In contrast to currently used single nucleotide polymorphism (SNP) panels, the use of whole-genome sequence data is expected to enable the direct estimation of the effects of causal mutations on a ...given trait. This could lead to higher reliabilities of genomic predictions compared to those based on SNP genotypes. Also, at each generation of selection, recombination events between a SNP and a mutation can cause decay in reliability of genomic predictions based on markers rather than on the causal variants. Our objective was to investigate the use of imputed whole-genome sequence genotypes versus high-density SNP genotypes on (the persistency of) the reliability of genomic predictions using real cattle data.
Highly accurate phenotypes based on daughter performance and Illumina BovineHD Beadchip genotypes were available for 5503 Holstein Friesian bulls. The BovineHD genotypes (631,428 SNPs) of each bull were used to impute whole-genome sequence genotypes (12,590,056 SNPs) using the Beagle software. Imputation was done using a multi-breed reference panel of 429 sequenced individuals. Genomic estimated breeding values for three traits were predicted using a Bayesian stochastic search variable selection (BSSVS) model and a genome-enabled best linear unbiased prediction model (GBLUP). Reliabilities of predictions were based on 2087 validation bulls, while the other 3416 bulls were used for training.
Prediction reliabilities ranged from 0.37 to 0.52. BSSVS performed better than GBLUP in all cases. Reliabilities of genomic predictions were slightly lower with imputed sequence data than with BovineHD chip data. Also, the reliabilities tended to be lower for both sequence data and BovineHD chip data when relationships between training animals were low. No increase in persistency of prediction reliability using imputed sequence data was observed.
Compared to BovineHD genotype data, using imputed sequence data for genomic prediction produced no advantage. To investigate the putative advantage of genomic prediction using (imputed) sequence data, a training set with a larger number of individuals that are distantly related to each other and genomic prediction models that incorporate biological information on the SNPs or that apply stricter SNP pre-selection should be considered.
In livestock, many studies have reported the results of imputation to 50k single nucleotide polymorphism (SNP) genotypes for animals that are genotyped with low-density SNP panels. The objective of ...this paper is to review different measures of correctness of imputation, and to evaluate their utility depending on the purpose of the imputed genotypes. Across studies, imputation accuracy, computed as the correlation between true and imputed genotypes, and imputation error rates, that counts the number of incorrectly imputed alleles, are commonly used measures of imputation correctness. Based on the nature of both measures and results reported in the literature, imputation accuracy appears to be a more useful measure of the correctness of imputation than imputation error rates, because imputation accuracy does not depend on minor allele frequency (MAF), whereas imputation error rate depends on MAF. Therefore imputation accuracy can be better compared across loci with different MAF. Imputation accuracy depends on the ability of identifying the correct haplotype of a SNP, but many other factors have been identified as well, including the number of genotyped immediate ancestors, the number of animals with genotypes at the high-density panel, the SNP density on the low- and high-density panel, the MAF of the imputed SNP and whether imputed SNP are located at the end of a chromosome or not. Some of these factors directly contribute to the linkage disequilibrium between imputed SNP and SNP on the low-density panel. When imputation accuracy is assessed as a predictor for the accuracy of subsequent genomic prediction, we recommend that: (1) individual-specific imputation accuracies should be used that are computed after centring and scaling both true and imputed genotypes; and (2) imputation of gene dosage is preferred over imputation of the most likely genotype, as this increases accuracy and reduces bias of the imputed genotypes and the subsequent genomic predictions.
We compared the performance of linear (GBLUP, BayesB, and elastic net) methods to a nonparametric tree-based ensemble (gradient boosting machine) method for genomic prediction of complex traits in ...mice. The dataset used contained genotypes for 50,112 SNP markers and phenotypes for 835 animals from 6 generations. Traits analyzed were bone mineral density, body weight at 10, 15, and 20 weeks, fat percentage, circulating cholesterol, glucose, insulin, triglycerides, and urine creatinine. The youngest generation was used as a validation subset, and predictions were based on all older generations. Model performance was evaluated by comparing predictions for animals in the validation subset against their adjusted phenotypes. Linear models outperformed gradient boosting machine for 7 out of 10 traits. For bone mineral density, cholesterol, and glucose, the gradient boosting machine model showed better prediction accuracy and lower relative root mean squared error than the linear models. Interestingly, for these 3 traits, there is evidence of a relevant portion of phenotypic variance being explained by epistatic effects. Using a subset of top markers selected from a gradient boosting machine model helped for some of the traits to improve the accuracy of prediction when these were fitted into linear and gradient boosting machine models. Our results indicate that gradient boosting machine is more strongly affected by data size and decreased connectedness between reference and validation sets than the linear models. Although the linear models outperformed gradient boosting machine for the polygenic traits, our results suggest that gradient boosting machine is a competitive method to predict complex traits with assumed epistatic effects.
The use of whole-genome sequence data can lead to higher accuracy in genome-wide association studies and genomic predictions. However, to benefit from whole-genome sequence data, a large dataset of ...sequenced individuals is needed. Imputation from SNP panels, such as the Illumina BovineSNP50 BeadChip and Illumina BovineHD BeadChip, to whole-genome sequence data is an attractive and less expensive approach to obtain whole-genome sequence genotypes for a large number of individuals than sequencing all individuals. Our objective was to investigate accuracy of imputation from lower density SNP panels to whole-genome sequence data in a typical dataset for cattle.
Whole-genome sequence data of chromosome 1 (1737 471 SNPs) for 114 Holstein Friesian bulls were used. Beagle software was used for imputation from the BovineSNP50 (3132 SNPs) and BovineHD (40 492 SNPs) beadchips. Accuracy was calculated as the correlation between observed and imputed genotypes and assessed by five-fold cross-validation. Three scenarios S40, S60 and S80 with respectively 40%, 60%, and 80% of the individuals as reference individuals were investigated.
Mean accuracies of imputation per SNP from the BovineHD panel to sequence data and from the BovineSNP50 panel to sequence data for scenarios S40 and S80 ranged from 0.77 to 0.83 and from 0.37 to 0.46, respectively. Stepwise imputation from the BovineSNP50 to BovineHD panel and then to sequence data for scenario S40 improved accuracy per SNP to 0.65 but it varied considerably between SNPs.
Accuracy of imputation to whole-genome sequence data was generally high for imputation from the BovineHD beadchip, but was low from the BovineSNP50 beadchip. Stepwise imputation from the BovineSNP50 to the BovineHD beadchip and then to sequence data substantially improved accuracy of imputation. SNPs with a low minor allele frequency were more difficult to impute correctly and the reliability of imputation varied more. Linkage disequilibrium between an imputed SNP and the SNP on the lower density panel, minor allele frequency of the imputed SNP and size of the reference group affected imputation reliability.
Abstract
Recent developments allowed generating multiple high-quality ‘omics’ data that could increase the predictive performance of genomic prediction for phenotypes and genetic merit in animals and ...plants. Here, we have assessed the performance of parametric and nonparametric models that leverage transcriptomics in genomic prediction for 13 complex traits recorded in 478 animals from an outbred mouse population. Parametric models were implemented using the best linear unbiased prediction, while nonparametric models were implemented using the gradient boosting machine algorithm. We also propose a new model named GTCBLUP that aims to remove between-omics-layer covariance from predictors, whereas its counterpart GTBLUP does not do that. While gradient boosting machine models captured more phenotypic variation, their predictive performance did not exceed the best linear unbiased prediction models for most traits. Models leveraging gene transcripts captured higher proportions of the phenotypic variance for almost all traits when these were measured closer to the moment of measuring gene transcripts in the liver. In most cases, the combination of layers was not able to outperform the best single-omics models to predict phenotypes. Using only gene transcripts, the gradient boosting machine model was able to outperform best linear unbiased prediction for most traits except body weight, but the same pattern was not observed when using both single nucleotide polymorphism genotypes and gene transcripts. Although the GTCBLUP model was not able to produce the most accurate phenotypic predictions, it showed the highest accuracies for breeding values for 9 out of 13 traits. We recommend using the GTBLUP model for prediction of phenotypes and using the GTCBLUP for prediction of breeding values.
Differences in linkage disequilibrium and in allele substitution effects of QTL (quantitative trait loci) may hinder genomic prediction across populations. Our objective was to develop a ...deterministic formula to estimate the accuracy of across-population genomic prediction, for which reference individuals and selection candidates are from different populations, and to investigate the impact of differences in allele substitution effects across populations and of the number of QTL underlying a trait on the accuracy.
A deterministic formula to estimate the accuracy of across-population genomic prediction was derived based on selection index theory. Moreover, accuracies were deterministically predicted using a formula based on population parameters and empirically calculated using simulated phenotypes and a GBLUP (genomic best linear unbiased prediction) model. Phenotypes of 1033 Holstein-Friesian, 105 Groninger White Headed and 147 Meuse-Rhine-Yssel cows were simulated by sampling 3000, 300, 30 or 3 QTL from the available high-density SNP (single nucleotide polymorphism) information of three chromosomes, assuming a correlation of 1.0, 0.8, 0.6, 0.4, or 0.2 between allele substitution effects across breeds. The simulated heritability was set to 0.95 to resemble the heritability of deregressed proofs of bulls.
Accuracies estimated with the deterministic formula based on selection index theory were similar to empirical accuracies for all scenarios, while accuracies predicted with the formula based on population parameters overestimated empirical accuracies by ~25 to 30%. When the between-breed genetic correlation differed from 1, i.e. allele substitution effects differed across breeds, empirical and deterministic accuracies decreased in proportion to the genetic correlation. Using a multi-trait model, it was possible to accurately estimate the genetic correlation between the breeds based on phenotypes and high-density genotypes. The number of QTL underlying the simulated trait did not affect the accuracy.
The deterministic formula based on selection index theory estimated the accuracy of across-population genomic predictions well. The deterministic formula using population parameters overestimated the across-population genomic accuracy, but may still be useful because of its simplicity. Both formulas could accommodate for genetic correlations between populations lower than 1. The number of QTL underlying a trait did not affect the accuracy of across-population genomic prediction using a GBLUP method.
Whole-genome sequence data is expected to capture genetic variation more completely than common genotyping panels. Our objective was to compare the proportion of variance explained and the accuracy ...of genomic prediction by using imputed sequence data or preselected SNPs from a genome-wide association study (GWAS) with imputed whole-genome sequence data.
Phenotypes were available for 5503 Holstein-Friesian bulls. Genotypes were imputed up to whole-genome sequence (13,789,029 segregating DNA variants) by using run 4 of the 1000 bull genomes project. The program GCTA was used to perform GWAS for protein yield (PY), somatic cell score (SCS) and interval from first to last insemination (IFL). From the GWAS, subsets of variants were selected and genomic relationship matrices (GRM) were used to estimate the variance explained in 2087 validation animals and to evaluate the genomic prediction ability. Finally, two GRM were fitted together in several models to evaluate the effect of selected variants that were in competition with all the other variants.
The GRM based on full sequence data explained only marginally more genetic variation than that based on common SNP panels: for PY, SCS and IFL, genomic heritability improved from 0.81 to 0.83, 0.83 to 0.87 and 0.69 to 0.72, respectively. Sequence data also helped to identify more variants linked to quantitative trait loci and resulted in clearer GWAS peaks across the genome. The proportion of total variance explained by the selected variants combined in a GRM was considerably smaller than that explained by all variants (less than 0.31 for all traits). When selected variants were used, accuracy of genomic predictions decreased and bias increased.
Although 35 to 42 variants were detected that together explained 13 to 19% of the total variance (18 to 23% of the genetic variance) when fitted alone, there was no advantage in using dense sequence information for genomic prediction in the Holstein data used in our study. Detection and selection of variants within a single breed are difficult due to long-range linkage disequilibrium. Stringent selection of variants resulted in more biased genomic predictions, although this might be due to the training population being the same dataset from which the selected variants were identified.
Genomic selection has revolutionized genetic improvement in animals and plants, but little is known about its long-term effects. Here, we investigated the long-term effects of genomic selection on ...response to selection, genetic variance, and the genetic architecture of traits using stochastic simulations. We defined the genetic architecture as the set of causal loci underlying each trait, their allele frequencies, and their statistical additive effects. We simulated a livestock population under 50 generations of phenotypic, pedigree, or genomic selection for a single trait, controlled by either only additive, additive and dominance, or additive, dominance, and epistatic effects. The simulated epistasis was based on yeast data.
Short-term response was always greatest with genomic selection, while response after 50 generations was greater with phenotypic selection than with genomic selection when epistasis was present, and was always greater than with pedigree selection. This was mainly because loss of genetic variance and of segregating loci was much greater with genomic and pedigree selection than with phenotypic selection. Compared to pedigree selection, selection response was always greater with genomic selection. Pedigree and genomic selection lost a similar amount of genetic variance after 50 generations of selection, but genomic selection maintained more segregating loci, which on average had lower minor allele frequencies than with pedigree selection. Based on this result, genomic selection is expected to better maintain genetic gain after 50 generations than pedigree selection. The amount of change in the genetic architecture of traits was considerable across generations and was similar for genomic and pedigree selection, but slightly less for phenotypic selection. Presence of epistasis resulted in smaller changes in allele frequencies and less fixation of causal loci, but resulted in substantial changes in statistical additive effects across generations.
Our results show that genomic selection outperforms pedigree selection in terms of long-term genetic gain, but results in a similar reduction of genetic variance. The genetic architecture of traits changed considerably across generations, especially under selection and when non-additive effects were present. In conclusion, non-additive effects had a substantial impact on the accuracy of selection and long-term response to selection, especially when selection was accurate.
Although the concept of genomic selection relies on linkage disequilibrium (LD) between quantitative trait loci and markers, reliability of genomic predictions is strongly influenced by family ...relationships. In this study, we investigated the effects of LD and family relationships on reliability of genomic predictions and the potential of deterministic formulas to predict reliability using population parameters in populations with complex family structures. Five groups of selection candidates were simulated by taking different information sources from the reference population into account: (1) allele frequencies, (2) LD pattern, (3) haplotypes, (4) haploid chromosomes, and (5) individuals from the reference population, thereby having real family relationships with reference individuals. Reliabilities were predicted using genomic relationships among 529 reference individuals and their relationships with selection candidates and with a deterministic formula where the number of effective chromosome segments (M(e)) was estimated based on genomic and additive relationship matrices for each scenario. At a heritability of 0.6, reliabilities based on genomic relationships were 0.002 ± 0.0001 (allele frequencies), 0.022 ± 0.001 (LD pattern), 0.018 ± 0.001 (haplotypes), 0.100 ± 0.008 (haploid chromosomes), and 0.318 ± 0.077 (family relationships). At a heritability of 0.1, relative differences among groups were similar. For all scenarios, reliabilities were similar to predictions with a deterministic formula using estimated M(e). So, reliabilities can be predicted accurately using empirically estimated M(e) and level of relationship with reference individuals has a much higher effect on the reliability than linkage disequilibrium per se. Furthermore, accumulated length of shared haplotypes is more important in determining the reliability of genomic prediction than the individual shared haplotype length.
Abstract
Because of variation in linkage phase and heterozygosity among individuals, some individuals produce genetically more variable gametes than others. With the availability of genomic EBVs ...(GEBVs) or estimates of SNP-effects together with phased genotypes, differences in gametic variability can be quantified by simulating a set of virtual gametes of each selection candidate. Previous results in dairy cattle show that gametic variance can be large. Here, we show that breeders can increase the probability of breeding a top-ranking genotype and response to recurrent selection by selecting parents that produce more variable gametes, using the index I=GEBV+2xpSDgGEBV, where xp is the standardized normal truncation point belonging to selected proportion p, and SDgGEBV is the SD of the GEBV of an individual’s gametes. Benefits of the index were considerably larger in an ongoing selection program with equilibrium genetic parameters than in an initially unselected population. Superiority of the index over selection on GEBV increased strongly with the magnitude of the SDgGEBV, indicating that benefits of the index may vary considerably among populations. Compared to selection on ordinary GEBV, the probability of breeding a top-ranking individual can be increased by ∼36%, and response to selection by ∼3.6% when selection is strong (P = 0.001) based on values for the Holstein-Friesian dairy cattle population. Two-stage selection, with a preselection on GEBV and a final selection on the index, considerably reduced computational requirements with little loss of benefits. Response to multiple generations of selection and inheritance of the SDgEBV require further study.
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