Comparison of Bayesian models to estimate direct genomic values in multi-breed commercial beef cattle

Background

While several studies have examined the accuracy of direct genomic breeding values (DGV) within and across purebred cattle populations, the accuracy of DGV in crossbred or multi-breed cattle populations has been less well examined. Interest in the use of genomic tools for both selection and management has increased within the hybrid seedstock and commercial cattle sectors and research is needed to determine their efficacy. We predicted DGV for six traits using training populations of various sizes and alternative Bayesian models for a population of 3240 crossbred animals. Our objective was to compare alternate models with different assumptions regarding the distributions of single nucleotide polymorphism (SNP) effects to determine the optimal model for enhancing feasibility of multi-breed DGV prediction for the commercial beef industry.

Results

Realized accuracies ranged from 0.40 to 0.78. Randomly assigning 60 to 70% of animals to training (n ≈ 2000 records) yielded DGV accuracies with the smallest coefficients of variation. Mixture models (BayesB95, BayesCπ) and models that allow SNP effects to be sampled from distributions with unequal variances (BayesA, BayesB95) were advantageous for traits that appear or are known to be influenced by large-effect genes. For other traits, models differed little in prediction accuracy (~0.3 to 0.6%), suggesting that they are mainly controlled by small-effect loci.

Conclusions

The proportion (60 to 70%) of data allocated to training that optimized DGV accuracy and minimized the coefficient of variation of accuracy was similar to large dairy populations. Larger effects were estimated for some SNPs using BayesA and BayesB95 models because they allow unequal SNP variances. This substantially increased DGV accuracy for Warner-Bratzler Shear Force, for which large-effect quantitative trait loci (QTL) are known, while no loss in accuracy was observed for traits that appear to follow the infinitesimal model. Large decreases in accuracy (up to 0.07) occurred when SNPs that presumably tag large-effect QTL were over-regressed towards the mean in BayesC0 analyses. The DGV accuracies achieved here indicate that genomic selection has predictive utility in the commercial beef industry and that using models that reflect the genomic architecture of the trait can have predictive advantages in multi-breed populations.

Electronic supplementary material

The online version of this article (doi:10.1186/s12711-015-0106-8) contains supplementary material, which is available to authorized users.     

Priority threat management of invasive animals to protect biodiversity under climate change

Climate change is a major threat to global biodiversity, and its impacts can act synergistically to heighten the severity of other threats. Most research on projecting species range shifts under climate change has not been translated to informing priority management strategies on the ground. We develop a prioritization framework to assess strategies for managing threats to biodiversity under climate change and apply it to the management of invasive animal species across one‐sixth of the Australian continent, the Lake Eyre Basin. We collected information from key stakeholders and experts on the impacts of invasive animals on 148 of the region's most threatened species and 11 potential strategies. Assisted by models of current distributions of threatened species and their projected distributions, experts estimated the cost, feasibility, and potential benefits of each strategy for improving the persistence of threatened species with and without climate change. We discover that the relative cost‐effectiveness of invasive animal control strategies is robust to climate change, with the management of feral pigs being the highest priority for conserving threatened species overall. Complementary sets of strategies to protect as many threatened species as possible under limited budgets change when climate change is considered, with additional strategies required to avoid impending extinctions from the region. Overall, we find that the ranking of strategies by cost‐effectiveness was relatively unaffected by including climate change into decision‐making, even though the benefits of the strategies were lower. Future climate conditions and impacts on range shifts become most important to consider when designing comprehensive management plans for the control of invasive animals under limited budgets to maximize the number of threatened species that can be protected.     

The extent and costs of reproductive interference among four species of true bug

Reproductive interference arises when individuals of one species engage in reproductive activities with individuals of another, leading to fitness costs in one or both species. Reproductive interference (RI) therefore has two components. First, there must be mis-directed mating interactions. Second, there must be costs associated with these mis-directed interactions. Here we consider RI between four species of true bug in the family Lygaeidae, focusing in particular on the fitness consequences to Lygaeus equestris. The species we consider vary in their relationships with each other, including species in the same or different genus, and with or without natural overlap in their geographic ranges. First we show that inter-specific mating interactions, although not a certain outcome, are common enough to perhaps influence mating behaviour in these species (arising in up to 10 % of inter-specific pairings). Second, we show that reproductive interference can seriously reduce female fitness in L. equestris. Importantly, different species impose different costs of RI on L. equestris, with interactions with male Spilostethus pandurus inflicting fitness costs of similar magnitude to the costs of mating with con-specifics. On the other hand, mating interactions with male Oncopeltus fasciatus appear to have no effect on female fitness. In a follow-up experiment, when we allowed competition amongst just females of S. pandurus and L. equestris, the fitness of the latter was not reduced, arguing more strongly for the role of reproductive interference. However, in our final experiments under mass mating conditions with extended ecological interactions (including scope for competition for resources and cannibalism), the costs of RI were less apparent. Our data therefore suggest that the costs of RI will be context-specific and may act in concert with, or be swamped by, other ecological effects. We suggest that comparative studies of this sort that both mimic naturally occurring reproductive interference events, and also artificially generate new ones, will be necessary if we are to better understand the ecological and evolutionary significance of reproductive interference.     

Derivation and validation of clinical phenotypes for COPD: a systematic review

Background

The traditional classification of COPD, which relies solely on spirometry, fails to account for the complexity and heterogeneity of the disease. Phenotyping is a method that attempts to derive a single or combination of disease attributes that are associated with clinically meaningful outcomes. Deriving phenotypes entails the use of cluster analyses, and helps individualize patient management by identifying groups of individuals with similar characteristics. We aimed to systematically review the literature for studies that had derived such phenotypes using unsupervised methods.

Methods

Two independent reviewers systematically searched multiple databases for studies that performed validated statistical analyses, free of definitive pre-determined hypotheses, to derive phenotypes among patients with COPD. Data were extracted independently.

Results

9156 citations were retrieved, of which, 8 studies were included. The number of subjects ranged from 213 to 1543. Most studies appeared to be biased: patients were more likely males, with severe disease, and recruited in tertiary care settings. Statistical methods used to derive phenotypes varied by study. The number of phenotypes identified ranged from 2 to 5. Two phenotypes, with poor longitudinal health outcomes, were common across multiple studies: young patients with severe respiratory disease, few cardiovascular co-morbidities, poor nutritional status and poor health status, and a phenotype of older patients with moderate respiratory disease, obesity, cardiovascular and metabolic co-morbidities.

Conclusions

The recognition that two phenotypes of COPD were often reported may have clinical implications for altering the course of the disease. This review also provided important information on limitations of phenotype studies in COPD and the need for improvement in future studies.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0208-4) contains supplementary material, which is available to authorized users.     

Discovery of microsomal triglyceride transfer protein (MTP) inhibitors with potential for decreased active metabolite load compared to dirlotapide

Analogues related to dirlotapide (1), a gut-selective inhibitor of microsomal triglyceride transfer protein (MTP) were prepared with the goal of further reducing the potential for unwanted liver MTP inhibition and associated side-effects. Compounds were designed to decrease active metabolite load: reducing MTP activity of likely human metabolites and increasing metabolite clearance to reduce exposure. Introduction of 4′-alkyl and 4′-alkoxy substituents afforded compounds exhibiting improved therapeutic index in rats with respect to liver triglyceride accumulation and enzyme elevation. Likely human metabolites of select compounds were prepared and characterized for their potential to inhibit MTP in vivo. Based on preclinical efficacy and safety data and its potential for producing short-lived, weakly active metabolites, compound 13 (PF-02575799) advanced into phase 1 clinical studies.     

Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 Å resolution

A high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase (MGL) is presented. The structure highlights a novel conformation of the regulatory lid-domain present in the lipase family as well as the binding mode of a pharmaceutically relevant reversible inhibitor. Analysis of the structure lacking the inhibitor indicates that the closed conformation can accommodate the native substrate 2-arachidonoyl glycerol. A model is proposed in which MGL undergoes conformational and electrostatic changes during the catalytic cycle ultimately resulting in its dissociation from the membrane upon completion of the cycle. In addition, the study outlines a successful approach to transform membrane associated proteins, which tend to aggregate upon purification, into a monomeric and soluble form.     

Dynamics of the phosphoinositide 3-kinase p110δ interaction with p85α and membranes reveals aspects of regulation distinct from p110α

Phosphoinositide 3-kinase δ is upregulated in lymphocytic leukemias. Because the p85-regulatory subunit binds to any class IA subunit, it was assumed there is a single universal p85-mediated regulatory mechanism; however, we find isozyme-specific inhibition by p85α. Using deuterium exchange mass spectrometry (DXMS), we mapped regulatory interactions of p110δ with p85α. Both nSH2 and cSH2 domains of p85α contribute to full inhibition of p110δ, the nSH2 by contacting the helical domain and the cSH2 via the C terminus of p110δ. The cSH2 inhibits p110β and p110δ, but not p110α, implying that p110α is uniquely poised for oncogenic mutations. Binding RTK phosphopeptides disengages the SH2 domains, resulting in exposure of the catalytic subunit. We find that phosphopeptides greatly increase the affinity of the heterodimer for PIP2-containing membranes measured by FRET. DXMS identified regions decreasing exposure at membranes and also regions gaining exposure, indicating loosening of interactions within the heterodimer at membranes.     

Federal Agency biodefense funding, FY2011-FY2012

Since 2001, the United States government has spent substantial resources on preparing the nation against a bioterrorist attack. Earlier articles in this series have analyzed civilian biodefense funding by the federal government for fiscal years (FY) 2001 through proposed funding for FY2011. This article updates those figures with budgeted amounts for FY2012, specifically analyzing the budgets and allocations for biodefense at the Departments of Health and Human Services, Defense, Homeland Security, Agriculture, Commerce, and State; the Environmental Protection Agency; and the National Science Foundation. This article also includes an updated assessment of the proportion of biodefense funding provided for programs that address multiple scientific, public health, healthcare, national security, and international security issues in addition to biodefense. The FY2012 federal budget for civilian biodefense totals $6.42 billion. Of that total, $5.78 billion (90%) is budgeted for programs that have both biodefense and nonbiodefense goals and applications, and $637.6 million (10%) is budgeted for programs that have objectives solely related to biodefense.