Bayesian Methods for Genomic Prediction and Genome-Wide Association Studies combining Information on Genotyped and Non-Genotyped Individuals

Genomic prediction involves using high-density marker genotypes to characterize the impact on performance of every region of the genome, and using that information to predict performance of genotyped selection candidates. This is a relatively new technology and is now gaining traction in personalized medicine and in various livestock industries. Our new approach promises to overcome serious limitations with existing techniques for genomic prediction

New Diabetes Therapies and Diabetic Kidney Disease Progression:the Role of SGLT-2 Inhibitors

Purpose of Review Sodium-glucose co-transporter 2 (SGLT-2) inhibitors have emerged as a promising drug class for the treatment of diabetic kidney disease. Developed originally as glucose-lowering drugs by enhancing urinary glucose excretion, these drugs also lower many other renal and cardiovascular risk factors such as body weight, blood pressure, albuminuria, and uric acid. Results from the EMPA-REG OUTCOME and CANVAS trials show that these salutary effects translate into a reduction in cardiovascular outcomes and have the potential to delay the progression of kidney function decline. This review summarizes recent studies on the mechanisms and rationale of renoprotective effects. Recent Findings Effects of SGLT-2 inhibitors on the kidney are likely explained by multiple pathways. SGLT-2 inhibitors may improve renal oxygenation and intra-renal inflammation thereby slowing the progression of kidney function decline. Additionally, SGLT-2 inhibitors are associated with a reduction in glomerular hyperfiltration, an effect which is mediated through increased natriuresis and tubuloglomerular feedback and independent of glycemic control. Analogous to diabetic kidney disease, various etiologies of non-diabetic kidney disease are also characterized by single nephron hyperfiltration and elevated albuminuria. This offers the opportunity to reposition SGLT-2 inhibitors from diabetic to non-diabetic kidney disease. Clinical trials are currently ongoing to characterize the efficacy and safety of SGLT-2 inhibitors in patients with diabetic and non-diabetic kidney disease. Summary The glucose-independent hemodynamic mechanisms of SGLT-2 inhibitors provide the possibility to extend the use of SGLT-2 inhibitors to non-diabetic kidney disease. Ongoing dedicated trials have the potential to change clinical practice and outlook of high-risk patients with diabetic (and non-diabetic) kidney disease

A Nested Mixture Model for Genomic Prediction Using Whole-Genome SNP Genotypes

We propose a novel model (BayesN) for genomic prediction, where multiple markers in a small segment are simultaneously fitted to jointly capture the effect of major genes (QTL) in the segment. Compared with BayesB, in which the effects of neighboring markers are a prioriassumed to be independent, BayesN gave higher accuracies of prediction and required less computing effort. BayesN is an accurate and practical method for analyzing high-density markers, especially for traits influenced by rare QTL allele

Improved Accuracy of Genomic Prediction for Traits with Rare QTL by Fitting Haplotypes

Genomic prediction estimates breeding values by exploiting linkage disequilibrium (LD) between quantitative trait loci (QTL) and single nucleotide polymorphisms (SNPs). High LD cannot occur when QTL and SNPs have different minor allele frequencies (MAF). Marker panels tend to use SNPs with high MAF and will have limited ability to predict rare QTL alleles. In practice, increasing SNP density has not improved prediction accuracy. A possible reason is that many traits are characterized by rare QTL. In that case, linear models fitting haplotypes could have advantage because haplotypes can be in complete LD with QTL alleles. SNP genotypes were simulated to resemble 600K chip for the bovine genome. Genomic breeding values were predicted using either SNP genotypes or non-overlapping haplotypes. When QTL had low MAF, the haplotype model had significantly higher accuracy than the SNP model. Results show that fitting haplotypes can improve the accuracy of genomic prediction for traits controlled by rare QTL

Recognising and defining a new crown clade within Stromboidea Rafinesque, 1815 (Mollusca, Gastropoda)

This paper defines a new crown clade Neostromboidea to separate the Strombidae, Rostellariidae, and Seraphsidae from their sister families Struthiolariidae and Aporrhaidae. There is significant value to understanding evolutionary processes within Stromboidea to recognise the universal similarity in the position of the eye on the end of peduncles and a diminished cephalic tentacle that arises from the middle to the end on that peduncle. This is in contrast to other members of the Stromboidea where the eye is located at the base of the cephalic tentacle. These physiological differences represent two set of organisms with divergent and independent evolutionary life histories and therefore these differences need to be identifiable within the nomenclature to bring meaning to the way we name things

Genomic Prediction Using Linkage Disequilibrium and Co-segregation

A linear mixed model fitting both genome-wide cosegregation (CS) and linkage disequilibrium (LD) was developed to improve accuracy of genetic prediction for pedigreed populations of unrelated families that have half sibs represented in both training and validation. Cosegregation was modeled as the effects of genome-wide1-centimorgan haplotypes that one individual inherits from pedigree founders through identity-by-descent, while LD was modeled as allele substitution effects of all marker genotypes. Prediction accuracy of the LD-CS method was compared to the accuracy of three LD methods – GBLUP, BayesA and BayesB, using simulated datasets of varying numbers of paternal half sib families. Results show that the LD-CS method tended to have higher accuracy than any of the LD methods. With an increase in the number of families, the accuracy of the LD-CS method persisted, while the accuracy of the LD methods dropped. The results indicate that by fitting CS explicitly, the LD-CS method has higher and more consistent prediction accuracy than LD methods

Genomic Selection of Purebred Animals for Crossbred Performance in the Presence of Dominant Gene Action

The primary objective of this study was to assess the performance of different genomic prediction models applied to the selection of purebreds for crossbred performancebased on high-density marker data. Our results suggest that in the presence of dominant gene action, selection based on the dominance model is superior to both the a breed-specific allele model and an additive model in terms of maximizing crossbred performance through purebred selection, especially when training is not updated each generatio

Associations of the porcine immune response and genetic polymorphisms with the shedding of Salmonella enterica serovar Typhimurium

A major focus of our collaborattve research is to investigate the porctne response to Infection with Salmonella to 1) identify porctne genes differentially regulated during Infection and 2) Identify and associate genetic polymorphisms within these genes with infection status across swine populations In the current study, 40 crossbred pigs were intranasally inoculated with Salmonella enterica serovar Typhimurium and monitored for Salmonella fecal shedding and blood 1mmune parameters at 2, 7, 14 and 20 days post-inoculation (dpi). Using a multivariate permutation test, a positive correlation was observed between Salmonella shedding and Interferon-gamma (IFNG) levels at 2 and 7 dpi (p\u3c0.05), with a greater number of Salmonella shedding 1n the animals with higher IFNG levels

Effects of the sodium-glucose co-transporter-2 inhibitor dapagliflozin on estimated plasma volume in patients with type 2 diabetes

Aims To compare the effects of the sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin on estimated (ePV) and measured plasma volume (mPV) and to characterize the effects of dapagliflozin on ePV in a broad population of patients with type 2 diabetes. Materials and methods The Strauss formula was used to calculate changes in ePV. Change in plasma volume measured with I-125-human serum albumin (mPV) was compared with change in ePV in 10 patients with type 2 diabetes randomized to dapagliflozin 10 mg/d or placebo. Subsequently, changes in ePV were measured in a pooled database of 13 phase 2b/3 placebo-controlled clinical trials involving 4533 patients with type 2 diabetes who were randomized to dapagliflozin 10 mg daily or matched placebo. Results The median change in ePV was similar to the median change in mPV (-9.4% and -9.0%) during dapagliflozin treatment. In the pooled analysis of clinical trials, dapagliflozin decreased ePV by 9.6% (95% confidence interval 9.0 to 10.2) compared to placebo after 24 weeks. This effect was consistent in various patient subgroups, including subgroups with or without diuretic use or established cardiovascular disease. Conclusions ePV may be used as a proxy to assess changes in plasma volume during dapagliflozin treatment. Dapagliflozin consistently decreased ePV compared to placebo in a broad population of patients with type 2 diabetes

Effect of WUR Genotype and PRRS Vaccination on Pigs Co-Infected with PRRS and PCV2b

Average daily gain (ADG) and viral load (VL) were evaluated for pigs co-infected with porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) and porcine circovirus type 2b (PCV2b). Pigs were pre-selected for WUR genotype (a marker on chromosome 4 associated with weight gain and VL under PRRSV-challenge), half were vaccinated for PRRS, and half were not. Results indicate that vaccination for PRRS resulted in slower growth prior to co-infection and that the AB WUR genotype was associated with faster growth prior to co-infection, lower PRRS VL, and lower PCV2b VL in vaccinated pigs