Alternative SNP weighting for multi-step and single-step genomic BLUP in the presence of causative variants.

The accuracy of genetic selection in dairy can be increased by the adoption of new technologies, such as the inclusion of sequence data. In simulation studies, assigning different weights to causative single-nucleotide polymorphism (SNP) markers led to better predictions depending on the genomic prediction method used. However, it is still not clear how the weights should be calculated. Our objective was to evaluate the accuracy of a multi-step method (GBLUP) and single-step GBLUP with simulated data using regular SNP, causatives variants (QTN) and the combination of both. Additionally, we compared the accuracies of all previous scenarios using alternatives for SNP weighting. The data were simulated assuming a single trait with a heritability of 0.3. The effective population size (Ne) was approximately 200. The pedigree contained 440,000 animals, and approximately 16,800 individuals were genotyped. A total of 49,974 SNP markers were evenly placed throughout the genome, and 100, 1000 and 2000 causative QTN were simulated. Both GBLUP and ssGBLUP were used in this study. We evaluated quadratic and nonlinear SNP weights in addition to the unweighted G. The inclusion of QTN to panels led to significant accuracy gains. Nonlinear A was demonstrated to be superior to quadratic weighting and unweighted approaches; however, results from Nonlinear A were dependent on the equation parameters. The unweighted approach was more suitable for less polygenic scenarios. Finally, SNP weighting might help elucidate trait architecture features based on changes in the accuracy of genomic prediction.

Grid search approach to discriminate between old and recent inbreeding using phenotypic, pedigree and genomic information.

BACKGROUND: Although inbreeding caused by the mating of animals related through a recent common ancestor is expected to have more harmful effects on phenotypes than ancient inbreeding (old inbreeding), estimating these effects requires a clear definition of recent (new) and ancient (old) inbreeding. Several methods have been proposed to classify inbreeding using pedigree and genomic data. Unfortunately, these methods are largely based on heuristic criteria such as the number of generations from a common ancestor or length of runs of homozygosity (ROH) segments. To mitigate these deficiencies, this study aimed to develop a method to classify pedigree and genomic inbreeding into recent and ancient classes based on a grid search algorithm driven by the assumption that new inbreeding tends to have a more pronounced detrimental effect on traits. The proposed method was tested using a cattle population characterized by a deep pedigree. RESULTS: Effects of recent and ancient inbreeding were assessed on four growth traits (birth, weaning and yearling weights and average daily gain). Thresholds to classify inbreeding into recent and ancient classes were trait-specific and varied across traits and sources of information. Using pedigree information, inbreeding generated in the last 10 to 11 generations was considered as recent. When genomic information (ROH) was used, thresholds ranged between four to seven generations, indicating, in part, the ability of ROH segments to characterize the harmful effects of inbreeding in shorter periods of time. Nevertheless, using the proposed classification method, the discrimination between new and old inbreeding was less robust when ROH segments were used compared to pedigree. Using several model comparison criteria, the proposed approach was generally better than existing methods. Recent inbreeding appeared to be more harmful across the growth traits analyzed. However, both new and old inbreeding were found to be associated with decreased yearling weight and average daily gain. CONCLUSIONS: The proposed method provided a more objective quantitative approach for the classification of inbreeding. The proposed method detected a clear divergence in the effects of old and recent inbreeding using pedigree data and it was superior to existing methods for all analyzed traits. Using ROH data, the discrimination between old and recent inbreeding was less clear and the proposed method was superior to existing approaches for two out of the four analyzed traits. Deleterious effects of recent inbreeding were detected sooner (fewer generations) using genomic information than pedigree. Difference in the results using genomic and pedigree information could be due to the dissimilarity in the number of generations to a common ancestor. Additionally, the uncertainty associated with the identification of ROH segments and associated inbreeding could have an effect on the results. Potential biases in the estimation of inbreeding effects may occur when new and old inbreeding are discriminated based on arbitrary thresholds. To minimize the impact of inbreeding, mating designs should take the different inbreeding origins into consideration.

Fast genomic prediction of breeding values using parallel Markov chain Monte Carlo with convergence diagnosis.

BACKGROUND: Running multiple-chain Markov Chain Monte Carlo (MCMC) provides an efficient parallel computing method for complex Bayesian models, although the efficiency of the approach critically depends on the length of the non-parallelizable burn-in period, for which all simulated data are discarded. In practice, this burn-in period is set arbitrarily and often leads to the performance of far more iterations than required. In addition, the accuracy of genomic predictions does not improve after the MCMC reaches equilibrium. RESULTS: Automatic tuning of the burn-in length for running multiple-chain MCMC was proposed in the context of genomic predictions using BayesA and BayesCπ models. The performance of parallel computing versus sequential computing and tunable burn-in MCMC versus fixed burn-in MCMC was assessed using simulation data sets as well by applying these methods to genomic predictions of a Chinese Simmental beef cattle population. The results showed that tunable burn-in parallel MCMC had greater speedups than fixed burn-in parallel MCMC, and both had greater speedups relative to sequential (single-chain) MCMC. Nevertheless, genomic estimated breeding values (GEBVs) and genomic prediction accuracies were highly comparable between the various computing approaches. When applied to the genomic predictions of four quantitative traits in a Chinese Simmental population of 1217 beef cattle genotyped by an Illumina Bovine 770 K SNP BeadChip, tunable burn-in multiple-chain BayesCπ (TBM-BayesCπ) outperformed tunable burn-in multiple-chain BayesCπ (TBM-BayesA) and Genomic Best Linear Unbiased Prediction (GBLUP) in terms of the prediction accuracy, although the differences were not necessarily caused by computational factors and could have been intrinsic to the statistical models per se. CONCLUSIONS: Automatically tunable burn-in multiple-chain MCMC provides an accurate and cost-effective tool for high-performance computing of Bayesian genomic prediction models, and this algorithm is generally applicable to high-performance computing of any complex Bayesian statistical model.

Genomic predictions combining SNP markers and copy number variations in Nellore cattle.

BACKGROUND: Due to the advancement in high throughput technology, single nucleotide polymorphism (SNP) is routinely being incorporated along with phenotypic information into genetic evaluation. However, this approach often cannot achieve high accuracy for some complex traits. It is possible that SNP markers are not sufficient to predict these traits due to the missing heritability caused by other genetic variations such as microsatellite and copy number variation (CNV), which have been shown to affect disease and complex traits in humans and other species. RESULTS: In this study, CNVs were included in a SNP based genomic selection framework. A Nellore cattle dataset consisting of 2230 animals genotyped on BovineHD SNP array was used, and 9 weight and carcass traits were analyzed. A total of six models were implemented and compared based on their prediction accuracy. For comparison, three models including only SNPs were implemented: 1) BayesA model, 2) Bayesian mixture model (BayesB), and 3) a GBLUP model without polygenic effects. The other three models incorporating both SNP and CNV included 4) a Bayesian model similar to BayesA (BayesA+CNV), 5) a Bayesian mixture model (BayesB+CNV), and 6) GBLUP with CNVs modeled as a covariable (GBLUP+CNV). Prediction accuracies were assessed based on Pearson's correlation between de-regressed EBVs (dEBVs) and direct genomic values (DGVs) in the validation dataset. For BayesA, BayesB and GBLUP, accuracy ranged from 0.12 to 0.62 across the nine traits. A minimal increase in prediction accuracy for some traits was noticed when including CNVs in the model (BayesA+CNV, BayesB+CNV, GBLUP+CNV). CONCLUSIONS: This study presents the first genomic prediction study integrating CNVs and SNPs in livestock. Combining CNV and SNP marker information proved to be beneficial for genomic prediction of some traits in Nellore cattle.

Reduced representation bisulphite sequencing of ten bovine somatic tissues reveals DNA methylation patterns and their impacts on gene expression.

BACKGROUND: As a major epigenetic component, DNA methylation plays important functions in individual development and various diseases. DNA methylation has been well studied in human and model organisms, but only limited data exist in economically important animals like cattle. RESULTS: Using reduced representation bisulphite sequencing (RRBS), we obtained single-base-resolution maps of bovine DNA methylation from ten somatic tissues. In total, we evaluated 1,868,049 cytosines in CG-enriched regions. While we found slightly low methylation levels (29.87 to 38.06 %) in cattle, the methylation contexts (CGs and non-CGs) of cattle showed similar methylation patterns to other species. Non-CG methylation was detected but methylation levels in somatic tissues were significantly lower than in pluripotent cells. To study the potential function of the methylation, we detected 10,794 differentially methylated cytosines (DMCs) and 836 differentially methylated CG islands (DMIs). Further analyses in the same tissues revealed many DMCs (including non-CGs) and DMIs, which were highly correlated with the expression of genes involved in tissue development. CONCLUSIONS: In summary, our study provides a baseline dataset and essential information for DNA methylation profiles of cattle.

Genome-wide CNV analysis reveals variants associated with growth traits in Bos indicus.

BACKGROUND: Apart from single nucleotide polymorphism (SNP), copy number variation (CNV) is another important type of genetic variation, which may affect growth traits and play key roles for the production of beef cattle. To date, no genome-wide association study (GWAS) for CNV and body traits in beef cattle has been reported, so the present study aimed to investigate this type of association in one of the most important cattle subspecies: Bos indicus (Nellore breed). RESULTS: We have used intensity data from over 700,000 SNP probes across the bovine genome to detect common CNVs in a sample of 2230 Nellore cattle, and performed GWAS between the detected CNVs and nine growth traits. After filtering for frequency and length, a total of 231 CNVs ranging from 894 bp to 4,855,088 bp were kept and tested as predictors for each growth trait using linear regression analysis with principal components correction. There were 49 significant associations identified among 17 CNVs and seven body traits after false discovery rate correction (P < 0.05). Among the 17 CNVs, three were significant or marginally significant for all the traits. We have compared the locations of associated CNVs with quantitative trait locus and the RefGene database, and found two sets of 9 CNVs overlapping with either known QTLs or genes, respectively. The gene overlapping with CNV100, KCNJ12, is a functional candidate for muscle development and plays critical roles in muscling traits. CONCLUSION: This study presents the first CNV-based GWAS of growth traits using high density SNP microarray data in cattle. We detected 17 CNVs significantly associated with seven growth traits and one of them (CNV100) may be involved in growth traits through KCNJ12.

The effects of genotype-by-environment interactions on body condition score across three winter supplemental feed environments in a composite beef cattle breed in Montana.

Cattle operations in the Northern Great Plains region of the United States face extreme cold weather conditions and require nutritional supplementation over the winter season in order for animals to maintain body condition. In cow-calf operations, body condition scores (BCS) measured at calving and breeding have been shown to be associated with several economically important health and fertility traits, so maintenance of BCS is both an animal welfare and economic concern. A low-to-medium heritability has been found for BCS when measured across various production stages, indicating a large environmental influence but sufficient genetic basis for selection. The present study evaluated BCS measured prior to calving (late winter) and breeding (early summer) under three winter supplementation environments in a multitrait linear mixed model. Traits were discretized by winter supplementation and genetic correlations between environments were considered a reflection of evidence for genotype-by-environment interactions between BCS and diet. Winter supplementation treatments were fed October through April and varied by range access and protein content: 1) feedlot environment with approximately 15% crude protein (CP) corn/silage diet, 2) native rangeland access with 1.8 kg of an 18% CP pellet supplement, and 3) native rangeland access with a self-fed 50% CP and mineral supplement. A total of 2,988 and 2,353 records were collected across multiple parities on 1,010 and 800 individuals for prebreeding and precalving BCS, respectively. Heifers and cows came from a composite beef cattle breed developed and maintained by the USDA Fort Keogh Livestock and Range Research Laboratory near Miles City, Montana. Genetic correlations between treatments 1 and 2, 1 and 3, and 2 and 3 were 0.98, 0.78, and 0.65 and 1.00, 0.98, and 0.99 for precalving and prebreeding BCS, respectively. This provides moderate evidence of genotype-by-environment interactions for precalving BCS under treatment 3 relative to treatments 1 and 2, but no evidence for genotype-by-environment interactions for prebreeding BCS. Treatment 3 differed substantially in CP content relative to treatments 1 and 2, indicating that some animals differ in their ability to maintain BCS up to spring calving across a protein gradient. These results indicate the potential for selection of animals with increased resilience under cold weather conditions and high protein, restricted energy diets to maintain BCS.

Genome wide association studies in presence of misclassified binary responses.

BACKGROUND: Misclassification has been shown to have a high prevalence in binary responses in both livestock and human populations. Leaving these errors uncorrected before analyses will have a negative impact on the overall goal of genome-wide association studies (GWAS) including reducing predictive power. A liability threshold model that contemplates misclassification was developed to assess the effects of mis-diagnostic errors on GWAS. Four simulated scenarios of case-control datasets were generated. Each dataset consisted of 2000 individuals and was analyzed with varying odds ratios of the influential SNPs and misclassification rates of 5% and 10%. RESULTS: Analyses of binary responses subject to misclassification resulted in underestimation of influential SNPs and failed to estimate the true magnitude and direction of the effects. Once the misclassification algorithm was applied there was a 12% to 29% increase in accuracy, and a substantial reduction in bias. The proposed method was able to capture the majority of the most significant SNPs that were not identified in the analysis of the misclassified data. In fact, in one of the simulation scenarios, 33% of the influential SNPs were not identified using the misclassified data, compared with the analysis using the data without misclassification. However, using the proposed method, only 13% were not identified. Furthermore, the proposed method was able to identify with high probability a large portion of the truly misclassified observations. CONCLUSIONS: The proposed model provides a statistical tool to correct or at least attenuate the negative effects of misclassified binary responses in GWAS. Across different levels of misclassification probability as well as odds ratios of significant SNPs, the model proved to be robust. In fact, SNP effects, and misclassification probability were accurately estimated and the truly misclassified observations were identified with high probabilities compared to non-misclassified responses. This study was limited to situations where the misclassification probability was assumed to be the same in cases and controls which is not always the case based on real human disease data. Thus, it is of interest to evaluate the performance of the proposed model in that situation which is the current focus of our research.

Misclassification in binary responses and effect on genome-wide association studies.

Misclassification of dependent variables is a major issue in many areas of science that can arise when indirect markers are used to classify subjects or continuous traits are treated as categorical. In human medicine, this can have significant impacts on diagnostic accuracy. In animal science applications, misclassification can negatively affect both the accuracy of selection and the ability to ascertain the biological mechanisms for traits of interest. When dealing with traits influenced by genetic factors, genomic markers, such as SNP, can provide direct measurements of the underlying mechanisms controlling phenotypic responses. Unfortunately, in the presence of misclassification in the discrete dependent variables, the robustness of the analysis and the validity of the results could be severely compromised. To quantify the impact of misclassification on genome-wide association studies for binary responses, a real databased simulation was carried out. The simulated data consisted of 2,400 animals genotyped for 50K SNP. A binary trait with heritability equal to 0.10 and prevalence of 20% was generated. A rate of 1, 5, and 10% misclassification was artificially introduced to the true binary responses. Using a latent-threshold model, 3 analyses were carried out for each misclassification rate using 1) the true data (M1), 2) the contaminated data and ignoring misclassification (M2), and 3) the contaminated data and accounting for misclassification (M3). The results indicate that ignoring misclassification, when it exists in the data such as in M2, will lead to major deterioration in the performance of the model. When misclassification was contemplated in the model (M2), the results indicated a strong capacity of the procedure in dealing with potential misclassification in the training set. In fact, a large portion of miscoded samples in the training set was identified and corrected. The results of this study suggest that the proposed method is adequate and effective for practical genome-wide association studies for binary response classification.

Genomic Analysis of Heterosis in an Angus × Hereford Cattle Population.

Crossbreeding is widely used in the beef cattle industry to exploit its several benefits. This study evaluated the effects of heterozygosity on growth traits in an Angus × Hereford cross-population. Moreover, a genome wide association study was conducted to detect regions in the genome with significant dominance effects on growth traits contributing to heterosis. A total of 1530 animals comprising of pure Line 1 Hereford, Angus and Angus × Line 1 Hereford cross. Growth phenotypes included birth weight, weaning weight and yearling weight. All animals were genotyped with GeneSeek GGP LD 50k. Significant effects of genomic heterozygosity on growth traits were detected. These effects were 0.03 kg (0.006), 5.13 kg (0.04), 6.02 kg (0.08) on birth weight, weaning weight and yearling weight, respectively. Genome wide association study revealed several SNP markers with significant heterotic effects associated with birth weight, weaning weight and yearling weight. These SNP markers were located on chromosomes 1, 2, 6, 21, 14, 19, 13 and 12. Genes in these regions were reported to be involved in growth and other important physiological mechanisms. Our study revealed several regions associated with dominance effects and contributing to heterosis. These results could be beneficial in optimizing crossbreeding.

Fuzzy Logic as a Strategy for Combining Marker Statistics to Optimize Preselection of High-Density and Sequence Genotype Data.

The high dimensionality of genotype data available for genomic evaluations has presented a motivation for developing strategies to identify subsets of markers capable of increasing the accuracy of predictions compared to the current commercial single nucleotide polymorphism (SNP) chips. In this simulation study, an algorithm for combining statistics used in the preselection and prioritization of SNP markers from a high-density panel (1.3 million SNPs) into a composite "fuzzy" ranking score based on a Sugeno-type fuzzy inference system (FIS) was developed and evaluated for performance in preselection for genomic predictions. FST scores, and p-values were evaluated as inputs for the FIS. The accuracy of genomic predictions for fuzzy-score-preselected panel sizes of 1-50 k SNPs ranged from -0.4-11.7 and -0.3-3.8% higher than FST and p-value preselection, respectively. Though gains in prediction accuracies using only two inputs to the FIS were modest, preselection based on fuzzy scores yielded more accurate predictions than both FST scores and p-values for the majority of evaluated panel sizes under all genetic architectures. FIS have the potential to aggregate information from multiple criteria that reflect SNP-trait associations and biological relevance in a flexible and efficient way to yield higher quality genomic predictions.

Genetic architecture of a composite beef cattle population.

Composite breeds are widely used in the beef industry. Composites allow producers to combine desirable traits from the progenitor breeds and simplify herd management, without repeated crossbreeding and maintenance of purebreds. In this study, genomic information was used to evaluate the genetic composition and characteristics of a three-breed beef cattle composite. This composite population referred to as Composite Gene Combination (CGC) consisted of 50% Red Angus, 25% Charolais, and 25% Tarentaise. A total of 248 animals were used in this study: CGC (n = 79), Red Angus (n = 61), Charolais (n = 79), and Tarentaise (n = 29). All animals were genotyped with 777k HD panel. Principal component and ADMIXTURE analyses were carried out to evaluate the genetic structure of CGC animals. The ADMIXTURE revealed the proportion of Tarentaise increased to approximately 57%, whereas Charolais decreased to approximately 5% and Red Angus decreased to 38% across generations. To evaluate these changes in the genomic composition across different breeds and in CGC across generations, runs of homozygosity (ROH) were conducted. This analysis showed Red Angus to have the highest total length of ROH segments per animal with a mean of 349.92 Mb and lowest in CGC with a mean of 141.10 Mb. Furthermore, it showed the formation of new haplotypes in CGC around the sixth generation. Selection signatures were evaluated through Fst and HapFlk analyses. Several selection sweeps in CGC were identified especially in chromosomes 5 and 14 which have previously been reported to be associated with coat color and growth traits. The study supports our previous findings that progenitor combinations are not stable over generations and that either direct or natural selection plays a role in modifying the progenitor proportions. Furthermore, the results showed that Tarentaise contributed useful attributes to the composite in a cool semi-arid environment and suggests a re-exploration of this breed's role may be warranted.

Composite breeds are commonly used in the U.S. beef industry since they provide producers with benefits such as breed complementarity and retained heterosis. However, cattle composite genomes are not well characterized. Therefore, in this study, genomic information was used to evaluate the genetic composition and characteristics of a three-breed composite (50% Red Angus, 25% Charolais, and 25% Tarentaise). The analysis showed an increase in the proportion of Tarentaise to approximately 57%, whereas Charolais decreased to approximately 5% and Red Angus decreased to 38%. Furthermore, new genome segments formed around the sixth generation. These changes show that progenitor breed proportions are not stable over generations and that either direct or natural selection plays a role in modifying the proportions. The increase in Tarentaise proportion suggests useful attributes to the composite in a cool semi-arid environment.

Inbreeding Calculated with Runs of Homozygosity Suggests Chromosome-Specific Inbreeding Depression Regions in Line 1 Hereford.

The goal of this study was to evaluate inbreeding in a closed beef cattle population and assess phenotype prediction accuracy using inbreeding information. Effects of inbreeding on average daily gain phenotype in the Line 1 Hereford cattle population were assessed in this study. Genomic data were used to calculate inbreeding based on runs of homozygosity (ROH), and pedigree information was used to calculate the probability of an allele being identical by descent. Prediction ability of phenotypes using inbreeding coefficients calculated based on pedigree information and runs of homozygosity over the whole genome was close to 0, even in the case of significant inbreeding coefficient effects. On the other hand, inbreeding calculated per individual chromosomes' ROH yielded higher accuracies of prediction. Additionally, including only ROH from chromosomes with higher predicting ability further increased prediction accuracy. Phenotype prediction accuracy, inbreeding depression, and the effects of chromosome-specific ROHs varied widely across the genome. The results of this study suggest that inbreeding should be evaluated per individual regions of the genome. Moreover, mating schemes to avoid inbreeding depression should focus more on specific ROH with negative effects. Finally, using ROH as added information may increase prediction of the genetic merit of animals in a genomic selection program.

Dissection of the impact of prioritized QTL-linked and -unlinked SNP markers on the accuracy of genomic selection1.

BACKGROUND: Use of genomic information has resulted in an undeniable improvement in prediction accuracies and an increase in genetic gain in animal and plant genetic selection programs in spite of oversimplified assumptions about the true biological processes. Even for complex traits, a large portion of markers do not segregate with or effectively track genomic regions contributing to trait variation; yet it is not clear how genomic prediction accuracies are impacted by such potentially nonrelevant markers. In this study, a simulation was carried out to evaluate genomic predictions in the presence of markers unlinked with trait-relevant QTL. Further, we compared the ability of the population statistic FST and absolute estimated marker effect as preselection statistics to discriminate between linked and unlinked markers and the corresponding impact on accuracy. RESULTS: We found that the accuracy of genomic predictions decreased as the proportion of unlinked markers used to calculate the genomic relationships increased. Using all, only linked, and only unlinked marker sets yielded prediction accuracies of 0.62, 0.89, and 0.22, respectively. Furthermore, it was found that prediction accuracies are severely impacted by unlinked markers with large spurious associations. FST-preselected marker sets of 10 k and larger yielded accuracies 8.97 to 17.91% higher than those achieved using preselection by absolute estimated marker effects, despite selecting 5.1 to 37.7% more unlinked markers and explaining 2.4 to 5.0% less of the genetic variance. This was attributed to false positives selected by absolute estimated marker effects having a larger spurious association with the trait of interest and more negative impact on predictions. The Pearson correlation between FST scores and absolute estimated marker effects was 0.77 and 0.27 among only linked and only unlinked markers, respectively. The sensitivity of FST scores to detect truly linked markers is comparable to absolute estimated marker effects but the consistency between the two statistics regarding false positives is weak. CONCLUSION: Identification and exclusion of markers that have little to no relevance to the trait of interest may significantly increase genomic prediction accuracies. The population statistic FST presents an efficient and effective tool for preselection of trait-relevant markers.

Effects of management decisions on genetic evaluation of simulated calving records using random regression.

The objective of this study was to evaluate the effects of various data structures on the genetic evaluation for the binary phenotype of reproductive success. The data were simulated based on an existing pedigree and an underlying fertility phenotype with a heritability of 0.10. A data set of complete observations was generated for all cows. This data set was then modified mimicking the culling of cows when they first failed to reproduce, cows having a missing observation at either their second or fifth opportunity to reproduce as if they had been selected as donors for embryo transfer, and censoring records following the sixth opportunity to reproduce as in a cull-for-age strategy. The data were analyzed using a third-order polynomial random regression model. The EBV of interest for each animal was the sum of the age-specific EBV over the first 10 observations (reproductive success at ages 2-11). Thus, the EBV might be interpreted as the genetic expectation of number of calves produced when a female is given 10 opportunities to calve. Culling open cows resulted in the EBV for 3-yr-old cows being reduced from 8.27 ± 0.03 when open cows were retained to 7.60 ± 0.02 when they were culled. The magnitude of this effect decreased as cows grew older when they first failed to reproduce and were subsequently culled. Cows that did not fail over the 11 yr of simulated data had an EBV of 9.43 ± 0.01 and 9.35 ± 0.01 based on analyses of the complete data and the data in which cows that failed to reproduce were culled, respectively. Cows that had a missing observation for their second record had a significantly reduced EBV, but the corresponding effect at the fifth record was negligible. The current study illustrates that culling and management decisions, and particularly those that affect the beginning of the trajectory of sustained reproductive success, can influence both the magnitude and accuracy of resulting EBV.

Runs of homozygosity and analysis of inbreeding depression.

Pedigree information was traditionally used to assess inbreeding. The availability of high-density marker panels provides an alternative to assess inbreeding, particularly in the presence of incomplete and error-prone pedigrees. Assessment of autozygosity across chromosomal segments using runs of homozygosity (ROH) has emerged as a valuable tool to estimate inbreeding due to its general flexibility and ability to quantify the chromosomal contribution to genome-wide inbreeding. Unfortunately, the identification of ROH segments is sensitive to the parameters used during the search process. These parameters are heuristically set, leading to significant variation in the results. The minimum length required to identify an ROH segment has major effects on the estimation of inbreeding and inbreeding depression, yet it is arbitrarily set. To overcome this limitation, a search algorithm to approximate mutation enrichment was developed to determine the minimum length of ROH segments. It consists of finding genome segments with significant effect differences in trait means between animals with high and low burdens of autozygous intervals with a specific length. The minimum length could be determined heuristically as the smallest interval at which a significant signal is detected. The proposed method was tested in an inbred Hereford cattle population genotyped for 30,220 SNPs. Phenotypes recorded for six traits were used for the approximation of mutation loads. The estimated minimum length was around 1 Mb for yearling weight (YW) and average daily gain (ADG) and 4 Mb for birth weight and weaning weight. These trait-specific thresholds estimated using the proposed method could be attributed to a trait-dependent effect of homozygosity. The detection of significant inbreeding effects was well aligned with the estimated thresholds, especially for YW and ADG. Although highly deleterious alleles are expected to be more frequent in recent inbreeding (long ROH), short ROH segments (<5 Mb) could contain a large number of less deleterious mutations with substantial joint effects on some traits (YW and ADG). Our results highlight the importance of accurate estimation of the ROH-based inbreeding and the necessity to consider a trait-specific minimum length threshold for the identification of ROH segments in inbreeding depression analyses. These thresholds could be determined using the proposed method provided the availability of phenotypic information.

Genomic Breed Composition of Selection Signatures in Brangus Beef Cattle.

Cattle breeding routinely uses crossbreeding between subspecies (Bos taurus taurus and Bos taurus indicus) to form composite breeds, such as Brangus. These composite breeds provide an opportunity to identify recent selection signatures formed in the new population and evaluate the genomic composition of these regions of the genome. Using high-density genotyping, we first identified runs of homozygosity (ROH) and calculated genomic inbreeding. Then, we evaluated the genomic composition of the regions identified as selected (selective sweeps) using a chromosome painting approach. The genomic inbreeding increased at approximately 1% per generation after composite breed formation, showing the need of inbreeding control even in composite breeds. Three selected regions in Brangus were also identified as Angus selection signatures. Two regions (chromosomes 14 and 21) were identified as signatures of selection in Brangus and both founder breeds. Five of the 10 homozygous regions in Brangus were predominantly Angus in origin (probability >80%), and the other five regions had a mixed origin but always with Brahman contributing less than 50%. Therefore, genetic events, such as drift, selection, and complementarity, are likely shaping the genetic composition of founder breeds in specific genomic regions. Such findings highlight a variety of opportunities to better control the selection process and explore heterosis and complementarity at the genomic level in composite breeds.

Multigenerational Effects.

Environmental influences resulting in epigenetic mediation of gene expression can affect multiple generations via direct effect (first generation); direct or maternally mediated effects on the fetus (second generation), or gonadal cell lines of the fetus (third generation) when pregnant animals are exposed to the stimuli; and through generational inheritance. The cumulative effects are rapid changes in phenotypic characteristics of the population when compared with rate of phenotypic change from genetic selection. With extensive data collection, significant potential exists to propagate desired characteristics in the livestock industry through epigenetic pathways.

A Weighted Genomic Relationship Matrix Based on Fixation Index (FST) Prioritized SNPs for Genomic Selection.

A dramatic increase in the density of marker panels has been expected to increase the accuracy of genomic selection (GS), unfortunately, little to no improvement has been observed. By including all variants in the association model, the dimensionality of the problem should be dramatically increased, and it could undoubtedly reduce the statistical power. Using all Single nucleotide polymorphisms (SNPs) to compute the genomic relationship matrix (G) does not necessarily increase accuracy as the additive relationships can be accurately estimated using a much smaller number of markers. Due to these limitations, variant prioritization has become a necessity to improve accuracy. The fixation index (FST) as a measure of population differentiation has been used to identify genome segments and variants under selection pressure. Using prioritized variants has increased the accuracy of GS. Additionally, FST can be used to weight the relative contribution of prioritized SNPs in computing G. In this study, relative weights based on FST scores were developed and incorporated into the calculation of G and their impact on the estimation of variance components and accuracy was assessed. The results showed that prioritizing SNPs based on their FST scores resulted in an increase in the genetic similarity between training and validation animals and improved the accuracy of GS by more than 5%.

Inbreeding depression in line 1 Hereford cattle population using pedigree and genomic information.

This study aimed at assessing inbreeding and its effect on growth and fertility traits using the longtime closed line 1 Hereford cattle population. Inbreeding was estimated based on pedigree (FPED) and genomic information. For the latter, three estimates were derived based on the diagonal elements of the genomic relationship matrix using estimated (FGRM) or fixed (FGRM0.5) minor allele frequencies or runs of homozygosity (ROH) (FROH). A pedigree containing 10,186 animals was used to calculate FPED. Genomic inbreeding was evaluated using 785 animals genotyped for 30,810 SNP. Traits analyzed were birth weight (BWT), weaning weight (WWT), yearling weight (YWT), ADG, and age at first calving (AFC). The number of ROH per animal ranged between 6 and 119 segments with an average of 83. The shortest and longest segments were 1.36 and 64.86 Mb long, respectively, reflecting both ancient and recent inbreeding occurring in the last 30 to 40 generations. The average inbreeding was 29.2%, 16.1%, 30.2%, and 22.9% for FPED, FGRM, FGRM0.5, and FROH, respectively. FROH provided the highest correlations with FPED (r = 0.66). Across paternal half-sib families, with minimal variation in FPED, there were substantial variations in their genomic inbreeding. Inbreeding depression analyses showed that a 1% increase in an animal's FPED resulted in a decrease of 1.20 kg, 2.03 kg, and 0.004 kg/d in WWT, YWT, and ADG, respectively. Maternal inbreeding showed significantly negative effects on progeny growth performance. AFC increased by 1.4 and 0.8 d for each 1% increase in FPED of the cow and her dam, respectively. Using genomic inbreeding, similar impact on growth traits was observed although the magnitude of the effect varied between methods. Across all genomic measures, WWT, YWT, and ADG decreased by 0.21 to 0.53 kg, 0.46 to 1.13 kg, and 0.002 to 0.006 kg/d for each 1% increase in genomic inbreeding, respectively. Four chromosomes (9, 12, 17, and 27) were identified to have a significant association between their homozygosity (FROH-CHR) and growth traits. Variability in genomic inbreeding could be useful when deciding between full and half-sib selection candidates. Despite the high level of inbreeding in this study, its negative impact on growth performance was not as severe as expected, which may be attributed to the purging of the deleterious alleles due to natural or artificial selection over time.