Use Of Haplotypes Research Articles

Predicting anxiety-related personality traits by means of serotonergic VNTR variants STin2 and 5-HTTLPR

Polymorphisms of the serotonergic system are amongst the most commonly investigated genetic variants with respect to anxiety-related personality traits and affective disorders. Mostly the prominent 5-HTTLPR, a functional VNTR in the 5-HTT promoter region, is intensively analysed but effect sizes in meta-analyses are small and results are inconsistent. We reinvestigated the association of 5-HTTLPR with harm avoidance (HA) and neuroticism taking another functional 5-HTT-VNTR (STin2) into account, as both VNTRs have transcription regulating properties and research points to combinatorial effects on transcription efficacy. N = 2969 participants, among them 447 inpatients suffering from affective disorders, were genotyped and filled in the TCI, NEO-FFI personality inventories besides the CLEq measuring the extent of experienced stressful life events. Significant main effects for the 5-HTTLPR with inpatients carrying the L+ allele having lower HA scores as well as for the STin2 with healthy controls carrying at least one STin2.12R allele having lower neuroticism scores were observed. Besides no gene-interaction occurred. However, specific haplotype effects were observed in healthy participants as well as in the total sample. More specifically, the 12/L variant was associated with significant lower HA and neuroticism scores. Results highlight the multifactorial interplay of 5-HTT genetic variants and the use of haplotypes in association studies on anxiety-related personality traits with impact on affective disorders.

Haplotype blocks for genomic prediction: a comparative evaluation in multiple crop datasets.

In modern plant breeding, genomic selection is becoming the gold standard for selection of superior genotypes. The basis for genomic prediction models is a set of phenotyped lines along with their genotypic profile. With high marker density and linkage disequilibrium (LD) between markers, genotype data in breeding populations tends to exhibit considerable redundancy. Therefore, interest is growing in the use of haplotype blocks to overcome redundancy by summarizing co-inherited features. Moreover, haplotype blocks can help to capture local epistasis caused by interacting loci. Here, we compared genomic prediction methods that either used single SNPs or haplotype blocks with regards to their prediction accuracy for important traits in crop datasets. We used four published datasets from canola, maize, wheat and soybean. Different approaches to construct haplotype blocks were compared, including blocks based on LD, physical distance, number of adjacent markers and the algorithms implemented in the software "Haploview" and "HaploBlocker". The tested prediction methods included Genomic Best Linear Unbiased Prediction (GBLUP), Extended GBLUP to account for additive by additive epistasis (EGBLUP), Bayesian LASSO and Reproducing Kernel Hilbert Space (RKHS) regression. We found improved prediction accuracy in some traits when using haplotype blocks compared to SNP-based predictions, however the magnitude of improvement was very trait- and model-specific. Especially in settings with low marker density, haplotype blocks can improve genomic prediction accuracy. In most cases, physically large haplotype blocks yielded a strong decrease in prediction accuracy. Especially when prediction accuracy varies greatly across different prediction models, prediction based on haplotype blocks can improve prediction accuracy of underperforming models. However, there is no "best" method to build haplotype blocks, since prediction accuracy varied considerably across methods and traits. Hence, criteria used to define haplotype blocks should not be viewed as fixed biological parameters, but rather as hyperparameters that need to be adjusted for every dataset.

Using haplotype and QTL analysis to fix favorable alleles in diploid potato breeding.

At present, the potato (Solanum tuberosum L.) of international commerce is autotetraploid, and the complexity of this genetic system creates limitations for breeding. Diploid potato breeding has long been used for population improvement, and because of an improved understanding of the genetics of gametophytic self-incompatibility, there is now sustained interest in the development of uniform F1 hybrid varieties based on inbred parents. We report here on the use of haplotype and quantitative trait locus (QTL) analysis in a modified backcrossing (BC) scheme, using primary dihaploids of S. tuberosum as the recurrent parental background. In Cycle 1, we selected XD3-36, a self-fertile F2 individual homozygous for the self-compatibility gene Sli (S-locus inhibitor). Signatures of gametic and zygotic selection were observed at multiple loci in the F2 generation, including Sli. In the BC1 cycle, an F1 population derived from XD3-36 showed a bimodal response for vine maturity, which led to the identification of late versus early alleles in XD3-36 for the gene CDF1 (Cycling DOF Factor 1). Greenhouse phenotypes and haplotype analysis were used to select a vigorous and self-fertile F2 individual with 43% homozygosity, including for Sli and the early-maturing allele CDF1.3. Partially inbred lines from the BC1 and BC2 cycles have been used to initiate new cycles of selection, with the goal of reaching higher homozygosity while maintaining plant vigor, fertility, and yield.

PSXIII-B-11 Identification of Haplotypes Associated with Fetal Loss in Dairy Cattle

Abstract Fetal loss occurs in 4 to 13% of dairy cattle worldwide with a subsequent $487 to $1900 economic loss per pregnancy. Previous studies have identified SNPs associated with fetal loss, but few have investigated haplotypes (DNA that segregates to offspring together) associated with fetal loss. The objective of this study was to identify haplotypes associated with fetal loss in Holstein heifers and cows that conceived to the first insemination. This study consisted of 529 Holstein heifers (470 maintained pregnancies to term while 59 experienced fetal loss) and 517 Holstein cows (490 maintained pregnancies to term while 28 suffered fetal loss). Cattle with fetal loss (cases) were genotyped using the Neogen BovineGGP50 BeadChip (SNPs = 43,938) and cattle that calved at term (controls) were genotyped with the Illumina BovineHD BeadChip (SNPs = 777,962). Cases were imputed to HD density using BEAGLE (4.1). Cases and controls were combined to identify 62,819 haplotypes. Haplotype association tests were run for three populations (heifers, cows, and combined) with a chi-squared Bonferroni (BF) corrected significance of p < 0.05. The haplotype analyses identified 121, 47, and 102 haplotypes associated with fetal loss in heifer, cow and combined populations, respectively. Of these, 37 haplotypes were shared between the heifer and cow populations, 39 between cows and the combined, 76 between the heifers and combined, and 37 across all analyses. Loci identified in the haplotype analyses were compared to loci associated (BF p < 0.05) with fetal loss in a SNP by SNP genome wide association analyses. There were 22 loci shared in heifers, 10 in cows and 21 in the combined population. The use of haplotypes, identified an additional 150 loci associated with fetal loss that can be further characterized for their value in selecting cattle that are less prone to late term abortions.

Increasing calling accuracy, coverage, and read-depth in sequence data by the use of haplotype blocks.

High-throughput genotyping of large numbers of lines remains a key challenge in plant genetics, requiring geneticists and breeders to find a balance between data quality and the number of genotyped lines under a variety of different existing genotyping technologies when resources are limited. In this work, we are proposing a new imputation pipeline ("HBimpute") that can be used to generate high-quality genomic data from low read-depth whole-genome-sequence data. The key idea of the pipeline is the use of haplotype blocks from the software HaploBlocker to identify locally similar lines and subsequently use the reads of all locally similar lines in the variant calling for a specific line. The effectiveness of the pipeline is showcased on a dataset of 321 doubled haploid lines of a European maize landrace, which were sequenced at 0.5X read-depth. The overall imputing error rates are cut in half compared to state-of-the-art software like BEAGLE and STITCH, while the average read-depth is increased to 83X, thus enabling the calling of copy number variation. The usefulness of the obtained imputed data panel is further evaluated by comparing the performance of sequence data in common breeding applications to that of genomic data generated with a genotyping array. For both genome-wide association studies and genomic prediction, results are on par or even slightly better than results obtained with high-density array data (600k). In particular for genomic prediction, we observe slightly higher data quality for the sequence data compared to the 600k array in the form of higher prediction accuracies. This occurred specifically when reducing the data panel to the set of overlapping markers between sequence and array, indicating that sequencing data can benefit from the same marker ascertainment as used in the array process to increase the quality and usability of genomic data.

Determination and use of haplotypes: Ethnic comparison and association of the lipoprotein lipase gene and coronary artery disease in Mexican-Americans

Purpose: To illustrate an approach of deriving haplotypes for genetic association studies, using the lipoprotein lipase (LPL) gene and coronary artery disease.Methods: Six polymorphisms sufficient to distinguish the most common haplotypes in the 3′ end of LPL were identified by genotyping 10 polymorphisms in a small pilot population. These were used to haplotype LPL in large family samples of Mexican-Americans and non-Hispanic Caucasians. A case-control association study was performed comparing Mexican-Americans with and without coronary artery disease.Results: The two ethnic groups exhibited significant genetic differences. Among Mexican-Americans, homozygosity for LPL haplotype 1 was protective against coronary artery disease (OR = 0.50, 95% CI 0.27–0.91).Conclusion: This study outlines the haplotype structure of the LPL gene, illustrates the utility of haplotype-based analysis in association studies, and demonstrates the importance of defining haplotype frequencies for different ethnic groups.

Genomic predictions based on haplotypes fitted as pseudo-SNP for milk production and udder type traits and SCS in French dairy goats

The development of statistical methods aiming to improve the accuracy of genomic predictions is of utmost value for dairy goat breeding programs. In this context, the use of haplotypes, instead of individual SNP, could improve the accuracy of genomic predictions by better capturing the effect of causal variants, instead of relying solely on linkage disequilibrium with individual SNP. Haplotypes can be included in genomic evaluation models in various ways, such as fitting them as pseudo-SNP (i.e., haplotypes converted into biallelic SNP format). This can be easily incorporated in the software already available for single-step genomic predictions (ssGBLUP). Therefore, the aim of this study was to compare the predictive performances of ssGBLUP and weighted ssGBLUP (WssGBLUP) based on individual SNP or on haplotypes fitted as pseudo-SNP. Performance was compared in terms of accuracy, bias, and weights for SNP versus pseudo-SNP. Genomic predictions were performed on 5 milk production traits, 5 udder type traits, and somatic cell score (SCS). The training population was formed by 307 Alpine and 247 Saanen progeny-tested bucks, genotyped using the Illumina Goat SNP50 BeadChip (Illumina, San Diego, CA). The validation population included 205 Alpine and 146 Saanen young bucks. The accuracy of genomic predictions was evaluated in the validation population as the Pearson correlation between genomic estimated breeding values (GEBV), predicted based on various methods, and daughter deviation (DD) based on the official genetic evaluation of January 2016. Haplotype-based models were shown to improve the performance of genomic predictions for some traits. Gains in accuracy of up to +19% (0.310 to 0.368 for fat yield) in Alpine and up to +3% (0.361 to 0.373 for udder shape) in Saanen were observed with ssGBLUP. The ssGBLUP accuracies averaged across all traits and methods were equal to 0.467 (SNP) versus 0.471 (pseudo-SNP) in Alpine and 0.528 (SNP) versus 0.523 (pseudo-SNP) in Saanen. With WssGBLUP, gains in accuracy of up to 24% (0.298 to 0.370 for fat yield) in Alpine and 14% (0.431 to 0.490 for SCS) in Saanen were observed with WssGBLUP. Accuracies of WssGBLUP averaged across all traits and methods were equal to 0.455 (SNP and pseudo-SNP) in Alpine and 0.542 (SNP) versus 0.528 (pseudo-SNP) in Saanen. The average (±SD) slope of the regression of DD on GEBV for the validation animals, across all breeds, traits and scenarios, were equal to 0.82 ± 0.20 (SNP) and 0.83 ± 0.18 (pseudo-SNP) for ssGBLUP and 0.67 ± 0.16 (SNP) and 0.65 ± 0.16 (pseudo-SNP) for WssGBLUP, which suggest that haplotype-based models and ssGBLUPSNP were similarly biased. However, WssGBLUP was more biased than ssGBLUP, and its gains in accuracies were limited to milk production traits. Despite the fact that genomic predictions based on haplotypes require additional steps and time, the observed gains in GEBV predictive performance indicate that haplotype-based methods could be recommended for some traits.

Improving Prediction Accuracy Using Multi-allelic Haplotype Prediction and Training Population Optimization in Wheat.

The use of haplotypes may improve the accuracy of genomic prediction over single SNPs because haplotypes can better capture linkage disequilibrium and genomic similarity in different lines and may capture local high-order allelic interactions. Additionally, prediction accuracy could be improved by portraying population structure in the calibration set. A set of 383 advanced lines and cultivars that represent the diversity of the University of Minnesota wheat breeding program was phenotyped for yield, test weight, and protein content and genotyped using the Illumina 90K SNP Assay. Population structure was confirmed using single SNPs. Haplotype blocks of 5, 10, 15, and 20 adjacent markers were constructed for all chromosomes. A multi-allelic haplotype prediction algorithm was implemented and compared with single SNPs using both k-fold cross validation and stratified sampling optimization. After confirming population structure, the stratified sampling improved the predictive ability compared with k-fold cross validation for yield and protein content, but reduced the predictive ability for test weight. In all cases, haplotype predictions outperformed single SNPs. Haplotypes of 15 adjacent markers showed the best improvement in accuracy for all traits; however, this was more pronounced in yield and protein content. The combined use of haplotypes of 15 adjacent markers and training population optimization significantly improved the predictive ability for yield and protein content by 14.3 (four percentage points) and 16.8% (seven percentage points), respectively, compared with using single SNPs and k-fold cross validation. These results emphasize the effectiveness of using haplotypes in genomic selection to increase genetic gain in self-fertilized crops.

Detecting rare haplotypes associated with complex diseases using both population and family data: Combined logistic Bayesian Lasso.

Haplotype-based association methods have been developed to understand the genetic architecture of complex diseases. Compared to single-variant-based methods, haplotype methods are thought to be more biologically relevant, since there are typically multiple non-independent genetic variants involved in complex diseases, and the use of haplotypes implicitly accounts for non-independence caused by linkage disequilibrium. In recent years, with the focus moving from common to rare variants, haplotype-based methods have also evolved accordingly to uncover the roles of rare haplotypes. One particular approach is regularization-based, with the use of Bayesian least absolute shrinkage and selection operator (Lasso) as an example. This type of methods has been developed for either case-control population data (the logistic Bayesian Lasso (LBL)) or family data (family-triad-based logistic Bayesian Lasso (famLBL)). In some situations, both family data and case-control data are available; therefore, it would be a waste of resources if only one of them could be analyzed. To make full usage of available data to increase power, we propose a unified approach that can combine both case-control and family data (combined logistic Bayesian Lasso (cLBL)). Through simulations, we characterized the performance of cLBL and showed the advantage of cLBL over existing methods. We further applied cLBL to the Framingham Heart Study data to demonstrate its utility in real data applications.

Genome-wide association study using haplotype alleles for the evaluation of reproductive traits in Nelore cattle

Zebu cattle (Bos taurus indicus) are highly adapted to tropical regions. However, females reach puberty after taurine heifers, which affects the economic efficiency of beef cattle breeding in the tropical regions. The aims of this study were to establish associations between the haplotype alleles of the bovine genome and age at first calving (AFC) in the Nelore cattle, and to identify the genes and quantitative trait loci (QTL) related to this phenotype. A total of 2,273 Nelore cattle (995 males and 1,278 females) genotyped using the Illumina BovineHD BeadChip were used in the current study. The association analysis included females with valid first calving records as well as open heifers. Linkage disequilibrium (LD) analysis among the markers was performed using blocks of 5, 10, and 15 markers, which were determined by sliding windows shifting one marker at a time. Then, the haplotype block size to be used in the association study was chosen based on the highest r2 average among the SNPs in the block. The five HapAlleles most strongly associated with the trait (top five) were considered as significant associations. The results of the analysis revealed four genomic regions related to AFC, which overlapped with 20 QTL of the reproductive traits reported previously. Furthermore, there were 19 genes related to reproduction in those regions. In conclusion, the use of haplotypes allowed the detection of chromosomal regions associated with AFC in Nelore cattle, and provided the basis for elucidating the mechanisms underlying this trait.

Genomic Prediction of Autogamous and Allogamous Plants by SNPs and Haplotypes

The implementation of single‐nucleotide polymorphism (SNP)‐based genomic selection has demonstrated great predictive potential in plants. However, its application is sometimes limited to the biallelism of the marker. In this context, the use of haplotype blocks as multiallelic markers might improve genomic prediction. This study was performed to compare the predictive ability of Bayesian genomic prediction models using haplotypes (confidence interval and four‐gamete), individual SNPs, and sets of SNPs selected according to haplotype construction. The use of haplotype matrices increased the predictive ability and selection coincidence with the phenotypic selection for the maize (Zea mays L.) breeding population. However, this was not observed for the rice (Oryza sativa L.) population, in which the use of the nonreduced SNP matrix was more efficient. Overall, the use of reduced SNP matrices did not lead to better predictive abilities. No difference was observed between the genomic prediction methods used. We found that the use of haplotypes has potential to increase predictive ability of genomic prediction in breeding populations of allogamous plants or plants with high multiallelism.

Use of haplotypes to identify regions harbouring lethal recessive variants in pigs

BackgroundLethal recessive genetic variants are maintained at relatively low frequencies in a population in the heterozygous state, but by definition are fatal and therefore unobserved in the homozygous state. Since haplotypes allow the tagging of rare and untyped genetic variants, they have potential for studying lethal recessive variants. In this study, we used a large commercial population to identify putative lethal recessive haplotypes that impact either the total number born (TNB) or the number born alive (NBA) as a proportion of the total number born (NBA/TNB). We also compared the use of haplotypes with a single nucleotide polymorphism (SNP)-by-SNP approach and examined the benefits of using additional haplotypes imputed from low-density genotype data for the detection of lethal recessive variants. Candidate haplotypes were identified using population-wide haplotype frequencies and within-family analyses. These candidate haplotypes were subsequently assessed for putative lethal recessive effects on TNB and NBA/TNB by comparing carrier-to-carrier matings with carrier-to-non-carrier matings.ResultsUsing both medium-density and imputed low-density genotype data six regions were identified as containing putative lethal recessive haplotypes that had an effect on TNB. It is likely that these regions were related to at least four putative lethal recessive variants, each located on a different chromosome. Evidence for putative lethal recessive effects on TNB was found on chromosomes 1, 6, 10 and 14 using haplotypes. Using haplotypes from individuals genotyped only at medium-density or a SNP-by-SNP approach did not detect any lethal recessive effects. No lethal recessive haplotypes or SNPs were detected that had an effect on NBA/TNB.ConclusionsWe show that the use of haplotypes from combining medium-density and imputed low-density genotype data is superior for the identification of lethal recessive variants compared to both a SNP-by-SNP approach and to the use of only medium-density data. We developed a formal statistical framework that provided sufficient power to detect lethal recessive variants in species, which produce large full-sib families, while reducing false positive or type I errors. Applying this framework results in improvements in reproductive performance by purging lethal recessive alleles from a population in a timely and cost-effective manner.

Multi-SNP Haplotype Analysis Methods for Association Analysis.

Haplotype analysis forms the basis of much of genetic association analysis using both related and unrelated individuals (we concentrate on unrelated). For example, haplotype analysis indirectly underlies the SNP imputation methods that are used for testing trait associations with known but unmeasured variants and for performing collaborative post-GWAS meta-analysis. This chapter is focused on the direct use of haplotypes in association testing. It reviews the rationale for haplotype-based association testing, discusses statistical issues related to haplotype uncertainty that affect the analysis, then gives practical guidance for testing haplotype-based associations with phenotype or outcome trait, first of candidate gene regions and then for the genome as a whole. Haplotypes are interesting for two reasons, first they may be in closer LD with a causal variant than any single measured SNP, and therefore may enhance the coverage value of the genotypes over single SNP analysis. Second, haplotypes may themselves be the causal variants of interest and some solid examples of this have appeared in the literature.This chapter discusses three possible approaches to incorporation of SNP haplotype analysis into generalized linear regression models: (1) a simple substitution method involving imputed haplotypes, (2) simultaneous maximum likelihood (ML) estimation of all parameters, including haplotype frequencies and regression parameters, and (3) a simplified approximation to full ML for case-control data.Examples of the various approaches for a haplotype analysis of a candidate gene are provided. We compare the behavior of the approximation-based methods and argue that in most instances the simpler methods hold up well in practice. We also describe the practical implementation of haplotype risk estimation genome-wide and discuss several shortcuts that can be used to speed up otherwise potentially very intensive computational requirements.

Selection of haplotype variables from a high-density marker map for genomic prediction.

BackgroundUsing haplotype blocks as predictors rather than individual single nucleotide polymorphisms (SNPs) may improve genomic predictions, since haplotypes are in stronger linkage disequilibrium with the quantitative trait loci than are individual SNPs. It has also been hypothesized that an appropriate selection of a subset of haplotype blocks can result in similar or better predictive ability than when using the whole set of haplotype blocks. This study investigated genomic prediction using a set of haplotype blocks that contained the SNPs with large effects estimated from an individual SNP prediction model. We analyzed protein yield, fertility and mastitis of Nordic Holstein cattle, and used high-density markers (about 770k SNPs). To reach an optimum number of haplotype variables for genomic prediction, predictions were performed using subsets of haplotype blocks that contained a range of 1000 to 50 000 main SNPs.ResultsThe use of haplotype blocks improved the prediction reliabilities, even when selection focused on only a group of haplotype blocks. In this case, the use of haplotype blocks that contained the 20 000 to 50 000 SNPs with the highest effect was sufficient to outperform the model that used all individual SNPs as predictors (up to 1.3 % improvement in prediction reliability for mastitis, compared to individual SNP approach), and the achieved reliabilities were similar to those using all haplotype blocks available in the genome data (from 0.6 % lower to 0.8 % higher reliability).ConclusionsHaplotype blocks used as predictors can improve the reliability of genomic prediction compared to the individual SNP model. Furthermore, the use of a subset of haplotype blocks that contains the main SNP effects from genomic data could be a feasible approach to genomic prediction in dairy cattle, given an increase in density of genotype data available. The predictive ability of the models that use a subset of haplotype blocks was similar to that obtained using either all haplotype blocks or all individual SNPs, with the benefit of having a much lower computational demand.

Frequent haplotypes of caged Caligus rogercresseyi in the austral south of Chile: The result of a long term serial passage experiment?

Caligus rogercresseyi is an ectoparasite that causes enormous economic losses to the Chilean salmon aquaculture industry. It has been proposed that native fish are a reservoir of this parasite and that pesticide treatments to control it have led to pharmacological resistance to the chemotherapeutic substances that are broadly used in the austral south of Chile. During 2012–2013, 686bp in the 18s rRNA gene of C. rogercresseyi were sequenced, collected from Salmo salar cultured in five areas between 41°30′S and 45°30′S in Chile. The results show a total of 24 haplotypes, two of which were highly frequent and present in all studied areas (A=36.7% and B=16.3%), as well as in larvae raised under laboratory conditions (A=44% and B=25%). A and B haplotypes were also present in stored sequences of this parasite in the GenBank database from 2003. Seven less frequent haplotypes were found dispersed in four of the areas studied, and the remaining fifteen haplotypes were only present in low frequencies and only in one area. Analysis of the population structure of C. rogercresseyi indicated that the samples collected are part of a panmictic population but with low genetic flow inside the study area, as following a bottleneck event. Hypothetically, after over a decade of this population parasitizing a caged host with low genetic diversity (S. salar), and after repeated exposure to neurotoxic pesticides, the most frequent haplotypes A and B could be the result of drug selective pressure acting inside the cages in a kind of long term serial passage experiment. Finally, the characterization of the molecular footprints of these most frequent haplotypes makes them good candidates for use in experiments to test their resistance to drug treatments. Statement of relevanceThe use of haplotypes described in this study, especially A and B, in experiments of drug resistance in this parasite is relevant compared to the use of unknown haplotypes. This could be important for determining the kind of drugs used against this parasite as well as in the study of resistance mechanisms to the chemotherapeutic substances used in Chilean aquaculture.

Bootstrap study of genome-enabled prediction reliabilities using haplotype blocks across Nordic Red cattle breeds

This study compared the accuracy of genome-enabled prediction models using individual single nucleotide polymorphisms (SNP) or haplotype blocks as covariates when using either a single breed or a combined population of Nordic Red cattle. The main objective was to compare predictions of breeding values of complex traits using a combined training population with haplotype blocks, with predictions using a single breed as training population and individual SNP as predictors. To compare the prediction reliabilities, bootstrap samples were taken from the test data set. With the bootstrapped samples of prediction reliabilities, we built and graphed confidence ellipses to allow comparisons. Finally, measures of statistical distances were used to calculate the gain in predictive ability. Our analyses are innovative in the context of assessment of predictive models, allowing a better understanding of prediction reliabilities and providing a statistical basis to effectively calibrate whether one prediction scenario is indeed more accurate than another. An ANOVA indicated that use of haplotype blocks produced significant gains mainly when Bayesian mixture models were used but not when Bayesian BLUP was fitted to the data. Furthermore, when haplotype blocks were used to train prediction models in a combined Nordic Red cattle population, we obtained up to a statistically significant 5.5% average gain in prediction accuracy, over predictions using individual SNP and training the model with a single breed.

Genomic evaluation of a relatively small dairy cattle population by combination with a larger population

The objectives were to investigate the accuracy of genomic evaluations obtained for a small dairy cattle population (Israeli Holsteins) via joint evaluation with a larger population (Dutch Holsteins), and to evaluate the use of pedigree data from foreign bulls computed by Interbull without daughter records in Israel. The training population included 4,010 Dutch bulls and 713 Israeli bulls. The validation population included 185 Israeli bulls with daughter records for milk production traits and slightly fewer bulls for the nonproduction traits. Milk, fat, and protein yields, somatic cell score, longevity, female fertility, direct and maternal calving ease, direct and maternal stillbirth, and the Israeli breeding index were analyzed. The genomic prediction model was based on the Bayesian multi-QTL model of Meuwissen and Goddard, where the effects of dense single nucleotide polymorphisms across the whole genome are fitted directly, without the use of haplotypes or identical-by-descent probabilities. Correlations of May 2014 estimated breeding values (EBV14) with genomic EBV (GEBV) were higher than the correlations of EBV14 with parent averages (PA) computed from the June 2009 evaluation for all traits. For the Israel selection index, the difference between EBV14 and GEBV correlation on the one hand and EBV14 and PA computed using Interbull data on the other hand was 15 percentage points. For protein, the difference between the corresponding correlations was 14 percentage points. Generally, correlations of EBV14 with PA based on Israeli EBV only were similar to correlations of EBV14 with PA including Interbull evaluations. Relative to EBV14, milk production traits were biased upwards for both GEBV and PA, but the bias was greater for PA. The Y-intercepts of regressions of EBV14 were significantly different from zero for regression on GEBV for all 3 milk production traits and the Israeli selection index. This was not the case for regression of EBV14 on PA. The regression line intersected with the line of unbiased estimation near the EBV of the bulls with highest values. Because only bulls with high evaluations are of interest for selection, GEBV for these bulls were less biased compared with that of bulls with lower evaluations. The difference in mean EBV14 between bulls born during 2007–2008 selected by GEBV and PA was 65 units. If half of all inseminations are by young bulls, then the annual genetic gain obtained by implementation of genomic evaluation will be 8 units per year (65/8). Because annual gain is currently 107 units, this is a gain of 7%.

Haplotype-assisted genomic evaluations in Nordic Red Dairy Cattle

In admixed populations originating from different base breeds, such as the Nordic Red Dairy Cattle, identity by state of haplotypes instead of single nucleotide polymorphisms (SNP) is a better surrogate for identity by descent. Therefore, haplotypes are expected to be more useful in recovering genetic relationships among animals and linkage disequilibrium between markers and quantitative trait loci (QTL). The objective of this study was to improve the prediction accuracy in genomic evaluations by the use of haplotypes of short chromosomal segments. In the first step, around 38,000 SNPs from a 50K chip were simultaneously scanned for QTL signals with BayesB. Based on these results, the SNPs with the strongest QTL signals were then pre-selected and haplotype blocks were constructed around these. In the second step, we estimated the relative variances for the pre-selected haplotypes with BayesA. In the final step, mixed model equations of the evaluation model were solved to estimate haplotype effects. Here, a pre-defined proportion of the genetic variance was assigned to a pedigree-based animal effect and the rest to haplotypes. The accuracies of several combinations for the number and the length of haplotype blocks were assessed by calculation of genome-enhanced breeding values and validation test reliabilities (R2). For three production traits (milk, protein, fat) and fertility, the highest R2 observed were 0.48, 0.41, 0.42 and 0.33, respectively. For milk and protein, we observed an improvement over G-BLUP of 3 and 1 percentage points, respectively. For fat and fertility, the highest R2 were the same as for GBLUP. Further analysis using only single SNPs instead of haplotype blocks yielded similar results. This may indicate a need to choose an alternative approach to pre-select haplotype blocks.

Combining Markers into Haplotypes Can Improve Population Structure Inference

High-throughput genotyping and sequencing technologies can generate dense sets of genetic markers for large numbers of individuals. For most species, these data will contain many markers in linkage disequilibrium (LD). To utilize such data for population structure inference, we investigate the use of haplotypes constructed by combining the alleles at single-nucleotide polymorphisms (SNPs). We introduce a statistic derived from information theory, the gain of informativeness for assignment (GIA), which quantifies the additional information for assigning individuals to populations using haplotype data compared to using individual loci separately. Using a two-loci-two-allele model, we demonstrate that combining markers in linkage equilibrium into haplotypes always leads to nonpositive GIA, suggesting that combining the two markers is not advantageous for ancestry inference. However, for loci in LD, GIA is often positive, suggesting that assignment can be improved by combining markers into haplotypes. Using GIA as a criterion for combining markers into haplotypes, we demonstrate for simulated data a significant improvement of assigning individuals to candidate populations. For the many cases that we investigate, incorrect assignment was reduced between 26% and 97% using haplotype data. For empirical data from French and German individuals, the incorrectly assigned individuals can, for example, be decreased by 73% using haplotypes. Our results can be useful for challenging population structure and assignment problems, in particular for studies where large-scale population-genomic data are available.

Genomic selection in French dairy cattle

Genomic selection is implemented in French Holstein, Montbéliarde, and Normande breeds (70%, 16% and 12% of French dairy cows). A characteristic of the model for genomic evaluation is the use of haplotypes instead of single-nucleotide polymorphisms (SNPs), so as to maximise linkage disequilibrium between markers and quantitative trait loci (QTLs). For each trait, a QTL-BLUP model (i.e. a best linear unbiased prediction model including QTL random effects) includes 300–700 trait-dependent chromosomal regions selected either by linkage disequilibrium and linkage analysis or by elastic net. This model requires an important effort to phase genotypes, detect QTLs, select SNPs, but was found to be the most efficient one among all tested ones. QTLs are defined within breed and many of them were found to be breed specific. Reference populations include 1800 and 1400 bulls in Montbéliarde and Normande breeds. In Holstein, the very large reference population of 18 300 bulls originates from the EuroGenomics consortium. Since 2008, ~65 000 animals have been genotyped for selection by Labogena with the 50k chip. Bulls genomic estimated breeding values (GEBVs) were made official in June 2009. In 2010, the market share of the young bulls reached 30% and is expected to increase rapidly. Advertising actions have been undertaken to recommend a time-restricted use of young bulls with a limited number of doses. In January 2011, genomic selection was opened to all farmers for females. Current developments focus on the extension of the method to a multi-breed context, to use all reference populations simultaneously in genomic evaluation.