Large Reference Population Research Articles

Effects of reference population size and structure on genomic prediction of maternal traits in two pig lines using whole-genome sequence-, high-density- and combined annotation-dependent depletion genotypes.

The aim of this study was to investigate the reference population size required to obtain substantial prediction accuracy within- and across-lines and the effect of using a multi-line reference population for genomic predictions of maternal traits in pigs. The data consisted of two nucleus pig populations, one pure-bred Landrace (L) and one Synthetic (S) Yorkshire/Large White line. All animals were genotyped with up to 30 K animals in each line, and all had records on maternal traits. Prediction accuracy was tested with three different marker data sets: High-density SNP (HD), whole genome sequence (WGS), and markers derived from WGS based on pig combined annotation dependent depletion-score (pCADD). Also, two different genomic prediction methods (GBLUP and Bayes GC) were compared for four maternal traits; total number piglets born (TNB), total number of stillborn piglets (STB), Shoulder Lesion Score and Body Condition Score. The main results from this study showed that a reference population of 3 K-6 K animals for within-line prediction generally was sufficient to achieve high prediction accuracy. However, when the number of animals in the reference population was increased to 30 K, the prediction accuracy significantly increased for the traits TNB and STB. For multi-line prediction accuracy, the accuracy was most dependent on the number of within-line animals in the reference data. The S-line provided a generally higher prediction accuracy compared to the L-line. Using pCADD scores to reduce the number of markers from WGS data in combination with the GBLUP method generally reduced prediction accuracies relative to GBLUP using HD genotypes. The BayesGC method benefited from a large reference population and was less dependent on the different genotype marker datasets to achieve a high prediction accuracy.

Multi-breed genomic evaluation for tropical beef cattle when no pedigree information is available

BackgroundIt has been challenging to implement genomic selection in multi-breed tropical beef cattle populations. If commercial (often crossbred) animals could be used in the reference population for these genomic evaluations, this could allow for very large reference populations. In tropical beef systems, such animals often have no pedigree information. Here we investigate potential models for such data, using marker heterozygosity (to model heterosis) and breed composition derived from genetic markers, as covariates in the model. Models treated breed effects as either fixed or random, and included genomic best linear unbiased prediction (GBLUP) and BayesR. A tropically-adapted beef cattle dataset of 29,391 purebred, crossbred and composite commercial animals was used to evaluate the models.ResultsTreating breed effects as random, in an approach analogous to genetic groups allowed partitioning of the genetic variance into within-breed and across breed-components (even with a large number of breeds), and estimation of within-breed and across-breed genomic estimated breeding values (GEBV). We demonstrate that moderately-accurate (0.30–0.43) GEBV can be calculated using these models. Treating breed effects as random gave more accurate GEBV than treating breed as fixed. A simple GBLUP model where no breed effects were fitted gave the same accuracy (and correlations of GEBV very close to 1) as a model where GEBV for within-breed and the GEBV for (random) across-breed effects were included. When GEBV were predicted for herds with no data in the reference population, BayesR resulted in the highest accuracy, with 3% accuracy improvement averaged across traits, especially when the validation population was less related to the reference population. Estimates of heterosis from our models were in line with previous estimates from beef cattle. A method for estimating the number of effective breed comparisons for each breed combination accumulated across contemporary groups is presented.ConclusionsWhen no pedigree is available, breed composition and heterosis for inclusion in multi-breed genomic evaluation can be estimated from genotypes. When GEBV were predicted for herds with no data in the reference population, BayesR resulted in the highest accuracy.

Novel Finnish-enriched variants causing severe hypercholesterolemia and their clinical impact on coronary artery disease

Background and aimsSevere hypercholesterolemia (LDL-cholesterol ≥ 5 mmol/l) is a major risk factor for coronary artery disease (CAD). The etiology incudes both genetic and nongenetic factors, but persons carrying mutations in known hypercholesterolemia-associated genes are at significantly higher CAD risk than non-carriers. Yet, a significant proportion of mutation carriers remains undetected while the assessment of genetic candidate variants in clinical practice is challenging. MethodsTo address these challenges, we set out to test the utility of a practical approach to leverage data from a large reference cohort, the FinnGen Study encompassing 356,082 persons with extensive longitudinal health record information, to aid the clinical evaluation of single genetic candidate genes variants detected by exome sequence analysis in a target population of 351 persons with severe hypercholesterolemia. ResultsWe identified 23 rare missense mutations in known hypercholesterolemia genes, 3 of which were previously described mutations (LDLR Pro309Lysfs, LDLR Arg595Gln and APOB Arg3527Gln). Subsequent in silico and clinical assessment of the remaining 20 variants pinpointed two likely hypercholesterolemia-associated variants in LDLR (Arg574Leu and Glu626Lys) and one in LDLRAP1 (Arg151Trp). Heterozygous carriers of the novel LDLR and LDLRAP1 variants received statin treatment more often than non-carriers (OR 2.1, p = 1.8e-6 and OR 1.4, p = 0.001) and untreated carriers had higher risk for ischemic heart disease (OR 2.0, p = 0.03 and OR 1.8, p = 0.008). ConclusionsOur data elucidate the wide spectrum of genetic variants impacting hypercholesterolemia and demonstrate the utility of a large reference population to assess the heterogeneous impact of candidate gene variants on cardiovascular disease risk.

The marker effects of a single-step random regression model for 4 test-day traits in German Holsteins

The single-step genomic model has become the golden standard for routine evaluation in livestock species, such as Holstein dairy cattle. The single-step genomic model with direct estimation of marker effects has been proven to be efficient in accurately accounting for millions of genotype records. For diverse applications including frequent genomic evaluation updates on a weekly basis, estimates of the marker effects from the single-step evaluations play a central role in genomic prediction. In this study we focused on exploring the marker effect estimates from the single-step evaluation. Phenotypic, genotypic, and pedigree data were taken from the official evaluation for German dairy breeds in April 2021. A multilactation random regression test-day model was applied to more than 242 million test-day records separately for 4 traits: milk, fat, and protein yields, and somatic cell scores (SCS). Approximately one million genotyped Holstein animals were considered in the single-step genomic evaluations including ∼21 million animals in pedigree. Deregressed multiple across-country breeding values of Holstein bulls having daughters outside Germany were integrated into the national test-day data to increase the reliability of genomic breeding values. To assess the stability and bias of the marker effects of the single-step model, test-day records of the last 4 yr were deleted, and the integrated bulls born in the last 4 yr were truncated from the complete phenotypic dataset. Estimates of the marker effects were shown to be highly correlated, with correlations ∼0.9, between the full and truncated evaluations. Regression slope values of the marker-effect estimates from the full on the truncated evaluations were all close to their expected value, being ∼1.03. Calculated using random regression coefficients of the marker effect estimates, drastically different shapes of the genetic lactation curve were seen for 2 markers on chromosome 14 for the 4 test-day traits. The contribution of individual chromosomes to the total additive genetic variances seemed to follow the polygenic inheritance mode for protein yield and SCS. However, chromosome 14 was found to make an exceptionally large contribution to the total additive genetic variance for milk and fat yields because of markers near the major gene DGAT1. For the first lactation test-day traits, we obtained ∼0 correlations of chromosomal direct genomic values between any pair of the chromosomes; no spurious correlations were found in our analysis, thanks to the large reference population. For trait milk yield, chromosomal direct genomic values appeared to have a large variation in the between-lactation correlations among the chromosomes, especially between first and second or third lactations. The optimal features of the random regression test-day model and the single-step marker model allowed us to track the differences in the shapes of genetic lactation curves down to the individual markers. Furthermore, the single-step random regression test-day model enabled us to better understand the inheritance mode of the yield traits and SCS (e.g., variable chromosomal contributions to the total additive genetic variance and to the genetic correlations between lactations).

EviGUIDE - a tool for evidence-based decision making in image-guided adaptive brachytherapy for cervical cancer

PurposeTo develop a novel decision-support system for radiation oncology that incorporates clinical, treatment and outcome data, as well as outcome models from a large clinical trial on magnetic resonance image-guided adaptive brachytherapy (MR-IGABT) for locally advanced cervical cancer (LACC). MethodsA system, called EviGUIDE, was developed that combines dosimetric information from the treatment planning system, patient and treatment characteristics, and established tumor control probability (TCP), and normal tissue complication probability (NTCP) models, to predict clinical outcome of radiotherapy treatment of LACC. Six Cox Proportional Hazards models based on data from 1341 patients of the EMBRACE-I study have been integrated. One TCP model for local tumor control, and five NTCP models for OAR morbidities. ResultsEviGUIDE incorporates TCP-NTCP graphs to help users visualize the clinical impact of different treatment plans and provides feedback on achievable doses based on a large reference population. It enables holistic assessment of the interplay between multiple clinical endpoints and tumour and treatment variables. Retrospective analysis of 45 patients treated with MR-IGABT showed that there exists a sub-cohort of patients (20%) with increased risk factors, that could greatly benefit from the quantitative and visual feedback. ConclusionA novel digital concept was developed that can enhance clinical decision- making and facilitate personalized treatment. It serves as a proof of concept for a new generation of decision support systems in radiation oncology, which incorporate outcome models and high-quality reference data, and aids the dissemination of evidence-based knowledge about optimal treatment and serve as a blueprint for other sites in radiation oncology.

Assessment of genomic breeding values and their accuracies for carcass traits in Jeju Black cattle using whole-genome SNP chip panels.

The objective of the present study was to evaluate the breeding value and accuracy of genomic estimated breeding values (GEBVs) of carcass traits in Jeju Black cattle (JBC) using Hanwoo steers and JBC as a reference population using the single-trait animal model. Our research included genotype and phenotype information on 19,154 Hanwoo steers with 1097 JBC acting as the reference population. Likewise, the test population consisted of 418 genotyped JBC individuals with no phenotypic records for those carcass traits. For estimating the accuracy of GEBV, we divided the entire population into three groups. Hanwoo and JBC make up the first group; Hanwoo and JBC, who has both the genotype and phenotypic records, are referred to as the reference (training) population, and JBC, who lacks phenotypic information is referred to as the test (validation) population. The second group consists of the JBC (without phenotype) as the test population and Hanwoo as a reference population with phenotype and genotypic data. The only JBCs in the third group are those who have genotypic and phenotypic data on them as a reference population but no phenotypic data on them as a test population. The single-trait animal model was used in all three groups for statistical purposes. The reference populations estimated heritabilities for carcass weight (CWT), eye muscle area (EMA), backfat thickness (BF), and marbling score (MS) as 0.30, 0.26, 0.26, and 0.34 for the Hanwoo steer and 0.42, 0.27, 0.26, and 0.48 for JBC. The average accuracy for carcass traits in Group 1 was 0.80 for the Hanwoo and JBC reference population compared with 0.73 for the JBC test population. Although the average accuracy for carcass traits in Group 2 was 0.80, it was 0.80 for the Hanwoo reference population and only 0.56 for the JBC test population. The average accuracy for the JBC reference and test populations was 0.68 and 0.50, respectively, when they were included in the accuracy comparison without the Hanwoo reference population. Groups 1 and 2 used Hanwoo as reference population, which led to a better average accuracy; however, Group 3 only used the JBC reference and test population, which led to a lower average accuracy. This might be due to the fact that Group 3 used a smaller reference size than the group that came before it and that the genetic makeup of the Hanwoo and JBC breeds differed. The GEBV accuracy for MS was higher than that of other traits across all three analysis groups, followed by CWT, EMA, and BF, which may be partially explained by the MS traits' higher heritability. This study suggests that in order to achieve more accuracy, a large reference population particular to a breed should be established. Therefore, to increase the accuracy of GEBV prediction and the genetic benefit from genomic selection in JBC, individual reference breeds, and large populations are required.

High genetic correlation for milk yield across Manech and Latxa dairy sheep from France and Spain

Spanish Latxa and French Manech are dairy sheep breeds that split into Blond (Latxa Cara Rubia, LCR; Manech Tête Rousse, MTR) and Black (Latxa Cara Negra of Navarre, LCN; Manech Tête Noire, MTN) strains. Exchange of genetic material (artificial insemination doses) is becoming more and more frequent across these breeds, within color, to boost both genomic precision using a larger reference population and genetic progress using a larger selection base. This exchange leads to some rams having descendance across both countries. However, additional gains can only be achieved if the selected traits are genetically similar across countries. The objective of this work was to estimate the genetic correlation across breeds for milk yield. We combine across-country, within-color records, pedigree, and marker information. The number of animals with records oscillates from 65,000 (LCN) to 544,000 (MTR), whereas the number of connecting artificial insemination rams (with more than 10 daughters in the other country) is 381 MTR rams in LCR and 58 MTN rams in LCN. Blond strains had a stronger and more extended-in-time connection. The number of genotyped rams goes from 328 (LCN) to 4,901 (MTR). The relatedness of populations was assessed by principal component analysis and Fst coefficients. The genetic correlation was estimated using 2 (one per color) 2-trait models (each country a trait), including all available data (records, pedigree and genotypes), by maximum profile likelihood while fixing other variance components to within-population estimates. Results showed a closer genetic relationship of Blond strains than of Black strains (Fst: 0.01 vs. 0.05, respectively). Genetic correlation estimates for milk yield were 0.70 in both cases. Based on Fst distances, we expected a lower correlation for Black strains than for Blond ones if dominance or epistasis are important. Thus, we attribute the value of this correlation not being close to 1 mostly to genotype-by-environment interaction, including on-farm management and trait modeling. Regardless, the correlation of 0.7 across populations is encouraging for future joint work of Latxa and Manech breeders, including joint genetic evaluations.

Genomic predictions for crossbred dairy cows by combining solutions from purebred evaluation based on breed origin of alleles

Genomic predictions have been applied for dairy cattle for more than a decade with great success, but genomic estimated breeding values (GEBV) are not widely available for crossbred dairy cows. The large reference populations already in place for genomic evaluations of many pure breeds makes it interesting to use the accurate solutions, in particular the estimated marker effects, from these evaluations for calculation of GEBV for crossbred heifers and cows. Effects of marker alleles in crossbred animals can depend on breed origin of the alleles (BOA). Therefore, our aim was to investigate if reliable GEBV for crossbred dairy cows can be obtained by combining estimated marker effects from purebred evaluations based on BOA. We used data on 5,467 Danish crossbred dairy cows with contributions from Holstein, Jersey, and Red Dairy Cattle breeds. We assessed BOA assignment on their genotypes and found that we could assign 99.3% of the alleles to a definite breed of origin. We compared GEBV for 2 traits, protein yield and interval between first and last insemination of cows, with 2 models that both combine estimated marker effects from the genomic evaluations of the pure breeds: a breed of origin model that accounts for BOA and a breed proportion model that only accounts for genomic breed proportions in the crossbred animals. We accounted for the difference in level between the purebred evaluations by including intercepts in the models based on phenotypic averages. The predictive ability for protein yield was significantly higher from the breed of origin model, 0.45 compared with 0.43 from the breed proportion model. Furthermore, for the breed proportion model, the GEBVs had level bias, which made comparison across groups with different breed composition skewed. We therefore concluded that reliable genomic predictions for crossbred dairy cows can be obtained by combining estimated marker effects from the genomic evaluations of purebreds using a model that accounts for BOA.

Infrared Predictions Are a Valuable Alternative to Actual Measures of Dry-Cured Ham Weight Loss in the Training of Genome-Enabled Prediction Models.

Simple SummaryExcessive ham weight losses during dry-curing (WL) result in a loss of marketable product, hindering the quality of dry-cured hams. Genetic selection for reducing WL requires individual traceability of hams throughout the dry-curing process and the measurement of WL is expensive, time-consuming, and can be performed only at the end of seasoning, resulting in long generation intervals. Infrared spectroscopy provides early, cost-effective, high-throughput predictions of WL that are highly genetically correlated with the actual measures. This study focused on the accuracy of genomic prediction models for observed and infrared-predicted WL. Models were tested on crossbred pigs and their purebred sires in random cross-validation and in a leave-one-family-out training-validation scheme. Accuracy of prediction of sire genetic merit, estimated from crossbred training data for actual ham WL, was 0.38, slightly higher than the accuracy attainable by a model trained on infrared-predicted WL (0.32). While the accuracy of genomic predictions is satisfactory for both the observed and infrared-predicted WL, the use of infrared predictions results in considerably lower phenotyping costs, enabling the construction of larger reference populations.Selection to reduce ham weight losses during dry-curing (WL) requires individual traceability of hams throughout dry-curing, with high phenotyping costs and long generation intervals. Infrared spectroscopy enables cost-effective, high-throughput phenotyping for WL 24 h after slaughter. Direct genomic values (DGV) of crossbred pigs and their purebred sires were estimated, for observed (OB) and infrared-predicted WL (IR), through models developed from 640 and 956 crossbred pigs, respectively. Five Bayesian models and two pseudo-phenotypes (estimated breeding value, EBV, and adjusted phenotype) were tested in random cross-validation and leave-one-family-out validation. The use of EBV as pseudo-phenotypes resulted in the highest accuracies. Accuracies in leave-one-family-out validation were much lower than those obtained in random cross-validation but still satisfactory and very similar for both traits. For sires in the leave-one-family-out validation scenario, the correlation between the DGV for IR and EBV for OB was slightly lower (0.32) than the correlation between the DGV for OB and EBV for OB (0.38). While genomic prediction of OB and IR can be equally suggested to be incorporated in future selection programs aiming at reducing WL, the use of IR enables an early, cost-effective phenotyping, favoring the construction of larger reference populations, with accuracies comparable to those achievable using OB phenotype.

Optimal population size to detect quantitative trait loci in Korean native chicken: a simulation study.

ObjectiveA genomic region associated with a particular phenotype is called quantitative trait loci (QTL). To detect the optimal F2 population size associated with QTLs in native chicken, we performed a simulation study on F2 population derived from crosses between two different breeds.MethodsA total of 15 males and 150 females were randomly selected from the last generation of each F1 population which was composed of different breed to create two different F2 populations. The progenies produced from these selected individuals were simulated for six more generations. Their marker genotypes were simulated with a density of 50K at three different heritability levels for the traits such as 0.1, 0.3, and 0.5. Our study compared 100, 500, 1,000 reference population (RP) groups to each other with three different heritability levels. And a total of 35 QTLs were used, and their locations were randomly created.ResultsWith a RP size of 100, no QTL was detected to satisfy Bonferroni value at three different heritability levels. In a RP size of 500, two QTLs were detected when the heritability was 0.5. With a RP size of 1,000, 0.1 heritability was detected only one QTL, and 0.5 heritability detected five QTLs. To sum up, RP size and heritability play a key role in detecting QTLs in a QTL study. The larger RP size and greater heritability value, the higher the probability of detection of QTLs.ConclusionOur study suggests that the use of a large RP and heritability can improve QTL detection in an F2 chicken population.

Simulation studies to optimize genomic selection in honey bees

BackgroundWith the completion of a single nucleotide polymorphism (SNP) chip for honey bees, the technical basis of genomic selection is laid. However, for its application in practice, methods to estimate genomic breeding values need to be adapted to the specificities of the genetics and breeding infrastructure of this species. Drone-producing queens (DPQ) are used for mating control, and usually, they head non-phenotyped colonies that will be placed on mating stations. Breeding queens (BQ) head colonies that are intended to be phenotyped and used to produce new queens. Our aim was to evaluate different breeding program designs for the initiation of genomic selection in honey bees.MethodsStochastic simulations were conducted to evaluate the quality of the estimated breeding values. We developed a variation of the genomic relationship matrix to include genotypes of DPQ and tested different sizes of the reference population. The results were used to estimate genetic gain in the initial selection cycle of a genomic breeding program. This program was run over six years, and different numbers of genotyped queens per year were considered. Resources could be allocated to increase the reference population, or to perform genomic preselection of BQ and/or DPQ.ResultsIncluding the genotypes of 5000 phenotyped BQ increased the accuracy of predictions of breeding values by up to 173%, depending on the size of the reference population and the trait considered. To initiate a breeding program, genotyping a minimum number of 1000 queens per year is required. In this case, genetic gain was highest when genomic preselection of DPQ was coupled with the genotyping of 10–20% of the phenotyped BQ. For maximum genetic gain per used genotype, more than 2500 genotyped queens per year and preselection of all BQ and DPQ are required.ConclusionsThis study shows that the first priority in a breeding program is to genotype phenotyped BQ to obtain a sufficiently large reference population, which allows successful genomic preselection of queens. To maximize genetic gain, DPQ should be preselected, and their genotypes included in the genomic relationship matrix. We suggest, that the developed methods for genomic prediction are suitable for implementation in genomic honey bee breeding programs.

Evaluation and Comparison with Other High-Sensitivity Methods of Analytical Performance and Measured Values of a New Laboratory Test for Cardiac Troponin I Assay.

The aim of this study was to evaluate both analytical characteristics and clinical results of a new chemiluminescent method for the measurement of cardiac troponin I (cTnI), named VITROS ® High Sensitivity Troponin I Assay, using the VITROS® 3600 automated platform. The results found with this new method were compared to those observed with hs-cTnI ARCHITECT and ECLIA hs-cTnT ELECSYS methods. For evaluation of analytical performance and comparison of clinical results, plasma samples (lithium-heparin), were collected from apparently healthy subjects and patients with cardiovascular diseases. The hs-cTnI VITROS method showed values for limit of blank (LoB 0.33 ng/L), limit of detection (LoD, 0.91 ng/L), limit of quantifications at 20% (LoQ 20% CV, 1.82 ng/L), and 10% (LoQ 10% CV, 4,74 ng/L), which are comparable to those previously reported for other hs-cTnI methods. Moreover, the clinical results of the hs-cTnI VITROS method were found to be closely correlated to those of hs-cTnI ARCHITECT (R = 0,9883, N = 198) and ECLIA hs-cTnT Elecsys (R = 0,9704, N = 293) methods. The hs-cTnI VITROS method shows analytical performance comparable to other cTnI and cTnT assay. The results of this study confirm that there are significant systematic differences among hs-cTnI methods. Further multicenter studies using larger reference populations are needed in order to obtain a better estimation, especially of the 99° percentile URL values categorized for sex and age of hs-cTnI and hs-cTnT methods.

Relatedness between numerically small Dutch Red dairy cattle populations and possibilities for multibreed genomic prediction

Red dairy breeds are a valuable cultural and historical asset, and often a source of unique genetic diversity. However, they have difficulties competing with other, more productive, dairy breeds. Improving competitiveness of Red dairy breeds, by accelerating their genetic improvement using genomic selection, may be a promising strategy to secure their long-term future. For many Red dairy breeds, establishing a sufficiently large breed-specific reference population for genomic prediction is often not possible, but may be overcome by adding individuals from another breed. Relatedness between breeds strongly decides the benefit of adding another breed to the reference population. To prioritize among available breeds, the effective number of chromosome segments (Me) can be used as an indicator of relatedness between individuals from different breeds. The Me is also an important parameter in determining the accuracy of genomic prediction. The Me can be estimated both within a population and between 2 populations or breeds, as the reciprocal of the variance of genomic relationships. We investigated relatedness between 6 Dutch Red cattle breeds, Groningen White Headed (GWH), Dutch Friesian (DF), Meuse-Rhine-Yssel (MRY), Dutch Belted (DB), Deep Red (DR), and Improved Red (IR), focusing primarily on the Me, to predict which of those breeds may benefit from including reference animals of the other breeds. All of these breeds, except MRY, are under high risk of extinction. Our results indicated high variability of Me, especially between Me ranging from ∼3,500 to ∼17,400, indicating different levels of relatedness between the breeds. Two clusters are especially important, one formed by MRY, DR, and IR, and the other comprising DF and DB. Although relatedness between breeds within each of these 2 clusters is high, across-breed genomic prediction is still limited by the current number of genotyped individuals, which for many breeds is low. However, adding MRY individuals would increase the reference population of DR substantially. We estimated that between 11 and 133 individuals from other breeds are needed to achieve accuracy of genomic prediction equivalent to using one additional individual from the same breed. Given the variation in size of the breeds in this study, the benefit of a multibreed reference population is expected to be lower for larger breeds than for the smaller ones.

The use of milk mid-infrared spectroscopy to improve genomic prediction accuracy of serum biomarkers

Breeding objectives in the dairy industry have shifted from being solely focused on production to including fertility, animal health, and environmental impact. Increased serum concentrations of candidate biomarkers of health and fertility, such as β-hydroxybutyric acid (BHB), fatty acids, and urea are difficult and costly to measure, and thus limit the number of records. Accurate genomic prediction requires a large reference population. The inclusion of milk mid-infrared (MIR) spectroscopic predictions of biomarkers may increase genomic prediction accuracy of these traits. Our objectives were to (1) estimate the heritability of, and genetic correlations between, selected serum biomarkers and their respective MIR predictions, and (2) evaluate genomic prediction accuracies of either only measured serum traits, or serum traits plus MIR-predicted traits. The MIR-predicted traits were either fitted in a single trait model, assuming the measured trait and predicted trait were the same trait, or in a multitrait model, where measured and predicted trait were assumed to be correlated traits. We performed all analyses using relationship matrices constructed from pedigree (A matrix), genotypes (G matrix), or both pedigree and genotypes (H matrix). Our data set comprised up to 2,198 and 9,657 Holstein cows with records for serum biomarkers and MIR-predicted traits, respectively. Heritabilities of measured serum traits ranged from 0.04 to 0.07 for BHB, from 0.13 to 0.21 for fatty acids, and from 0.10 to 0.12 for urea. Heritabilities for MIR-predicted traits were not significantly different from those for the measured traits. Genetic correlations between measured traits and MIR-predicted traits were close to 1 for urea. For BHB and fatty acids, genetic correlations were lower and had large standard errors. The inclusion of MIR predicted urea substantially increased prediction accuracy for urea. For BHB, including MIR-predicted BHB reduced the genomic prediction accuracy, whereas for fatty acids, prediction accuracies were similar with either measured fatty acids, MIR-predicted fatty acids, or both. The high genetic correlation between urea and MIR-predicted urea, in combination with the increased prediction accuracy, demonstrated the potential of using MIR-predicted urea for genomic prediction of urea. For BHB and fatty acids, further studies with larger data sets are required to obtain more accurate estimates of genetic correlations.

Factors affecting accuracy of estimated effective number of chromosome segments for numerically small breeds.

For numerically small breeds, obtaining a sufficiently large breed‐specific reference population for genomic prediction is challenging or simply not possible, but may be overcome by adding individuals from another breed. To prioritize among available breeds, the effective number of chromosome segments (M e) can be used as an indicator of relatedness between individuals from different breeds. The M e is also an important parameter in determining the accuracy of genomic prediction. The M e can be estimated both within a population and between two populations or breeds, as the reciprocal of the variance of genomic relationships. However, the threshold for number of individuals needed to accurately estimate within or between populations M e is currently unknown. It is also unknown if a discrepancy in number of genotyped individuals in two breeds affects the estimates of M e between populations. In this study, we conducted a simulation that mimics current domestic cattle populations in order to investigate how estimated M e is affected by number of genotyped individuals, single‐nucleotide polymorphism (SNP) density and pedigree availability. Our results show that a small sample of 10 genotyped individuals may result in substantial over or underestimation of M e. While estimates of within population M e were hardly affected by SNP density, between population M e values were highly dependent on the number of available SNPs, with higher SNP densities being able to detect more independent chromosome segments. When subtracting pedigree from genomic relationships before computing M e, estimates of within population M e were three to four times higher than estimates with genotypes only; however, between M e estimates remained the same. For accurate estimation of within and between population M e, at least 50 individuals should be genotyped per population. Estimates of within M e were highly affected by whether pedigree was used or not. For within M e, even the smallest SNP density (~11k) resulted in accurate representation of family relationships in the population; however, for between M e, many more markers are needed to capture all independent segments.

The Brazilian Initiative on Precision Medicine (BIPMed): fostering genomic data-sharing of underrepresented populations

The development of precision medicine strategies requires prior knowledge of the genetic background of the target population. However, despite the availability of data from admixed Americans within large reference population databases, we cannot use these data as a surrogate for that of the Brazilian population. This lack of transferability is mainly due to differences between ancestry proportions of Brazilian and other admixed American populations. To address the issue, a coalition of research centres created the Brazilian Initiative on Precision Medicine (BIPMed). In this study, we aim to characterise two datasets obtained from 358 individuals from the BIPMed using two different platforms: whole-exome sequencing (WES) and a single nucleotide polymorphism (SNP) array. We estimated allele frequencies and variant pathogenicity values from the two datasets and compared our results using the BIPMed dataset with other public databases. Here, we show that the BIPMed WES dataset contains variants not included in dbSNP, including 6480 variants that have alternative allele frequencies (AAFs) >1%. Furthermore, after merging BIPMed WES and SNP array data, we identified 809,589 variants (47.5%) not present within the 1000 Genomes dataset. Our results demonstrate that, through the incorporation of Brazilian individuals into public genomic databases, BIPMed not only was able to provide valuable knowledge needed for the implementation of precision medicine but may also enhance our understanding of human genome variability and the relationship between genetic variation and disease predisposition.

Identifying modifier genes for hypertrophic cardiomyopathy

BackgroundHypertrophic cardiomyopathy (HCM) severity greatly varies among patients even with the same HCM gene mutations. This variation is largely regulated by modifier gene(s), which, however, remain largely unknown. The current study is aimed to identify modifier genes using BXD strains, a large murine genetic reference population (GRP) derived from crosses between C57BL/6 J (B6) and D2 DBA/2 J (D2) mice. D2 mice natualy carrythe genetic basis and phenotypes of HCM. MethodsMyocardial hypertrophy, the major phenotype of HCM, was determined by cardiomyocyte size on cardiac sections in 30 BXD strains, and their parental B6 and D2 strains and morphometric analysis was performed. Quantitative Trait Locus (QTL) mapping for cardiomyocyte sizes was conducted with WebQTL in GeneNetwork. Correlation of cardiomyocyte size and cardiac gene expression in BXDs accessed from GeneNetwork were evaluated. QTL candidate genes associated with cardiomyocyte sizes were prioritized based on the score system. ResultsCardiomyocyte size varied significantly among BXD strains. Interval mapping on cardiomyocyte size data showed a significant QTL on chromosome (Chr) 2 at 66– 73.5 Mb and a suggestive QTL on Chr 5 at 20.9–39.7 Mb. Further score system revealed a high QTL score for Xirp2 in Chr 2. Xirp2 encodes xin actin-binding repeat containing 2, which is highly expressed in cardiac tissue and associate with cardiomyopathy and heart failure. In Chr5 QTL, Nos3, encoding nitric oxide synthase 3, received the highest score, which is significantly correlated with cardiomyocyte size. ConclusionThese results indicate that Xirp2 and Nos3 serve as novel candidate modifier genes for myocardial hypertrophy in HCM. These candidate genes will be validated in our future studies.

Using Graduation to Modify the Estimation of Lee–Carter Model for Small Populations

Many mortality models, such as the Lee–Carter model, have unsatisfactory estimation in the case of small populations. Increasing population size is a natural choice to stabilize the estimation, if we can find a larger reference population that has a mortality profile similar to that of the small population. Aggregating historical data of the small populations is a fine candidate for the reference population. However, it is often not feasible in practice and we need to rely on other reference populations. In this study, we explore whether graduation methods can be used if the mortality profile of a small population differs from that of the reference population. To explore the appropriate occasion to use graduation methods, we create several mortality scenarios and similarity types between small and reference populations. We propose combining the graduation methods and mortality models, either graduating mortality rates first or applying the mortality model first, and determine whether they can improve the model fit. We use computer simulation to determine whether the proposed approach has better mortality estimation than the Lee–Carter model and the the Li–Lee model. We found that the Li–Lee model always has smaller estimation errors than the Lee–Carter model, and the proposed approach has smaller estimation errors than the Li–Lee model in most cases.

Genotyping more cows increases genetic gain and reduces rate of true inbreeding in a dairy cattle breeding scheme using female reproductive technologies

Both small dairy cattle populations and dairy cattle populations with a low level of linkage disequilibrium (LD) suffer from low reliability of genomic prediction. In this study, we investigated whether adding more genotyped cows to the reference population influences the rate of genetic gain and rate of inbreeding by affecting the reliability. A standard breeding program with a large reference population and high LD, which mimicked a breeding program for Danish Holstein population, was simulated as a reference. A Danish Jersey population with a small reference population and high LD and a Red Dairy Cattle population with a large reference population and low LD were also simulated. Two additional breeding programs were simulated for Danish Jersey and Red Dairy Cattle populations, where 2,000 additional genotyped cows were included in the population for genomic selection. All 5 simulated breeding programs were initiated by a founder population to generate LD resembling the real LD pattern, followed by a 20-yr conventional progeny-testing scheme with 1,000 or 10,000 genotyped progeny-tested bulls and a 10-yr genomic selection scheme with or without 2,000 additional genotyped cows. Evaluation criteria were annual monetary genetic gain and rate of true inbreeding. Our results showed that adding more genotyped cows to the reference in dairy cattle populations has the potential to increase genetic gain and reduce the rate of inbreeding, regardless of reference population size and level of LD. However, it is still not possible to reach the same genetic gain as in the simulated Danish Holstein population with either a small reference population or low LD. Our results also showed that in a small reference population with high LD, it is difficult to manage inbreeding because of lower accuracy compared with the simulated Danish Holstein population and a smaller number of relevant families to select from. Therefore, breeding strategies need to be chosen to match population size and structure. The rate of true inbreeding is always underestimated by pedigree inbreeding and even more in genomic breeding programs, indicating that some forms of genome-wide inbreeding, instead of pedigree-based inbreeding, should be used to monitor inbreeding when genomic selection is implemented.

Theoretical Evaluation of Multi-Breed Genomic Prediction in Chinese Indigenous Cattle.

Simple SummaryIn order to evaluate the potential application of genomic selection (GS) for Chinese indigenous cattle, we assessed the influence of combining multiple populations on the reliability of genomic predictions for 10 indigenous breeds of Chinese cattle using simulated data. We found the predictive accuracies to be low when the reference and validation populations were sampled from different breeds. When using multiple breeds for the reference population, the predictive accuracies were higher if the reference was comprised of breeds with close relationships. In addition, the accuracy increased in all scenarios when the heritability increased, and the genetic architecture of the QTL can affect genomic prediction. Our study suggested that the application of meta-populations can increase accuracy in scenarios with a reduced size of reference populations.Genomic selection (GS) has been widely considered as a valuable strategy for enhancing the rate of genetic gain in farm animals. However, the construction of a large reference population is a big challenge for small populations like indigenous cattle. In order to evaluate the potential application of GS for Chinese indigenous cattle, we assessed the influence of combining multiple populations on the reliability of genomic predictions for 10 indigenous breeds of Chinese cattle using simulated data. Also, we examined the effect of different genetic architecture on prediction accuracy. In this study, we simulated a set of genotype data by a resampling approach which can reflect the realistic linkage disequilibrium pattern for multiple populations. We found within-breed evaluations yielded the highest accuracies ranged from 0.64 to 0.68 for four different simulated genetic architectures. For scenarios using multiple breeds as reference, the predictive accuracies were higher when the reference was comprised of breeds with a close relationship, while the accuracies were low when prediction were carried out among breeds. In addition, the accuracy increased in all scenarios with the heritability increased. Our results suggested that using meta-population as reference can increase accuracy of genomic predictions for small populations. Moreover, multi-breed genomic selection was feasible for Chinese indigenous populations with genetic relationships.