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Abstract Two previously described QTL mapping methods, which combine linkage analysis (LA) and linkage disequilibrium analysis (LD), were compared for their ability to detect and map multiple QTL. The methods were tested on five different simulated data sets in which the exact QTL positions were known. Every simulated data set contained two QTL, but the distances between these QTL were varied from 15 to 150 cM. The results show that the single QTL mapping method (LDLA) gave good results as long as the distance between the QTL was large (> 90 cM). When the distance between the QTL was reduced, the single QTL method had problems positioning the two QTL and tended to position only one QTL, i.e. a "ghost" QTL, in between the two real QTL positions. The multi QTL mapping method (MP-LDLA) gave good results for all evaluated distances between the QTL. For the large distances between the QTL (> 90 cM) the single QTL method more often positioned the QTL in the correct marker bracket, but considering the broader likelihood peaks of the single point method it could be argued that the multi QTL method was more precise. Since the distances were reduced the multi QTL method was clearly more accurate than the single QTL method. The two methods combine well, and together provide a good tool to position single or multiple QTL in practical situations, where the number of QTL and their positions are unknown.

Abstract Two random regression models, where the effect of a putative QTL was regressed on an environmental gradient, are described. The first model estimates the correlation between intercept and slope of the random regression, while the other model restricts this correlation to 1 or -1, which is expected under a bi-allelic QTL model. The random regression models were compared to a model assuming no gene by environment interactions. The comparison was done with regards to the models ability to detect QTL, to position them accurately and to detect possible QTL by environment interactions. A simulation study based on a granddaughter design was conducted, and QTL were assumed, either by assigning an effect independent of the environment or as a linear function of a simulated environmental gradient. It was concluded that the random regression models were suitable for detection of QTL effects, in the presence and absence of interactions with environmental gradients. Fixing the correlation between intercept and slope of the random regression had a positive effect on power when the QTL effects re-ranked between environments.

Abstract Extinction of breeds threatens genetic diversity of livestock species. The need to conserve genetic diversity is widely accepted but involves in general two questions: (i) is the expected loss of diversity in a set of breeds within a defined future time horizon large enough to establish a conservation plan, and if so (ii) which breeds should be prioritised for such a conservation plan? The present study uses a marker assisted methodology to address these questions. The methodology combines core set diversity measures with a stochastic method for the estimation of expected future diversity and breed marginal diversities. The latter is defined as the change in the total diversity of all breeds caused by a one unit decrease in extinction probability of a particular breed. The stochastic method was validated by means of simulations. A large field data set consisting of 44 North Eurasian cattle breeds was analysed using simplified determined extinction probabilities. The results show that the expected loss of diversity in this set within the next 20 to 50 years is between 1 and 3% of the actual diversity, provided that the extinction probabilities which were used are approximately valid. If this loss is to be reduced, it is sufficient to include those three to five breeds with the highest marginal diversity in a conservation scheme.

Abstract The need for conservation of farm animal genetic resources is widely accepted. A key question is the choice of breeds to be conserved. For this purpose, a core set of breeds was introduced in that the total genetic variance of a hypothetical quantitative trait was maximised (MVT core set). For each breed the relative contribution to the core set was estimated and the breeds were ranked for conservation priority according to their relative contribution. The method was based on average kinships between and within breeds and these can be estimated using genetic marker data. The method was compared to a recently published core set method that maximises the variance of a hypothetical population that could be obtained by interbreeding the conserved breeds (MVO core set). The results show that the MVT (MVO) core set favours breeds with a high (low) within breed kinship that are not related to other breeds. Following this, the MVT core set method suggests conserving breeds that show a large difference in the respective population mean of a hypothetical quantitative trait. This maximises the speed of achieving selection response for this hypothetical selection direction. Additionally, bootstrap based methods for the estimation of the breed's contribution to the core sets were introduced, substantially improving the accuracy of the contribution estimates.

Abstract A multi-locus QTL mapping method is presented, which combines linkage and linkage disequilibrium (LD) information and uses multitrait data. The method assumed a putative QTL at the midpoint of each marker bracket. Whether the putative QTL had an effect or not was sampled using Markov chain Monte Carlo (MCMC) methods. The method was tested in dairy cattle data on chromosome 14 where the DGAT1 gene was known to be segregating. The DGAT1 gene was mapped to a region of 0.04 cM, and the effects of the gene were accurately estimated. The fitting of multiple QTL gave a much sharper indication of the QTL position than a single QTL model using multitrait data, probably because the multi-locus QTL mapping reduced the carry over effect of the large DGAT1 gene to adjacent putative QTL positions. This suggests that the method could detect secondary QTL that would, in single point analyses, remain hidden under the broad peak of the dominant QTL. However, no indications for a second QTL affecting dairy traits were found on chromosome 14.

Abstract The ordinary-, penalized-, and bootstrap t-test, least squares and best linear unbiased prediction were compared for their false discovery rates (FDR), i.e. the fraction of falsely discovered genes, which was empirically estimated in a duplicate of the data set. The bootstrap-t-test yielded up to 80% lower FDRs than the alternative statistics, and its FDR was always as good as or better than any of the alternatives. Generally, the predicted FDR from the bootstrapped P-values agreed well with their empirical estimates, except when the number of mRNA samples is smaller than 16. In a cancer data set, the bootstrap-t-test discovered 200 differentially regulated genes at a FDR of 2.6%, and in a knock-out gene expression experiment 10 genes were discovered at a FDR of 3.2%. It is argued that, in the case of microarray data, control of the FDR takes sufficient account of the multiple testing, whilst being less stringent than Bonferoni-type multiple testing corrections. Extensions of the bootstrap simulations to more complicated test-statistics are discussed.

Abstract We studied different genetic models and evaluation systems to select against a genetic disease with additive, recessive or polygenic inheritance in genetic conservation schemes. When using optimum contribution selection with a restriction on the rate of inbreeding (ΔF) to select against a disease allele, selection directly on DNA-genotypes is, as expected, the most efficient strategy. Selection for BLUP or segregation analysis breeding value estimates both need 1–2 generations more to halve the frequency of the disease allele, while these methods do not require knowledge of the disease mutation at the DNA level. BLUP and segregation analysis methods were equally efficient when selecting against a disease with single gene or complex polygene inheritance, i.e. knowledge about the mode of inheritance of the disease was not needed for efficient selection against the disease. Smaller schemes or schemes with a more stringent restriction on ΔF needed more generations to halve the frequency of the disease alleles or the fraction of diseased animals. Optimum contribution selection maintained ΔF at its predefined level, even when selection of females was at random. It is argued that in the investigated small conservation schemes with selection against a genetic defect, control of ΔF is very important.

Abstract The quantitative assessment of genetic diversity within and between populations is important for decision making in genetic conservation plans. In this paper we define the genetic diversity of a set of populations, S, as the maximum genetic variance that can be obtained in a random mating population that is bred from the set of populations S. First we calculated the relative contribution of populations to a core set of populations in which the overlap of genetic diversity was minimised. This implies that the mean kinship in the core set should be minimal. The above definition of diversity differs from Weitzman diversity in that it attempts to conserve the founder population (and thus minimises the loss of alleles), whereas Weitzman diversity favours the conservation of many inbred lines. The former is preferred in species where inbred lines suffer from inbreeding depression. The application of the method is illustrated by an example involving 45 Dutch poultry breeds. The calculations used were easy to implement and not computer intensive. The method gave a ranking of breeds according to their contributions to genetic diversity. Losses in genetic diversity ranged from 2.1% to 4.5% for different subsets relative to the entire set of breeds, while the loss of founder genome equivalents ranged from 22.9% to 39.3%.

Abstract Minimum coancestry mating with a maximum of one offspring per mating pair (MC1) is compared with random mating schemes for populations with overlapping generations. Optimum contribution selection is used, whereby ΔF is restricted. For schemes with ΔF restricted to 0.25% per year, 256 animals born per year and heritability of 0.25, genetic gain increased with 18% compared with random mating. The effect of MC1 on genetic gain decreased for larger schemes and schemes with a less stringent restriction on inbreeding. Breeding schemes hardly changed when omitting the iteration on the generation interval to find an optimum distribution of parents over age-classes, which saves computer time, but inbreeding and genetic merit fluctuated more before the schemes had reached a steady-state. When bulls were progeny tested, these progeny tested bulls were selected instead of the young bulls, which led to increased generation intervals, increased selection intensity of bulls and increased genetic gain (35% compared to a scheme without progeny testing for random mating). The effect of MC1 decreased for schemes with progeny testing. MC1 mating increased genetic gain from 11–18% for overlapping and 1–4% for discrete generations, when comparing schemes with similar genetic gain and size.

Abstract The prediction of identity by descent (IBD) probabilities is essential for all methods that map quantitative trait loci (QTL). The IBD probabilities may be predicted from marker genotypes and/or pedigree information. Here, a method is presented that predicts IBD probabilities at a given chromosomal location given data on a haplotype of markers spanning that position. The method is based on a simplification of the coalescence process, and assumes that the number of generations since the base population and effective population size is known, although effective size may be estimated from the data. The probability that two gametes are IBD at a particular locus increases as the number of markers surrounding the locus with identical alleles increases. This effect is more pronounced when effective population size is high. Hence as effective population size increases, the IBD probabilities become more sensitive to the marker data which should favour finer scale mapping of the QTL. The IBD probability prediction method was developed for the situation where the pedigree of the animals was unknown (i.e. all information came from the marker genotypes), and the situation where, say T, generations of unknown pedigree are followed by some generations where pedigree and marker genotypes are known.

Abstract The effect of non-random mating on genetic response was compared for populations with discrete generations. Mating followed a selection step where the average coancestry of selected animals was constrained, while genetic response was maximised. Minimum coancestry (MC), Minimum coancestry with a maximum of one offspring per mating pair (MC1) and Minimum variance of the relationships of offspring (MVRO) mating schemes resulted in a delay in inbreeding of about two generations compared with Random, Random factorial and Compensatory mating. In these breeding schemes where selection constrains the rate of inbreeding, ΔF, the improved family structure due to non-random mating increased genetic response. For schemes with ΔF constrained to 1.0% and 100 selection candidates, genetic response was 22% higher for the MC1 and MVRO schemes compared with Random mating schemes. For schemes with a less stringent constraint on ΔF or more selection candidates, the superiority of the MC1 and MVRO schemes was smaller (5–6%). In general, MC1 seemed to be the preferred mating method, since it almost always yielded the highest genetic response. MC1 mainly achieved these high genetic responses by avoiding extreme relationships among the offspring, i.e. fullsib offspring are avoided, and by making the contributions of ancestors to offspring more equal by mating least related animals.

Abstract Background Simulation studies have shown that accuracy and genetic gain are increased in genomic selection schemes compared to traditional aquaculture sib-based schemes. In genomic selection, accuracy of selection can be maximized by increasing the precision of the estimation of SNP effects and by maximizing the relationships between test sibs and candidate sibs. Another means of increasing the accuracy of the estimation of SNP effects is to create individuals in the test population with extreme genotypes. The latter approach was studied here with creation of double haploids and use of non-random mating designs. Methods Six alternative breeding schemes were simulated in which the design of the test population was varied: test sibs inherited maternal (Mat), paternal (Pat) or a mixture of maternal and paternal (MatPat) double haploid genomes or test sibs were obtained by maximum coancestry mating (MaxC), minimum coancestry mating (MinC), or random (RAND) mating. Three thousand test sibs and 3000 candidate sibs were genotyped. The test sibs were recorded for a trait that could not be measured on the candidates and were used to estimate SNP effects. Selection was done by truncation on genome-wide estimated breeding values and 100 individuals were selected as parents each generation, equally divided between both sexes. Results Results showed a 7 to 19% increase in selection accuracy and a 6 to 22% increase in genetic gain in the MatPat scheme compared to the RAND scheme. These increases were greater with lower heritabilities. Among all other scenarios, i.e. Mat, Pat, MaxC, and MinC, no substantial differences in selection accuracy and genetic gain were observed. Conclusions In conclusion, a test population designed with a mixture of paternal and maternal double haploids, i.e. the MatPat scheme, increases substantially the accuracy of selection and genetic gain. This will be particularly interesting for traits that cannot be recorded on the selection candidates and require the use of sib tests, such as disease resistance and meat quality.

Abstract Background In the past, pedigree relationships were used to control and monitor inbreeding because genomic relationships among selection candidates were not available until recently. The aim of this study was to understand the consequences for genetic variability across the genome when genomic information is used to estimate breeding values and in managing the inbreeding generated in the course of selection on genome-enhanced estimated breeding values. Methods These consequences were measured by genetic gain, pedigree- and genome-based rates of inbreeding, and local inbreeding across the genome. Breeding schemes were compared by simulating truncation selection or optimum contribution selection with a restriction on pedigree- or genome-based inbreeding, and with selection using estimated breeding values based on genome- or pedigree-based BLUP. Trait information was recorded on full-sibs of the candidates. Results When the information used to estimate breeding values and to constrain rates of inbreeding were either both pedigree-based or both genome-based, rates of genomic inbreeding were close to the desired values and the identical-by-descent profiles were reasonably uniform across the genome. However, with a pedigree-based inbreeding constraint and genome-based estimated breeding values, genomic rates of inbreeding were much higher than expected. With pedigree-instead of genome-based estimated breeding values, the impact of the largest QTL on the breeding values was much smaller, resulting in a more uniform genome-wide identical-by-descent profile but genomic rates of inbreeding were still higher than expected based on pedigree relationships, because they measure the inbreeding at a neutral locus not linked to any QTL. Neutral loci did not exist here, where there were 100 QTL on each chromosome. With a pedigree-based inbreeding constraint and genome-based estimated breeding values, genomic rates of inbreeding substantially exceeded the value of its constraint. In contrast, with a genome-based inbreeding constraint and genome-based estimated breeding values, marker frequencies changed, but this change was limited by the inbreeding constraint at the marker position. Conclusions To control inbreeding, it is necessary to account for it on the same basis as what is used to estimate breeding values, i.e. pedigree-based inbreeding control with traditional pedigree-based BLUP estimated breeding values and genome-based inbreeding control with genome-based estimated breeding values.

Abstract Background It is commonly assumed that prediction of genome-wide breeding values in genomic selection is achieved by capitalizing on linkage disequilibrium between markers and QTL but also on genetic relationships. Here, we investigated the reliability of predicting genome-wide breeding values based on population-wide linkage disequilibrium information, based on identity-by-descent relationships within the known pedigree, and to what extent linkage disequilibrium information improves predictions based on identity-by-descent genomic relationship information. Methods The study was performed on milk, fat, and protein yield, using genotype data on 35 706 SNP and deregressed proofs of 1086 Italian Brown Swiss bulls. Genome-wide breeding values were predicted using a genomic identity-by-state relationship matrix and a genomic identity-by-descent relationship matrix (averaged over all marker loci). The identity-by-descent matrix was calculated by linkage analysis using one to five generations of pedigree data. Results We showed that genome-wide breeding values prediction based only on identity-by-descent genomic relationships within the known pedigree was as or more reliable than that based on identity-by-state, which implicitly also accounts for genomic relationships that occurred before the known pedigree. Furthermore, combining the two matrices did not improve the prediction compared to using identity-by-descent alone. Including different numbers of generations in the pedigree showed that most of the information in genome-wide breeding values prediction comes from animals with known common ancestors less than four generations back in the pedigree. Conclusions Our results show that, in pedigreed breeding populations, the accuracy of genome-wide breeding values obtained by identity-by-descent relationships was not improved by identity-by-state information. Although, in principle, genomic selection based on identity-by-state does not require pedigree data, it does use the available pedigree structure. Our findings may explain why the prediction equations derived for one breed may not predict accurate genome-wide breeding values when applied to other breeds, since family structures differ among breeds.

Abstract Background In classical pedigree-based analysis, additive genetic variance is estimated from between-family variation, which requires the existence of larger phenotyped and pedigreed populations involving numerous families (parents). However, estimation is often complicated by confounding of genetic and environmental family effects, with the latter typically occurring among full-sibs. For this reason, genetic variance is often inferred based on covariance among more distant relatives, which reduces the power of the analysis. This simulation study shows that genome-wide identity-by-descent sharing among close relatives can be used to quantify additive genetic variance solely from within-family variation using data on extremely small family samples. Methods Identity-by-descent relationships among full-sibs were simulated assuming a genome size similar to that of humans (effective number of loci ~80). Genetic variance was estimated from phenotypic data assuming that genomic identity-by-descent relationships could be accurately re-created using information from genome-wide markers. The results were compared with standard pedigree-based genetic analysis. Results For a polygenic trait and a given number of phenotypes, the most accurate estimates of genetic variance were based on data from a single large full-sib family only. Compared with classical pedigree-based analysis, the proposed method is more robust to selection among parents and for confounding of environmental and genetic effects. Furthermore, in some cases, satisfactory results can be achieved even with less ideal data structures, i.e., for selectively genotyped data and for traits for which the genetic variance is largely under the control of a few major genes. Conclusions Estimation of genetic variance using genomic identity-by-descent relationships is especially useful for studies aiming at estimating additive genetic variance of highly fecund species, using data from small populations with limited pedigree information and/or few available parents, i.e., parents originating from non-pedigreed or even wild populations.

Abstract Background The risk of long-term unequal contribution of mating pairs to the gene pool is that deleterious recessive genes can be expressed. Such consequences could be alleviated by appropriately designing and optimizing breeding schemes i.e. by improving selection and mating procedures. Methods We studied the effect of mating designs, random, minimum coancestry and minimum covariance of ancestral contributions on rate of inbreeding and genetic gain for schemes with different information sources, i.e. sib test or own performance records, different genetic evaluation methods, i.e. BLUP or genomic selection, and different family structures, i.e. factorial or pair-wise. Results Results showed that substantial differences in rates of inbreeding due to mating design were present under schemes with a pair-wise family structure, for which minimum coancestry turned out to be more effective to generate lower rates of inbreeding. Specifically, substantial reductions in rates of inbreeding were observed in schemes using sib test records and BLUP evaluation. However, with a factorial family structure, differences in rates of inbreeding due mating designs were minor. Moreover, non-random mating had only a small effect in breeding schemes that used genomic evaluation, regardless of the information source. Conclusions It was concluded that minimum coancestry remains an efficient mating design when BLUP is used for genetic evaluation or when the size of the population is small, whereas the effect of non-random mating is smaller in schemes using genomic evaluation.

Abstract Genome-wide breeding value (GWEBV) estimation methods can be classified based on the prior distribution assumptions of marker effects. Genome-wide BLUP methods assume a normal prior distribution for all markers with a constant variance, and are computationally fast. In Bayesian methods, more flexible prior distributions of SNP effects are applied that allow for very large SNP effects although most are small or even zero, but these prior distributions are often also computationally demanding as they rely on Monte Carlo Markov chain sampling. In this study, we adopted the Pareto principle to weight available marker loci, i.e., we consider that x% of the loci explain (100 - x)% of the total genetic variance. Assuming this principle, it is also possible to define the variances of the prior distribution of the 'big' and 'small' SNP. The relatively few large SNP explain a large proportion of the genetic variance and the majority of the SNP show small effects and explain a minor proportion of the genetic variance. We name this method MixP, where the prior distribution is a mixture of two normal distributions, i.e. one with a big variance and one with a small variance. Simulation results, using a real Norwegian Red cattle pedigree, show that MixP is at least as accurate as the other methods in all studied cases. This method also reduces the hyper-parameters of the prior distribution from 2 (proportion and variance of SNP with big effects) to 1 (proportion of SNP with big effects), assuming the overall genetic variance is known. The mixture of normal distribution prior made it possible to solve the equations iteratively, which greatly reduced computation loads by two orders of magnitude. In the era of marker density reaching million(s) and whole-genome sequence data, MixP provides a computationally feasible Bayesian method of analysis.

Abstract Background Boar taint is observed in a high proportion of uncastrated male pigs and is characterized by an unpleasant odor/flavor in cooked meat, primarily caused by elevated levels of androstenone and skatole. Androstenone is a steroid produced in the testis in parallel with biosynthesis of other sex steroids like testosterone and estrogens. This represents a challenge when performing selection against androstenone in breeding programs, without simultaneously decreasing levels of other steroids. The aim of this study was to use high-density genome wide association (GWA) in combination with linkage disequilibrium-linkage analysis (LDLA) to identify quantitative trait loci (QTL) associated with boar taint compounds and related sex steroids in commercial Landrace (n = 1,251) and Duroc (n = 918) breeds. Results Altogether, 14 genome wide significant (GWS) QTL regions for androstenone in subcutaneous fat were obtained from the LDLA study in Landrace and 14 GWS QTL regions in Duroc. LDLA analysis revealed that 7 of these QTL regions, located on SSC 1, 2, 3, 7 and 15, were obtained in both breeds. All 14 GWS androstenone QTLs in Landrace are also affecting the estrogens at chromosome wise significance (CWS) or GWS levels, while in Duroc, 3 of the 14 QTLs affect androstenone without affecting any of the estrogens. For skatole, 10 and 4 QTLs were GWS in the LDLA analysis for Landrace and Duroc respectively, with 4 of these detected in both breeds. The GWS QTLs for skatole obtained by LDLA are located at SSC 1, 5, 6, 7, 10, 11, 13 and 14. Conclusion This is the first report applying the Porcine 60 K SNP array for simultaneous analysis of boar taint compounds and related sex hormones, using both GWA and LDLA approaches. Several QTLs are involved in regulation of androstenone and skatole, and most of the QTLs for androstenone are also affecting the levels of estrogens. Seven QTLs for androstenone were detected in one breed and confirmed in the other, i.e. in an independent sample, although the majority of QTLs are breed specific. Most QTLs for skatole do not negatively affect other sex hormones and should be easier to implement into the breeding scheme.

Abstract Background Genetically, SNP that are in complete linkage disequilibrium with the causative SNP cannot be distinguished from the causative SNP. The Complete Linkage Disequilibrium (CLD) test presented here tests whether a SNP is in complete LD with the causative mutation or not. The performance of the CLD test is evaluated in 1000 simulated datasets. Methods The CLD test consists of two steps i.e. analysis I and analysis II. Analysis I consists of an association analysis of the investigated region. The log-likelihood values from analysis I are next ranked in descending order and in analysis II the CLD test evaluates differences in log-likelihood ratios between the best and second best markers. Under the null-hypothesis distribution, the best SNP is in greater LD with the QTL than the second best, while under the alternative-CLD-hypothesis, the best SNP is alike-in-state with the QTL. To find a significance threshold, the test was also performed on data excluding the causative SNP. The 5th, 10th and 50th highest TCLD value from 1000 replicated analyses were used to control the type-I-error rate of the test at p = 0.005, p = 0.01 and p = 0.05, respectively. Results In a situation where the QTL explained 48% of the phenotypic variance analysis I detected a QTL in 994 replicates (p = 0.001), where 972 were positioned in the correct QTL position. When the causative SNP was excluded from the analysis, 714 replicates detected evidence of a QTL (p = 0.001). In analysis II, the CLD test confirmed 280 causative SNP from 1000 simulations (p = 0.05), i.e. power was 28%. When the effect of the QTL was reduced by doubling the error variance, the power of the test reduced relatively little to 23%. When sequence data were used, the power of the test reduced to 16%. All SNP that were confirmed by the CLD test were positioned in the correct QTL position. Conclusions The CLD test can provide evidence for a causative SNP, but its power may be low in situations with closely linked markers. In such situations, also functional evidence will be needed to definitely conclude whether the SNP is causative or not.

Abstract Background In aquaculture breeding, resistance against infectious diseases is commonly assessed as time until death under exposure to a pathogen. For some diseases, a fraction of the individuals may appear as "cured" (non-susceptible), and the resulting survival time may thus be a result of two confounded underlying traits, i.e., endurance (individual hazard) and susceptibility (whether at risk or not), which may be accounted for by fitting a cure survival model. We applied a cure model to survival data of Pacific white shrimp (Penaeus vannamei) challenged with the Taura syndrome virus, which is one of the major pathogens of Panaeid shrimp species. Methods In total, 15,261 individuals of 513 full-sib families from three generations were challenge-tested in 21 separate tests (tanks). All challenge-tests were run until mortality naturally ceased. Time-until-event data were analyzed with a mixed cure survival model using Gibbs sampling, treating susceptibility and endurance as separate genetic traits. Results Overall mortality at the end of test was 28%, while 38% of the population was considered susceptible to the disease. The estimated underlying heritability was high for susceptibility (0.41 ± 0.07), but low for endurance (0.07 ± 0.03). Furthermore, endurance and susceptibility were distinct genetic traits (rg = 0.22 ± 0.25). Estimated breeding values for endurance and susceptibility were only moderately correlated (0.50), while estimated breeding values from classical models for analysis of challenge-test survival (ignoring the cured fraction) were closely correlated with estimated breeding values for susceptibility, but less correlated with estimated breeding values for endurance. Conclusions For Taura syndrome resistance, endurance and susceptibility are apparently distinct genetic traits. However, genetic evaluation of susceptibility based on the cure model showed clear associations with standard genetic evaluations that ignore the cure fraction for these data. Using the current testing design, genetic variation in observed survival time and absolute survival at the end of test were most likely dominated by genetic variation in susceptibility. If the aim is to reduce susceptibility, earlier termination of the challenge-test or back-truncation of the follow-up period should be avoided, as this may shift focus of selection towards endurance rather than susceptibility.

Abstract Background Traditional family-based aquaculture breeding programs, in which families are kept separately until individual tagging and most traits are measured on the sibs of the candidates, are costly and require a high level of reproductive control. The most widely used alternative is a selection scheme, where families are reared communally and the candidates are selected based on their own individual measurements of the traits under selection. However, in the latter selection schemes, inclusion of new traits depends on the availability of non-invasive techniques to measure the traits on selection candidates. This is a severe limitation of these schemes, especially for disease resistance and fillet quality traits. Methods Here, we present a new selection scheme, which was validated using computer simulations comprising 100 families, among which 1, 10 or 100 were reared communally in groups. Pooling of the DNA from 2000, 20000 or 50000 test individuals with the highest and lowest phenotypes was used to estimate 500, 5000 or 10000 marker effects. One thousand or 2000 out of 20000 candidates were preselected for a growth-like trait. These pre-selected candidates were genotyped, and they were selected on their genome-wide breeding values for a trait that could not be measured on the candidates. Results A high accuracy of selection, i.e. 0.60-0.88 was obtained with 20000-50000 test individuals but it was reduced when only 2000 test individuals were used. This shows the importance of having large numbers of phenotypic records to accurately estimate marker effects. The accuracy of selection decreased with increasing numbers of families per group. Conclusions This new selection scheme combines communal rearing of families, pre-selection of candidates, DNA pooling and genomic selection and makes multi-trait selection possible in aquaculture selection schemes without keeping families separately until individual tagging is possible. The new scheme can also be used for other farmed species, for which the cost of genotyping test individuals may be high, e.g. if trait heritability is low.

Abstract Background The information provided by dense genome-wide markers using high throughput technology is of considerable potential in human disease studies and livestock breeding programs. Genome-wide association studies relate individual single nucleotide polymorphisms (SNP) from dense SNP panels to individual measurements of complex traits, with the underlying assumption being that any association is caused by linkage disequilibrium (LD) between SNP and quantitative trait loci (QTL) affecting the trait. Often SNP are in genomic regions of no trait variation. Whole genome Bayesian models are an effective way of incorporating this and other important prior information into modelling. However a full Bayesian analysis is often not feasible due to the large computational time involved. Results This article proposes an expectation-maximization (EM) algorithm called emBayesB which allows only a proportion of SNP to be in LD with QTL and incorporates prior information about the distribution of SNP effects. The posterior probability of being in LD with at least one QTL is calculated for each SNP along with estimates of the hyperparameters for the mixture prior. A simulated example of genomic selection from an international workshop is used to demonstrate the features of the EM algorithm. The accuracy of prediction is comparable to a full Bayesian analysis but the EM algorithm is considerably faster. The EM algorithm was accurate in locating QTL which explained more than 1% of the total genetic variation. A computational algorithm for very large SNP panels is described. Conclusions emBayesB is a fast and accurate EM algorithm for implementing genomic selection and predicting complex traits by mapping QTL in genome-wide dense SNP marker data. Its accuracy is similar to Bayesian methods but it takes only a fraction of the time.

Abstract Background In the genetic analysis of binary traits with one observation per animal, animal threshold models frequently give biased heritability estimates. In some cases, this problem can be circumvented by fitting sire- or sire-dam models. However, these models are not appropriate in cases where individual records exist on parents. Therefore, the aim of our study was to develop a new Gibbs sampling algorithm for a proper estimation of genetic (co)variance components within an animal threshold model framework. Methods In the proposed algorithm, individuals are classified as either "informative" or "non-informative" with respect to genetic (co)variance components. The "non-informative" individuals are characterized by their Mendelian sampling deviations (deviance from the mid-parent mean) being completely confounded with a single residual on the underlying liability scale. For threshold models, residual variance on the underlying scale is not identifiable. Hence, variance of fully confounded Mendelian sampling deviations cannot be identified either, but can be inferred from the between-family variation. In the new algorithm, breeding values are sampled as in a standard animal model using the full relationship matrix, but genetic (co)variance components are inferred from the sampled breeding values and relationships between "informative" individuals (usually parents) only. The latter is analogous to a sire-dam model (in cases with no individual records on the parents). Results When applied to simulated data sets, the standard animal threshold model failed to produce useful results since samples of genetic variance always drifted towards infinity, while the new algorithm produced proper parameter estimates essentially identical to the results from a sire-dam model (given the fact that no individual records exist for the parents). Furthermore, the new algorithm showed much faster Markov chain mixing properties for genetic parameters (similar to the sire-dam model). Conclusions The new algorithm to estimate genetic parameters via Gibbs sampling solves the bias problems typically occurring in animal threshold model analysis of binary traits with one observation per animal. Furthermore, the method considerably speeds up mixing properties of the Gibbs sampler with respect to genetic parameters, which would be an advantage of any linear or non-linear animal model.

Abstract Background When estimating marker effects in genomic selection, estimates of marker effects may simply act as a proxy for pedigree, i.e. their effect may partially be attributed to their association with superior parents and not be linked to any causative QTL. Hence, these markers mainly explain polygenic effects rather than QTL effects. However, if a polygenic effect is included in a Bayesian model, it is expected that the estimated effect of these markers will be more persistent over generations without having to re-estimate the marker effects every generation and will result in increased accuracy and reduced bias. Methods Genomic selection using the Bayesian method, 'BayesB' was evaluated for different marker densities when a polygenic effect is included (GWpEBV) and not included (GWEBV) in the model. Linkage disequilibrium and a mutation drift balance were obtained by simulating a population with a Ne of 100 over 1,000 generations. Results Accuracy of selection was slightly higher for the model including a polygenic effect than for the model not including a polygenic effect whatever the marker density. The accuracy decreased in later generations, and this reduction was stronger for lower marker densities. However, no significant difference in accuracy was observed between the two models. The linear regression of TBV on GWEBV and GWpEBV was used as a measure of bias. The regression coefficient was more stable over generations when a polygenic effect was included in the model, and was always between 0.98 and 1.00 for the highest marker density. The regression coefficient decreased more quickly with decreasing marker density. Conclusions Including a polygenic effect had no impact on the selection accuracy, but showed reduced bias, which is especially important when estimates of genome-wide markers are used to estimate breeding values over more than one generation.

Abstract Background Selection schemes aiming at introgressing genetic material from a donor into a recipient line may be performed by backcross-breeding programs combined with selection to preserve the favourable characteristics of the donor population. This stochastic simulation study investigated whether genomic selection can be effective in preserving a major quantitative trait locus (QTL) allele from a donor line during the backcrossing phase. Methods In a simulation study, two fish populations were generated: a recipient line selected for a production trait and a donor line characterized by an enhanced level of disease resistance. Both traits were polygenic, but one major QTL affecting disease resistance was segregating only within the donor line. Backcrossing was combined with three types of selection (for total merit index) among the crossbred individuals: classical selection, genomic selection using genome-wide dense marker maps, and gene-assisted genomic selection. It was assumed that production could be observed directly on the selection candidates, while disease resistance had to be inferred from tested sibs of the selection candidates. Results Classical selection was inefficient in preserving the target QTL through the backcrossing phase. In contrast, genomic selection (without specific knowledge of the target QTL) was usually effective in preserving the target QTL, and had higher genetic response to selection, especially for disease resistance. Compared with pure genomic selection, gene-assisted selection had an advantage with respect to disease resistance (28–40% increase in genetic gain) and acted as an extra precaution against loss of the target QTL. However, for total merit index the advantage of gene-assisted genomic selection over genomic selection was lower (4–5% increase in genetic gain). Conclusion Substantial differences between introgression programs using classical and genomic selection were observed, and the former was generally inferior with respect to both genetic gain and the ability to preserve the target QTL. Combining genomic selection with gene-assisted selection for the target QTL acted as an extra precaution against loss of the target QTL and gave additional genetic gain for disease resistance. However, the effect on total merit index was limited.

Abstract Background Boar taint is an unpleasant odour and flavour of the meat from some uncastrated male pigs primarily caused by elevated levels of androstenone and skatole in adipose tissue. Androstenone is produced in the same biochemical pathway as testosterone and estrogens, which represents a particular challenge when selecting against high levels of androstenone in the breeding programme, without simultaneously decreasing levels of other steroids. Detection of single nucleotide polymorphisms (SNPs) associated with compounds affecting boar taint is important both for gaining a better understanding of the complex regulation of the trait and for the purpose of identifying markers that can be used to improve the gain of breeding. The beneficial SNPs to be used in breeding would have the combinational effects of reducing levels of boar taint without affecting fertility of the animals. The aim of this study was to detect SNPs in boar taint candidate genes and to perform association studies for both single SNPs and haplotypes with levels of boar taint compounds and phenotypes related to reproduction. Results An association study involving 275 SNPs in 121 genes and compounds related to boar taint and reproduction were carried out in Duroc and Norwegian Landrace boars. Phenotypes investigated were levels of androstenone, skatole and indole in adipose tissue, levels of androstenone, testosterone, estrone sulphate and 17β-estradiol in plasma, and length of bulbo urethralis gland. The SNPs were genotyped in more than 2800 individuals and several SNPs were found to be significantly (LRT > 5.4) associated with the different phenotypes. Genes with significant SNPs in either of the traits investigated include cytochrome P450 members CYP2E1, CYP21, CYP2D6 and CYP2C49, steroid 5α-reductase SRD5A2, nuclear receptor NGFIB, catenin CTNND1, BRCA1 associated protein BAP1 and hyaluronoglucosaminidase HYAL2. Haplotype analysis provided additional evidence for an effect of CYP2E1 on levels of skatole and indole, and for BAP1, HYAL2 and SRD5A2 on levels of androstenone. Conclusion The findings in this study indicate that polymorphisms in CYP2E1, CYP21, CYP2D6, CYP2C49, NGFIB and CTNND1 might be used to reduce levels of boar taint without affecting levels of testosterone, estrone sulphate, 17β-estradiol or length of bulbo urethralis gland.

Abstract Background Genomic selection is a selection method where effects of dense genetic markers are first estimated in a test population and later used to predict breeding values of selection candidates. The aim of this paper was to investigate genetic gains, inbreeding and the accuracy of selection in a general genomic selection scheme for aquaculture, where the test population consists of sibs of the candidates. Methods The selection scheme started after simulating 4000 generations in a Fisher-Wright population with a size of 1000 to create a founder population. The basic scheme had 3000 selection candidates, 3000 tested sibs of the candidates, 100 full-sib families, a trait heritability of 0.4 and a marker density of 0.5Ne/M. Variants of this scheme were also analysed. Results The accuracy of selection in generation 5 was 0.823 for the basic scheme when the sib-testing was performed every generation. The accuracy was hardly reduced by selection, probably because the increased frequency of favourable alleles compensated for the Bulmer effect. When sib-testing was performed only in the first generation, in order to reduce costs, accuracy of selection in generation 5 dropped to 0.304, the main reduction occurring in the first generation. The genetic level in generation 5 was 6.35σa when sib-testing was performed every generation, which was 72%, 12% and 9% higher than when sib-testing was performed only in the first generation, only in the first three generations or every second generation, respectively. A marker density above 0.5Ne/M hardly increased accuracy of selection further. For the basic scheme, rates of inbreeding were reduced by 81% in these schemes compared to traditional selection schemes, due to within-family selection. Increasing the number of sibs to 6000 hardly affected the accuracy of selection, and increasing the number of candidates to 6000 increased genetic gain by 10%, mainly because of increased selection intensity. Conclusion Various strategies were evaluated to reduce the amount of sib-testing and genotyping, but all resulted in loss of selection accuracy and thus of genetic gain. Rates of inbreeding were reduced by 81% in genomic selection schemes compared to traditional selection schemes for the parameters of the basic scheme, due to within-family selection.

Abstract Background Recent developments in SNP discovery and high throughput genotyping technology have made the use of high-density SNP markers to predict breeding values feasible. This involves estimation of the SNP effects in a training data set, and use of these estimates to evaluate the breeding values of other 'evaluation' individuals. Simulation studies have shown that these predictions of breeding values can be accurate, when training and evaluation individuals are (closely) related. However, many general applications of genomic selection require the prediction of breeding values of 'unrelated' individuals, i.e. individuals from the same population, but not particularly closely related to the training individuals. Methods Accuracy of selection was investigated by computer simulation of small populations. Using scaling arguments, the results were extended to different populations, training data sets and genome sizes, and different trait heritabilities. Results Prediction of breeding values of unrelated individuals required a substantially higher marker density and number of training records than when prediction individuals were offspring of training individuals. However, when the number of records was 2*Ne*L and the number of markers was 10*Ne*L, the breeding values of unrelated individuals could be predicted with accuracies of 0.88 – 0.93, where Ne is the effective population size and L the genome size in Morgan. Reducing this requirement to 1*Ne*L individuals, reduced prediction accuracies to 0.73–0.83. Conclusion For livestock populations, 1NeL requires about ~30,000 training records, but this may be reduced if training and evaluation animals are related. A prediction equation is presented, that predicts accuracy when training and evaluation individuals are related. For humans, 1NeL requires ~350,000 individuals, which means that human disease risk prediction is possible only for diseases that are determined by a limited number of genes. Otherwise, genotyping and phenotypic recording need to become very common in the future.

Abstract The combination of a sire model and a random regression term describing genotype by environment interactions may lead to biased estimates of genetic variance components because of heterogeneous residual variance. In order to test different models, simulated data with genotype by environment interactions, and dairy cattle data assumed to contain such interactions, were analyzed. Two animal models were compared to four sire models. Models differed in their ability to handle heterogeneous variance from different sources. Including an individual effect with a (co)variance matrix restricted to three times the sire (co)variance matrix permitted the modeling of the additive genetic variance not covered by the sire effect. This made the ability of sire models to handle heterogeneous genetic variance approximately equivalent to that of animal models. When residual variance was heterogeneous, a different approach to account for the heterogeneity of variance was needed, for example when using dairy cattle data in order to prevent overestimation of genetic heterogeneity of variance. Including environmental classes can be used to account for heterogeneous residual variance.

Abstract Partial least square regression (PLSR) and principal component regression (PCR) are methods designed for situations where the number of predictors is larger than the number of records. The aim was to compare the accuracy of genome-wide breeding values (EBV) produced using PLSR and PCR with a Bayesian method, 'BayesB'. Marker densities of 1, 2, 4 and 8 Ne markers/Morgan were evaluated when the effective population size (Ne) was 100. The correlation between true breeding value and estimated breeding value increased with density from 0.611 to 0.681 and 0.604 to 0.658 using PLSR and PCR respectively, with an overall advantage to PLSR of 0.016 (s.e = 0.008). Both methods gave a lower accuracy compared to the 'BayesB', for which accuracy increased from 0.690 to 0.860. PLSR and PCR appeared less responsive to increased marker density with the advantage of 'BayesB' increasing by 17% from a marker density of 1 to 8Ne/M. PCR and PLSR showed greater bias than 'BayesB' in predicting breeding values at all densities. Although, the PLSR and PCR were computationally faster and simpler, these advantages do not outweigh the reduction in accuracy, and there is a benefit in obtaining relevant prior information from the distribution of gene effects.

Abstract The aim of this paper was to compare the effect of haplotype definition on the precision of QTL-mapping and on the accuracy of predicted genomic breeding values. In a multiple QTL model using identity-by-descent (IBD) probabilities between haplotypes, various haplotype definitions were tested i.e. including 2, 6, 12 or 20 marker alleles and clustering base haplotypes related with an IBD probability of > 0.55, 0.75 or 0.95. Simulated data contained 1100 animals with known genotypes and phenotypes and 1000 animals with known genotypes and unknown phenotypes. Genomes comprising 3 Morgan were simulated and contained 74 polymorphic QTL and 383 polymorphic SNP markers with an average r2 value of 0.14 between adjacent markers. The total number of haplotypes decreased up to 50% when the window size was increased from two to 20 markers and decreased by at least 50% when haplotypes related with an IBD probability of > 0.55 instead of > 0.95 were clustered. An intermediate window size led to more precise QTL mapping. Window size and clustering had a limited effect on the accuracy of predicted total breeding values, ranging from 0.79 to 0.81. Our conclusion is that different optimal window sizes should be used in QTL-mapping versus genome-wide breeding value prediction.

Abstract Genomic selection uses genome-wide dense SNP marker genotyping for the prediction of genetic values, and consists of two steps: (1) estimation of SNP effects, and (2) prediction of genetic value based on SNP genotypes and estimates of their effects. For the former step, BayesB type of estimators have been proposed, which assume a priori that many markers have no effects, and some have an effect coming from a gamma or exponential distribution, i.e. a fat-tailed distribution. Whilst such estimators have been developed using Monte Carlo Markov chain (MCMC), here we derive a much faster non-MCMC based estimator by analytically performing the required integrations. The accuracy of the genome-wide breeding value estimates was 0.011 (s.e. 0.005) lower than that of the MCMC based BayesB predictor, which may be because the integrations were performed one-by-one instead of for all SNPs simultaneously. The bias of the new method was opposite to that of the MCMC based BayesB, in that the new method underestimates the breeding values of the best selection candidates, whereas MCMC-BayesB overestimated their breeding values. The new method was computationally several orders of magnitude faster than MCMC based BayesB, which will mainly be advantageous in computer simulations of entire breeding schemes, in cross-validation testing, and practical schemes with frequent re-estimation of breeding values.

Abstract Background Boar taint is the unpleasant odour and flavour of the meat of uncastrated male pigs that is primarily caused by high levels of androstenone and skatole in adipose tissue. Androstenone is a steroid and its levels are mainly genetically determined. Studies on androstenone metabolism have, however, focused on a limited number of genes. Identification of additional genes influencing levels of androstenone may facilitate implementation of marker assisted breeding practices. In this study, microarrays were used to identify differentially expressed genes and pathways related to androstenone metabolism in the liver from boars with extreme levels of androstenone in adipose tissue. Results Liver tissue samples from 58 boars of the two breeds Duroc and Norwegian Landrace, 29 with extreme high and 29 with extreme low levels of androstenone, were selected from more than 2500 individuals. The samples were hybridised to porcine cDNA microarrays and the 1% most significant differentially expressed genes were considered significant. Among the differentially expressed genes were metabolic phase I related genes belonging to the cytochrome P450 family and the flavin-containing monooxygenase FMO1. Additionally, phase II conjugation genes including UDP-glucuronosyltransferases UGT1A5, UGT2A1 and UGT2B15, sulfotransferase STE, N-acetyltransferase NAT12 and glutathione S-transferase were identified. Phase I and phase II metabolic reactions increase the water solubility of steroids and play a key role in their elimination. Differential expression was also found for genes encoding 17beta-hydroxysteroid dehydrogenases (HSD17B2, HSD17B4, HSD17B11 and HSD17B13) and plasma proteins alpha-1-acid glycoprotein (AGP) and orosomucoid (ORM1). 17beta-hydroxysteroid dehydrogenases and plasma proteins regulate the availability of steroids by controlling the amount of active steroids accessible to receptors and available for metabolism. Differences in the expression of FMO1, NAT12, HSD17B2 and HSD17B13 were verified by quantitative real competitive PCR. Conclusion A number of genes and pathways related to metabolism of androstenone in liver were identified, including new candidate genes involved in phase I oxidation metabolism, phase II conjugation metabolism, and regulation of steroid availability. The study is a first step towards a deeper understanding of enzymes and regulators involved in pathways of androstenone metabolism and may ultimately lead to the discovery of markers to reduce boar taint.

Abstract Background Infectious Salmon Anaemia (ISA) is a viral disease affecting farmed Atlantic salmon (Salmo salar) worldwide. The identification of Quantitative Trait Loci (QTL) affecting resistance to the disease could improve our understanding of the genetics underlying the trait and provide a means for Marker-Assisted Selection. We previously performed a genome scan on commercial Atlantic salmon families challenge tested for ISA resistance, identifying several putative QTL. In the present study, we set out to validate the strongest of these QTL in a larger family material coming from the same challenge test, and to determine the position of the QTL by interval mapping. We also wanted to explore different ways of performing QTL analysis within a survival analysis framework (i.e. using time-to-event data), and to compare results using survival analysis with results from analysis on the dichotomous trait 'affected/resistant'. Results The QTL, located on Atlantic salmon linkage group 8 (following SALMAP notation), was confirmed in the new data set. Its most likely position was at a marker cluster containing markers BHMS130, BHMS170 and BHMS553. Significant segregation distortion was observed in the same region, but was shown to be unrelated to the QTL. A maximum likelihood procedure for identifying QTL, based on the Cox proportional hazard model, was developed. QTL mapping was also done using the Haley-Knott method (affected/resistant data), and within a variance-component framework (affected/resistant data and time-to-event data). In all cases, analysis using affected/resistant data gave stronger evidence for a QTL than did analysis using time-to-event data. Conclusion A QTL for resistance to Infectious Salmon Anaemia in Atlantic salmon was validated in this study, and its more precise location on linkage group eight was determined. The QTL explained 6% of the phenotypic variation in resistance to the disease. The linkage group also displayed significant segregation distortion. Survival models proved in this case not to be more suitable than models based on the dichotomous trait 'affected/resistant' for analysing the data.

Background: Genomic selection makes it possible to reduce pedigree-based inbreeding over best linear unbiased prediction (BLUP) by increasing emphasis on own rather than family information. However, pedigree inbreeding might not accurately reflect loss of genetic variation and the true level of inbreeding due to changes in allele frequencies and hitch-hiking. This study aimed at understanding the impact of using long-term genomic selection on changes in allele frequencies, genetic variation and level of inbreeding. Methods: Selection was performed in simulated scenarios with a population of 400 animals for 25 consecutive generations. Six genetic models were considered with different heritabilities and numbers of QTL (quantitative trait loci) affecting the trait. Four selection criteria were used, including selection on own phenotype and on estimated breeding values (EBV) derived using phenotype-BLUP, genomic BLUP and Bayesian Lasso. Changes in allele frequencies at QTL, markers and linked neutral loci were investigated for the different selection criteria and different scenarios, along with the loss of favourable alleles and the rate of inbreeding measured by pedigree and runs of homozygosity. Results: For each selection criterion, hitch-hiking in the vicinity of the QTL appeared more extensive when accuracy of selection was higher and the number of QTL was lower. When inbreeding was measured by pedigree information, selection on genomic BLUP EBV resulted in lower levels of inbreeding than selection on phenotype BLUP EBV, but this did not always apply when inbreeding was measured by runs of homozygosity. Compared to genomic BLUP, selection on EBV from Bayesian Lasso led to less genetic drift, reduced loss of favourable alleles and more effectively controlled the rate of both pedigree and genomic inbreeding in all simulated scenarios. In addition, selection on EBV from Bayesian Lasso showed a higher selection differential for mendelian sampling terms than selection on genomic BLUP EBV. Conclusions: Neutral variation can be shaped to a great extent by the hitch-hiking effects associated with selection, rather than just by genetic drift. When implementing long-term genomic selection, strategies for genomic control of inbreeding are essential, due to a considerable hitch-hiking effect, regardless of the method that is used for prediction of EBV. [ABSTRACT FROM AUTHOR]