the estimated breeding values (EBVs) from single-step genomic best linear unbiased prediction (SSGBLUP) models to the EBV from ordinary pedigree-based BLUP models. We analyzed seven size and quality traits from the live grading of brown mink. The phenotype data consisted of ~20,600 records for the seven traits from the mink born between 2013 and 2016. Genotype data included 2,103 mink born between 2010 and 2014, mostly breeding animals. In total, 28,336 SNP markers from 391 scaffolds were available for genomic prediction. The pedigree file included 29,212 mink. The predictive ability was assessed by the correlation (r) between progeny trait deviation (PTD) and EBV, and the regression of PTD on EBV, using 5-fold cross-validation. For each fold, one-fifth of animals born in 2014 formed the validation set. For all traits, the SSGBLUP model resulted in higher accuracies than the BLUP model. The average increase in accuracy was 15% (between 3% for fur clarity and 28% for body weight). For three traits (body weight, silky appearance of the under wool, and guard hair thickness), the difference in r between the two models was significant (P < 0.05). For all traits, the regression slopes of PTD on EBV from SSGBLUP models were closer to 1 than regression slopes from BLUP models, indicating SSGBLUP models resulted in less bias of EBV for selection candidates than the BLUP models. However, the regression coefficients did not differ significantly. In conclusion, the SSGBLUP model is superior to conventional BLUP model in the accurate selection of superior animals, and, thus, it would increase genetic gain in a selective breeding program. In addition, this study shows that GBS data work well in genomic prediction in mink, demonstrating the potential of GBS for genomic selection in livestock species.

Novel approach to incorporate information about recessive lethal genes increases the accuracy of genomic prediction for mortality traits.

The genetic underpinnings of calf mortality can be partly polygenic and partly due to deleterious effects of recessive lethal alleles. Prediction of the genetic merits of selection candidates should thus take into account both genetic components contributing to calf mortality. However, simultaneously modeling polygenic risk and recessive lethal allele effects in genomic prediction is challenging due to effects that behave differently. In this study, we present a novel approach where mortality risk probabilities from polygenic and lethal allele components are predicted separately to compute the total risk probability of an individual for its future offspring as a basis for selection. We present methods for transforming genomic estimated breeding values of polygenic effect into risk probabilities using normal density and cumulative distribution functions and show computations of risk probability from recessive lethal alleles given sire genotypes and population recessive allele frequencies. Simulated data were used to test the novel approach as implemented in probit, logit, and linear models. In the simulation study, the accuracy of predicted risk probabilities was computed as the correlation between predicted mortality probabilities and observed calf mortality for validation sires. The results indicate that our novel approach can greatly increase the accuracy of selection for mortality traits compared with the accuracy of predictions obtained without distinguishing polygenic and lethal gene effects.

Novel haplotypes responsible for prenatal death in Nordic Red and Danish Jersey cattle.

Haplotypes that are common in a population but not observed as homotypes in living animals may harbor lethal alleles that compromise embryo survival. In this study, we searched for homozygous-deficient haplotypes in the genomes of 19,309 Nordic Red Dairy (RDC) and 4,291 Danish Jersey (JER) cattle genotyped using the Illumina BovineSNP50 BeadChip (Illumina Inc., San Diego, CA). For statistically significant deficient haplotypes, we evaluated the effect on nonreturn rate in at-risk matings (mating between carrier bull and daughter of carrier sire) versus not-at-risk matings (mating between noncarrier bull and daughter of noncarrier sire). Next, we analyzed whole-genome sequence variants from the 1000 Bull Genomes Project to identify putative causal variants underlying these haplotypes. In RDC, we identified 3 homozygous-deficient regions (HDR) that overlapped with known recessive lethal mutations: a 662-kb deletion on chromosome 12 in RDC [Online Mendelian Inheritance in Animals (OMIA) 001901-9913), a missense mutation in TUBD1, g.11063520T>C, in Braunvieh cattle (OMIA 001939-9913), and a 525-kb deletion on chromosome 23 in RDC (OMIA 001991-9913)]. In addition, we identified 15 novel HDR and their tag haplotypes for the underlying causative variants. The tag haplotype located between 39.2 and 40.3 Mbp on chromosome 18 had a negative effect on nonreturn rate in at-risk mating, confirming embryonic lethality. In Danish Jersey, we identified 12 novel HDR and their tag haplotypes for underlying causative variants. For 3 of these 12 tag haplotypes, insemination records of at-risk mating showed a negative effect on nonreturn rate, confirming the association with early embryonic mortality. Cattle that had both genotype and whole-genome sequence data were analyzed to detect the causative variants underlying each tag haplotype. However, none of the functional variants or deletions showed concordance with carrier status of the novel tag haplotypes. Carrier status of these detected haplotypes can be used to select bulls to reduce the frequencies of lethal alleles in the population and to avoid at-risk matings.

Correction: Multi-trait single-step genomic prediction accounting for heterogeneous (co)variances over the genome.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Multi-trait single-step genomic prediction accounting for heterogeneous (co)variances over the genome.

Widely used genomic prediction models may not properly account for heterogeneous (co)variance structure across the genome. Models such as BayesA and BayesB assume locus-specific variance, which are highly influenced by the prior for (co)variance of single nucleotide polymorphism (SNP) effect, regardless of the size of data. Models such as BayesC or GBLUP assume a common (co)variance for a proportion (BayesC) or all (GBLUP) of the SNP effects. In this study, we propose a multi-trait Bayesian whole genome regression method (BayesN0), which is based on grouping a number of predefined SNPs to account for heterogeneous (co)variance structure across the genome. This model was also implemented in single-step Bayesian regression (ssBayesN0). For practical implementation, we considered multi-trait single-step SNPBLUP models, using (co)variance estimates from BayesN0 or ssBayesN0. Genotype data were simulated using haplotypes on first five chromosomes of 2200 Danish Holstein cattle, and phenotypes were simulated for two traits with heritabilities 0.1 or 0.4, assuming 200 quantitative trait loci (QTL). We compared prediction accuracy from different prediction models and different region sizes (one SNP, 100 SNPs, one chromosome or whole genome). In general, highest accuracies were obtained when 100 adjacent SNPs were grouped together. The ssBayesN0 improved accuracies over BayesN0, and using (co)variance estimates from ssBayesN0 generally yielded higher accuracies than using (co)variance estimates from BayesN0, for the 100 SNPs region size. Our results suggest that it could be a good strategy to estimate (co)variance components from ssBayesN0, and then to use those estimates in genomic prediction using multi-trait single-step SNPBLUP, in routine genomic evaluations.

Quantifying the contribution of sequence variants with regulatory and evolutionary significance to 34 bovine complex traits.

Many genome variants shaping mammalian phenotype are hypothesized to regulate gene transcription and/or to be under selection. However, most of the evidence to support this hypothesis comes from human studies. Systematic evidence for regulatory and evolutionary signals contributing to complex traits in a different mammalian model is needed. Sequence variants associated with gene expression (expression quantitative trait loci [eQTLs]) and concentration of metabolites (metabolic quantitative trait loci [mQTLs]) and under histone-modification marks in several tissues were discovered from multiomics data of over 400 cattle. Variants under selection and evolutionary constraint were identified using genome databases of multiple species. These analyses defined 30 sets of variants, and for each set, we estimated the genetic variance the set explained across 34 complex traits in 11,923 bulls and 32,347 cows with 17,669,372 imputed variants. The per-variant trait heritability of these sets across traits was highly consistent (r > 0.94) between bulls and cows. Based on the per-variant heritability, conserved sites across 100 vertebrate species and mQTLs ranked the highest, followed by eQTLs, young variants, those under histone-modification marks, and selection signatures. From these results, we defined a Functional-And-Evolutionary Trait Heritability (FAETH) score indicating the functionality and predicted heritability of each variant. In additional 7,551 cattle, the high FAETH-ranking variants had significantly increased genetic variances and genomic prediction accuracies in 3 production traits compared to the low FAETH-ranking variants. The FAETH framework combines the information of gene regulation, evolution, and trait heritability to rank variants, and the publicly available FAETH data provide a set of biological priors for cattle genomic selection worldwide.

Haplotypes responsible for early embryonic lethality detected in Nordic Holsteins.

Widespread use of a limited number of elite sires in dairy cattle breeding increases the risk of some deleterious allelic variants spreading in the population. Genomic data are being used to detect relatively common (frequency >1%) haplotypes that never occur in the homozygous state in live animals. Such haplotypes likely include recessive lethal or semilethal alleles. The aim of this study was to detect such haplotypes in the Nordic Holstein population and to identify causal genetic factors underlying these haplotypes. Illumina BovineSNP50 BeadChip (Illumina Inc., San Diego, CA) genotypes for 26,312 Nordic Holstein animals were phased to construct haplotypes. Haplotypes that are common in the population but never observed as homozygous were identified. Two such haplotypes overlapped with previously identified recessive lethal mutations in Holsteins-namely, structural maintenance of chromosomes 2 (HH3) and brachyspina. In addition, we identified 9 novel putative recessive lethal-carrying haplotypes, with 26 to 36 homozygous individuals expected among the genotyped animals but only 0 to 3 homozygotes observed. For 2 out of 9 homozygous-deficient haplotypes, insemination records of at-risk mating (carrier bull with daughter of carrier sire) showed reduced insemination success compared with not-at-risk mating (noncarrier bull with daughter of noncarrier sire), supporting early embryonic mortality. To detect the causative variant underlying each homozygous-deficient haplotype, data from the 1000 Bull Genome Project were used. However, no variants or deletions identified in the chromosome regions covered by the haplotypes showed concordance with haplotype carrier status. The carrier status of detected haplotypes could be used to select bulls to reduce the frequency of the latent lethal mutations in the population. If desired, at-risk matings could be avoided.

Use of a Bayesian model including QTL markers increases prediction reliability when test animals are distant from the reference population.

Relatedness between reference and test animals has an important effect on the reliability of genomic prediction for test animals. Because genomic prediction has been widely applied in practical cattle breeding and bulls have been selected according to genomic breeding value without progeny testing, the sires or grandsires of candidates might not have phenotypic information and might not be in the reference population when the candidates are selected. The objective of this study was to investigate the decreasing trend of the reliability of genomic prediction given distant reference populations, using genomic best linear unbiased prediction (GBLUP) and Bayesian variable selection models with or without including the quantitative trait locus (QTL) markers detected from sequencing data. The data used in this study consisted of 22,242 bulls genotyped using the 54K SNP array from EuroGenomics. Among them, 1,444 Danish bulls born from 2006 to 2010 were selected as test animals. Different reference populations with varying relationships to test animals were created according to pedigree-based relationships. The reference individuals having a relationship with one or more test animals higher than 0.4 (scenario ρ < 0.4), 0.2 (ρ < 0.2), or 0.1 (ρ < 0.1, where ρ = relationship coefficient) were removed from reference sets; these represented the distance between reference and test animals being 2 generations, 3 generations, and 4 generations, respectively. Imputed whole-genome sequencing data of bulls from Denmark were used to conduct a genome-wide association study (GWAS). A small number of significant variants (QTL markers) from the GWAS were added to the array data. To compare the effects of different models, the basic GBLUP model, a Bayesian selection variable model, a GBLUP model with 2 components of genetic effects, and a Bayesian model with pooled array data and QTL markers were used for estimating genomic estimated breeding values (GEBV) of test animals. The reliability of genomic prediction decreased when the test animals were more generations away from the reference population. The reliability of genomic prediction was 0.461 for 1 generation away and 0.396 for 3 generations away, with the same number of individuals in the reference set, using a GBLUP model with chip markers only. The results showed that using the Bayesian method and QTL markers improved the reliability of genomic prediction in all scenarios of relationship between test and reference animals, in a range of 1.3% and 65.1% (4 generations away with only 841 individuals in the reference set). However, most gains were for predictions of milk yield and fat yield. There was little improvement for predictions of protein yield and mastitis, and no improvement for prediction of fertility, except for scenario ρ < 0.1, in which there was a large improvement for predictions of all traits. On the other hand, models including more than 10% polygenic effect decreased prediction reliability when the relationship between test and reference animals was distant.

Reliability of genomic prediction for milk fatty acid composition by using a multi-population reference and incorporating GWAS results.

BACKGROUND: Large-scale phenotyping for detailed milk fatty acid (FA) composition is difficult due to expensive and time-consuming analytical techniques. Reliability of genomic prediction is often low for traits that are expensive/difficult to measure and for breeds with a small reference population size. An effective method to increase reference population size could be to combine datasets from different populations. Prediction models might also benefit from incorporation of information on the biological underpinnings of quantitative traits. Genome-wide association studies (GWAS) show that genomic regions on Bos taurus chromosomes (BTA) 14, 19 and 26 underlie substantial proportions of the genetic variation in milk FA traits. Genomic prediction models that incorporate such results could enable improved prediction accuracy in spite of limited reference population sizes. In this study, we combine gas chromatography quantified FA samples from the Chinese, Danish and Dutch Holstein populations and implement a genomic feature best linear unbiased prediction (GFBLUP) model that incorporates variants on BTA14, 19 and 26 as genomic features for which random genetic effects are estimated separately. Prediction reliabilities were compared to those estimated with traditional GBLUP models. RESULTS: Predictions using a multi-population reference and a traditional GBLUP model resulted in average gains in prediction reliability of 10% points in the Dutch, 8% points in the Danish and 1% point in the Chinese populations compared to predictions based on population-specific references. Compared to the traditional GBLUP, implementation of the GFBLUP model with a multi-population reference led to further increases in prediction reliability of up to 38% points in the Dutch, 23% points in the Danish and 13% points in the Chinese populations. Prediction reliabilities from the GFBLUP model were moderate to high across the FA traits analyzed. CONCLUSIONS: Our study shows that it is possible to predict genetic merits for milk FA traits with reasonable accuracy by combining related populations of a breed and using models that incorporate GWAS results. Our findings indicate that international collaborations that facilitate access to multi-population datasets could be highly beneficial to the implementation of genomic selection for detailed milk composition traits.

Selection for temperament has no negative consequences on important production traits in farmed mink1.

Danish and European legislation recommend mink breeding programs that include selection for "confidence," defined as exploratory activity in a standardized behavioral test. Although this recommendation may improve mink welfare, farmers may consider this criterion risky due to possible negative consequences on other traits. The overall objectives of this study were to estimate the heritability of exploratory/fearful behavior and to identify genetic correlations with other traits of major economic importance in mink fur production. Various aspects of social influence on exploratory/fearful behavior, such as effects of the mother and litter siblings before weaning, the mother's age, and cage mates after weaning, were analyzed. In total, 26,371 1-yr-old Brown mink (Neovison vison) individuals born during the period of 2013 to2016 were included in the study. Exploratory/fearful behavior was the main trait analyzed. The production traits analyzed were live pelt quality and body weight. Both of these traits were assessed during live grading in November. Pelt length and quality were determined using the dried pelts of nonbreeders. Fertility data were obtained from the Fur Farm database. Linear mixed models were run using the restricted maximum-likelihood method. The genetic correlation between female and male behavior was 0.95 (SE = 0.06), indicating similar genetic backgrounds for both sexes (P = 0.40). For both sexes, the estimated heritability of behavior was 0.19 (SE = 0.03). We found no significant genetic correlation between behavior and production/fertility traits (P > 0.05). Common litter variance indicated a preweaning effect of litter mates and/or dam on postweaning temperament. There was a tendency for offspring from older mothers to explore more than offspring from 1-yr-old mothers. This trend was especially pronounced for males of 2-yr-old mothers (P = 0.05) and females of 4-yr-old mothers (P = 0.06). We conclude that confidence may be selected for among farm mink without detrimental effects on economically important production traits, such as pelt quality and fertility.

Introgression of Chinese haplotypes contributed to the improvement of Danish Duroc pigs.

The distribution of Asian ancestry in the genome of Danish Duroc pigs was investigated using whole-genome sequencing data from European wild boars, Danish Duroc, Chinese Meishan and Bamaxiang pigs. Asian haplotypes deriving from Meishan and Bamaxiang occur widely across the genome. Signatures of selection on Asian haplotypes are common in the genome, but few of these haplotypes have been fixed. By defining 50-kb windows with more than 50% Chinese ancestry, which did not exhibit extreme genetic differentiation between Meishan and Bamaxiang as candidate regions, the enrichment of quantitative trait loci in candidate regions supports that Asian haplotypes under selection play an important role in contributing genetic variation underlying production, reproduction, meat and carcass, and exterior traits. Gene annotation of regions with the highest proportion of Chinese ancestry revealed genes of biological interest, such as NR6A1. Further haplotype clustering analysis suggested that a haplotype of Chinese origin around the NR6A1 gene was introduced to Europe and then underwent a selective sweep in European pigs. Besides, functional genes in candidate regions, such as AHR and PGRMC2, associated with fertility, and SAL1, associated with meat quality, were identified. Our results demonstrate the contribution of Asian haplotypes to the genomes of European pigs. Findings herein facilitate further genomic studies such as genomewide association study and genomic prediction by providing ancestry information of variants.

A Meta-Analysis Including Pre-selected Sequence Variants Associated With Seven Traits in Three French Dairy Cattle Populations.

A within-breed genome-wide association study (GWAS) is useful when identifying the QTL that segregates in a breed. However, an across-breed meta-analysis can be used to increase the power of identification and precise localization of QTL that segregate in multiple breeds. Precise localization will allow including QTL information from other breeds in genomic prediction due to the persistence of the linkage phase between the causal variant and the marker. This study aimed to identify and confirm QTL detected in within-breed GWAS through a meta-analysis in three French dairy cattle breeds. A set of sequence variants selected based on their functional annotations were imputed into 50 k genotypes for 46,732 Holstein, 20,096 Montbeliarde, and 11,944 Normande cows to identify QTL for milk production, the success rate at insemination of cows (fertility) and stature. We conducted within-breed GWAS followed by across-breed meta-analysis using a weighted Z-scores model on the GWAS summary data (i.e., P-values, effect direction, and sample size). After Bonferroni correction, the GWAS result identified 21,956 significantly associated SNP (P FWER < 0.05), while meta-analysis result identified 9,604 significant SNP (P FWER < 0.05) associated with the phenotypes. The meta-analysis identified 36 QTL for milk yield, 48 QTL for fat yield and percentage, 29 QTL for protein yield and percentage, 13 QTL for fertility, and 16 QTL for stature. Some of these QTL were not significant in the within-breed GWAS. Some previously identified causal variants were confirmed, e.g., BTA14:1802265 (fat percentage, P = 1.5 × 10-760; protein percentage, P = 7.61 × 10-348) both mapping the DGAT1-K232A mutation and BTA14:25006125 (P = 8.58 × 10-140) mapping PLAG1 gene was confirmed for stature in Montbeliarde. New QTL lead SNP shared between breeds included the intronic variant rs109205829 (NFIB gene), and the intergenic variant rs41592357 (1.38 Mb upstream of the CNTN6 gene and 0.65 Mb downstream of the CNTN4 gene). Rs110425867 (ZFAT gene) was the top variant associated with fertility, and new QTL lead SNP included rs109483390 (0.1 Mb upstream of the TNFAIP3 gene and 0.07 Mb downstream of PERP gene), and rs42412333 (0.45 Mb downstream of the RPL10L gene). An across-breed meta-analysis had greater power to detect QTL as opposed to a within breed GWAS. The QTL detected here can be incorporated in routine genomic predictions.

Genomic Prediction Using Multi-trait Weighted GBLUP Accounting for Heterogeneous Variances and Covariances Across the Genome.

Implicit assumption of common (co)variance for all loci in multi-trait Genomic Best Linear Unbiased Prediction (GBLUP) results in a genomic relationship matrix (G) that is common to all traits. When this assumption is violated, Bayesian whole genome regression methods may be superior to GBLUP by accounting for unequal (co)variance for all loci or genome regions. This study aimed to develop a strategy to improve the accuracy of GBLUP for multi-trait genomic prediction, using (co)variance estimates of SNP effects from Bayesian whole genome regression methods. Five generations (G1-G5, test populations) of genotype data were available by simulations based on data of 2,200 Danish Holstein cows (G0, reference population). Two correlated traits with heritabilities of 0.1 or 0.4, and a genetic correlation of 0.45 were generated. First, SNP effects and breeding values were estimated using BayesAS method, assuming (co)variance was the same for SNPs within a genome region, and different between regions. Region size was set as one SNP, 100 SNPs, a whole chromosome or whole genome. Second, posterior (co)variances of SNP effects were used to weight SNPs in construction of G matrices. In general, region size of 100 SNPs led to highest prediction accuracies using BayesAS, and wGBLUP outperformed GBLUP at this region size. Our results suggest that when genetic architectures of traits favor Bayesian methods, the accuracy of multi-trait GBLUP can be as high as the Bayesian method if SNPs are weighted by the Bayesian posterior (co)variances.

Meta-analysis of genome-wide association studies for cattle stature identifies common genes that regulate body size in mammals.

Stature is affected by many polymorphisms of small effect in humans 1 . In contrast, variation in dogs, even within breeds, has been suggested to be largely due to variants in a small number of genes2,3. Here we use data from cattle to compare the genetic architecture of stature to those in humans and dogs. We conducted a meta-analysis for stature using 58,265 cattle from 17 populations with 25.4 million imputed whole-genome sequence variants. Results showed that the genetic architecture of stature in cattle is similar to that in humans, as the lead variants in 163 significantly associated genomic regions (P < 5 × 10-8) explained at most 13.8% of the phenotypic variance. Most of these variants were noncoding, including variants that were also expression quantitative trait loci (eQTLs) and in ChIP-seq peaks. There was significant overlap in loci for stature with humans and dogs, suggesting that a set of common genes regulates body size in mammals.

Modeling heterogeneous (co)variances from adjacent-SNP groups improves genomic prediction for milk protein composition traits.

BACKGROUND: Accurate genomic prediction requires a large reference population, which is problematic for traits that are expensive to measure. Traits related to milk protein composition are not routinely recorded due to costly procedures and are considered to be controlled by a few quantitative trait loci of large effect. The amount of variation explained may vary between regions leading to heterogeneous (co)variance patterns across the genome. Genomic prediction models that can efficiently take such heterogeneity of (co)variances into account can result in improved prediction reliability. In this study, we developed and implemented novel univariate and bivariate Bayesian prediction models, based on estimates of heterogeneous (co)variances for genome segments (BayesAS). Available data consisted of milk protein composition traits measured on cows and de-regressed proofs of total protein yield derived for bulls. Single-nucleotide polymorphisms (SNPs), from 50K SNP arrays, were grouped into non-overlapping genome segments. A segment was defined as one SNP, or a group of 50, 100, or 200 adjacent SNPs, or one chromosome, or the whole genome. Traditional univariate and bivariate genomic best linear unbiased prediction (GBLUP) models were also run for comparison. Reliabilities were calculated through a resampling strategy and using deterministic formula. RESULTS: BayesAS models improved prediction reliability for most of the traits compared to GBLUP models and this gain depended on segment size and genetic architecture of the traits. The gain in prediction reliability was especially marked for the protein composition traits ß-CN, κ-CN and ß-LG, for which prediction reliabilities were improved by 49 percentage points on average using the MT-BayesAS model with a 100-SNP segment size compared to the bivariate GBLUP. Prediction reliabilities were highest with the BayesAS model that uses a 100-SNP segment size. The bivariate versions of our BayesAS models resulted in extra gains of up to 6% in prediction reliability compared to the univariate versions. CONCLUSIONS: Substantial improvement in prediction reliability was possible for most of the traits related to milk protein composition using our novel BayesAS models. Grouping adjacent SNPs into segments provided enhanced information to estimate parameters and allowing the segments to have different (co)variances helped disentangle heterogeneous (co)variances across the genome.

Sequence variants selected from a multi-breed GWAS can improve the reliability of genomic predictions in dairy cattle.

BACKGROUND: Sequence data can potentially increase the reliability of genomic predictions, because such data include causative mutations instead of relying on linkage disequilibrium (LD) between causative mutations and prediction variants. However, the location of the causative mutations is not known, and the presence of many variants that are in low LD with the causative mutations may reduce prediction reliability. Our objective was to investigate whether the use of variants at quantitative trait loci (QTL) that are identified in a multi-breed genome-wide association study (GWAS) for milk, fat and protein yield would increase the reliability of within- and multi-breed genomic predictions in Holstein, Jersey and Danish Red cattle. A wide range of scenarios that test different strategies to select prediction markers, for both within-breed and multi-breed prediction, were compared. RESULTS: For all breeds and traits, the use of variants selected from a multi-breed GWAS resulted in substantial increases in prediction reliabilities compared to within-breed prediction using a 50 K SNP array. Reliabilities depended highly on the choice of the prediction markers, and the scenario that led to the highest reliability varied between breeds and traits. While genomic correlations across breeds were low for genome-wide sequence variants, the effects of the QTL variants that yielded the highest reliabilities were highly correlated across breeds. CONCLUSIONS: Our results show that the use of sequence variants, which are located near peaks of QTL that are detected in a multi-breed GWAS, can increase reliability of genomic predictions.

Using Sequence Variants in Linkage Disequilibrium with Causative Mutations to Improve Across-Breed Prediction in Dairy Cattle: A Simulation Study.

Sequence data are expected to increase the reliability of genomic prediction by containing causative mutations directly, especially in cases where low linkage disequilibrium between markers and causative mutations limits prediction reliability, such as across-breed prediction in dairy cattle. In practice, the causative mutations are unknown, and prediction with only variants in perfect linkage disequilibrium with the causative mutations is not realistic, leading to a reduced reliability compared to knowing the causative variants. Our objective was to use sequence data to investigate the potential benefits of sequence data for the prediction of genomic relationships, and consequently reliability of genomic breeding values. We used sequence data from five dairy cattle breeds, and a larger number of imputed sequences for two of the five breeds. We focused on the influence of linkage disequilibrium between markers and causative mutations, and assumed that a fraction of the causative mutations was shared across breeds and had the same effect across breeds. By comparing the loss in reliability of different scenarios, varying the distance between markers and causative mutations, using either all genome wide markers from commercial SNP chips, or only the markers closest to the causative mutations, we demonstrate the importance of using only variants very close to the causative mutations, especially for across-breed prediction. Rare variants improved prediction only if they were very close to rare causative mutations, and all causative mutations were rare. Our results show that sequence data can potentially improve genomic prediction, but careful selection of markers is essential.