Genomics and breeding innovations for enhancing genetic gain for climate resilience and nutrition traits

Accelerating genetic gain in crop improvement programs with respect to climate resilience and nutrition traits, and the realization of the improved gain in farmers’ fields require integration of several approaches. This article focuses on innovative approaches to address core components of the breeder’s equation. A prerequisite to enhancing genetic variance (σ2g) is the identification or creation of favorable alleles/haplotypes and their deployment for improving key traits. Novel alleles for new and existing target traits need to be accessed and added to the breeding population while maintaining genetic diversity. Selection intensity (i) in the breeding program can be improved by testing a larger population size, enabled by the statistical designs with minimal replications and high-throughput phenotyping. Selection priorities and criteria to select appropriate portion of the population too assume an important role. The most important component of breeder′s equation is heritability (h2). Heritability estimates depend on several factors including the size and the type of population and the statistical methods. The present article starts with a brief discussion on the potential ways to enhance σ2g in the population. We highlight statistical methods and experimental designs that could improve trait heritability estimation. We also offer a perspective on reducing the breeding cycle time (t), which could be achieved through the selection of appropriate parents, optimizing the breeding scheme, rapid fixation of target alleles, and combining speed breeding with breeding programs to optimize trials for release. Finally, we summarize knowledge from multiple disciplines for enhancing genetic gains for climate resilience and nutritional traits

Generation of Large-Scale Vorticity in a Homogeneous Turbulence with a Mean Velocity Shear

An effect of a mean velocity shear on a turbulence and on the effective force which is determined by the gradient of Reynolds stresses is studied. Generation of a mean vorticity in a homogeneous incompressible turbulent flow with an imposed mean velocity shear due to an excitation of a large-scale instability is found. The instability is caused by a combined effect of the large-scale shear motions (''skew-induced" deflection of equilibrium mean vorticity) and ''Reynolds stress-induced" generation of perturbations of mean vorticity. Spatial characteristics, such as the minimum size of the growing perturbations and the size of perturbations with the maximum growth rate, are determined. This instability and the dynamics of the mean vorticity are associated with the Prandtl's turbulent secondary flows. This instability is similar to the mean-field magnetic dynamo instability. Astrophysical applications of the obtained results are discussed.Comment: 8 pages, 3 figures, REVTEX4, submitted to Phys. Rev.

Modulation of GLP-1 levels by a genetic variant that regulates the cardiovascular effects of intensive glycemic control in ACCORD

OBJECTIVE A genome-wide association study in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial identified two markers (rs57922 and rs9299870) that were significantly associated with cardiovascular mortality during intensive glycemic control and could potentially be used, when combined into a genetic risk score (GRS), to identify patients with diabetes likely to derive benefit from intensive control rather than harm. The aim of this study was to gain insights into the pathways involved in the modulatory effect of these variants. RESEARCH DESIGN AND METHODS Fasting levels of 65 biomarkers were measured at baseline and at 12 months of follow-up in the ACCORD-Memory in Diabetes (ACCORD- MIND) MRI substudy (n = 562). Using linear regression models, we tested the association of the GRS with baseline and 12-month biomarker levels, and with their difference (D), among white subjects, with genotype data (n = 351) stratified by intervention arm. RESULTS A significant association was observed between GRS and DGLP-1 (glucagon-like peptide 1, active) in the intensive arm (P = 3 3 1024). This effect was driven by rs57922 (P = 5 3 1024). C/C homozygotes, who had been found to derive cardiovascular benefits from intensive treatment, showed a 22% increase in GLP-1 levels during follow-up. By contrast, T/T homozygotes, who had been found to experience increased cardiac mortality with intensive treatment, showed a 28% reduction in GLP-1 levels. No association between DGLP-1 and GRS or rs57922 was observed in the standard treatment arm. CONCLUSIONS Differences in GLP-1 axis activation may mediate the modulatory effect of variant rs57922 on the cardiovascular response to intensive glycemic control. These findings highlight the importance of GLP-1 as a cardioprotective factor

A genetic locus on chromosome 2q24 predicting peripheral neuropathy risk in type 2 diabetes: Results from the ACCORD and BARI 2D studies

Genetic factors have been postulated to be involved in the etiology of diabetic peripheral neuropathy (DPN), but their identity remains mostly unknown. The aim of this study was to conduct a systematic search for genetic variants influencing DPN risk using two wellcharacterized cohorts. A genome-wide association study (GWAS) testing 6.8 million single nucleotide polymorphisms was conducted among participants of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial. Included were 4,384 white case patients with type 2 diabetes (T2D) and prevalent or incident DPN (defined as a Michigan Neuropathy Screening Instrument clinical examination score >2.0) and 784 white control subjects with T2D and no evidence of DPN at baseline or during follow-up. Replication of significant loci was sought among white subjects with T2D (791 DPN-positive case subjects and 158 DPNnegative control subjects) from the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial. Association between significant variants and gene expression in peripheral nerves was evaluated in the Genotype-Tissue Expression (GTEx) database. A cluster of 28 SNPs on chromosome 2q24 reached GWAS significance (P < 5×10-8) in ACCORD. The minor allele of the lead SNP (rs13417783,minor allele frequency = 0.14) decreased DPN odds by 36%(odds ratio [OR] 0.64, 95% CI 0.55-0.74, P = 1.9×10-9). This effect was not influenced by ACCORD treatment assignments (P for interaction = 0.6) or mediated by an association with known DPN risk factors. This locus was successfully validated in BARI 2D (OR 0.57, 95%CI 0.42-0.80,P=9×10-4; summary P=7.9×10-12). In GTEx, the minor, protective allele at this locus was associated with higher tibial nerve expression of an adjacent gene (SCN2A) coding for human voltage-gated sodium channel NaV1.2 (P = 9×10-4). To conclude, we have identified and successfully validated a previously unknown locus with a powerful protective effect on the development of DPN in T2D. These results may provide novel insights into DPN pathogenesis and point to a potential target for novel interventions

Effects of Natura 2000 on nontarget bird and butterfly species based on citizen science data

ABSTRACT The European Union's Natura 2000 (N2000), is one of the largest international networks of protected areas. One of its aims is to secure the status of a pre-determined set of (targeted) bird and butterfly species. However, also non-target species may benefit from N2000. We evaluated how the terrestrial component of this network relates to the abundance of non-targeted, more common bird and butterfly species using data from long-term volunteer-based monitoring programs in 9,602 sites for birds and 2,001 sites for butterflies. In almost half of the 155 bird species assessed, and particularly among woodland specialists, abundance increased with the proportion of N2000 sites in the landscape. The corresponding positive relationship was found for 27 of the 104 butterfly species, although most of these species were generalists. These positive relationships disappeared for most of the species when land-cover covariates were taken into account, hinting that land-cover is a primary factor defining the positive effects of the N2000 network. The increase in abundance with N2000 was correlated with the specialization index for bird species, but not for butterfly species. Although the N2000 network supports higher abundance of a large spectrum of species, the low number of specialist butterfly species showing a positive association stresses the need to implement management plan improving the quality of habitats of N2000 areas potentially harboring openland butterfly specialists. For a better understanding of the processes involved, we advocate for a standardized collection of data on N2000 sites. Article impact statement: Across Europe the abundance of a majority of nontarget birds and a quarter of nontarget butterflies increased with Natura 2000 coverage. This article is protected by copyright. All rights reservedpeerReviewe

Motion Planning via Manifold Samples

We present a general and modular algorithmic framework for path planning of robots. Our framework combines geometric methods for exact and complete analysis of low-dimensional configuration spaces, together with practical, considerably simpler sampling-based approaches that are appropriate for higher dimensions. In order to facilitate the transfer of advanced geometric algorithms into practical use, we suggest taking samples that are entire low-dimensional manifolds of the configuration space that capture the connectivity of the configuration space much better than isolated point samples. Geometric algorithms for analysis of low-dimensional manifolds then provide powerful primitive operations. The modular design of the framework enables independent optimization of each modular component. Indeed, we have developed, implemented and optimized a primitive operation for complete and exact combinatorial analysis of a certain set of manifolds, using arrangements of curves of rational functions and concepts of generic programming. This in turn enabled us to implement our framework for the concrete case of a polygonal robot translating and rotating amidst polygonal obstacles. We demonstrate that the integration of several carefully engineered components leads to significant speedup over the popular PRM sampling-based algorithm, which represents the more simplistic approach that is prevalent in practice. We foresee possible extensions of our framework to solving high-dimensional problems beyond motion planning.Comment: 18 page

Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies

We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (β-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10−8). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10−4, Beta = 3.09, diastolic BP response P = 5 × 10−3, Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients’ subgroup (P = 2.35 × 10−4, odds ratio = 1.57, 95% confidence interval = 1.23–1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted

Genetic variants in CPA6 and PRPF31 are associated with variation in response to metformin in individuals with type 2 diabetes

Metformin is the first-line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here, we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA 1c response to metformin treatment and followed up these findings in four replication cohorts. Common variants in PRPF31 and CPA6 were associated with worse and better metformin response, respectively (P < 5 3 10 26 ), and meta-analysis in independent cohorts displayed similar associations with metformin response (P = 1.2 3 10 2 8 and P = 0.005, respectively). Previous studies have shown that PRPF31(+/2) knockout mice have increased total body fat (P = 1.78 3 10 26 ) and increased fasted circulating glucose (P = 5.73 3 10 26 ). Furthermore, rare variants in STAT3 associated with worse metformin response (q <0.1). STAT3 is a ubiquitously expressed pleiotropic transcriptional activator that participates in the regulation of metabolism and feeding behavior. Here, we provide novel evidence for associations of common and rare variants in PRPF31, CPA6, and STAT3 with metformin response that may provide insight into mechanisms important for metformin efficacy in T2D

Genetic tools for coronary risk assessment in type 2 diabetes: A cohort study from the ACCORD clinical trial

OBJECTIVE We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk. RESEARCH DESIGN AND METHODS A weighted genetic risk score (GRS) derived from 204 variants representative of all the 160 CAD loci identified in the general population as of December 2017 was calculated in 5,360 and 1,931 white participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, respectively. The association between GRS and MCE (combining fatal CAD events, nonfatal myocardial infarction, and unstable angina) was assessed by Cox proportional hazards regression. RESULTS The GRS was associated with MCE risk in both ACCORD and ORIGIN (hazard ratio [HR] per SD 1.27, 95% CI 1.18–1.37, P = 4 3 10210, and HR per SD 1.35, 95% CI 1.16–1.58, P = 2 3 1024, respectively). This association was independent from interventions tested in the trials and persisted, though attenuated, after adjustment for classic cardiovascular risk predictors. Adding the GRS to clinical predictors improved incident MCE risk classification (relative integrated discrimination improvement +8%, P = 7 3 1024). The performance of this GRS was superior to that of GRS based on the smaller number of CAD loci available in previous years. CONCLUSIONS When combined into a GRS, CAD loci identified in the general population are associated with CAD also in type 2 diabetes. This GRS provides a significant improvement in the ability to correctly predict future MCE, which may increase further with the discovery of new CAD loci