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Point mutation in acetolactate synthase confers sulfonylurea and imidazolinone herbicide resistance in spiny annual sow-thistle [Sonchus asper (L.) Hill]
Suspected thifensulfuron resistant spiny annual sow-thistle was identified near Colfax, Washington, in two fields with a winter wheat and lentil rotation. Therefore, studies were conducted to examine resistance of spiny annual sow-thistle to thifensulfuron and cross-resistance to other acetolactate synthase inhibitors and to determine the physiological and molecular basis for herbicide resistance. Whole-plant bioassay confirmed that the biotype was highly resistant to the sulfonylurea (SU) herbicides, thifensulfuron, metsulfuron, and prosulfuron. The resistant (R) biotype was also highly resistant to the imidazolinone (IMI) herbicides, imazamox and imazethapyr. An in vivo acetolactate synthase (ALS) assay indicated that the concentrations of SU and IMI herbicides required for 50% inhibition (Iâ‚…â‚€) were more than 10 times greater for R biotype compared with susceptible (S) biotype. Analysis of the nucleotide and predicted amino acid sequences for ALS genes demonstrated a single-point mutation from C to T at the als1 gene, conferring the substitution of the amino acid leucine for proline in the R biotype at position197. The results of this research indicate that the resistance of spiny annual sow-thistle to SU and IMI herbicides is due to on altered target site and caused by a point mutation in the als1 geneKeywords: Acetolactate synthase, Point mutation, Cross-resistance, Herbicide resistance, Als gene, Spiny annual sow-thistl
The effect of artificial selection on phenotypic plasticity in maize
Remarkable productivity has been achieved in crop species through artificial selection and adaptation to modern agronomic practices. Whether intensive selection has changed the ability of improved cultivars to maintain high productivity across variable environments is unknown. Understanding the genetic control of phenotypic plasticity and genotype by environment (G × E) interaction will enhance crop performance predictions across diverse environments. Here we use data generated from the Genomes to Fields (G2F) Maize G × E project to assess the effect of selection on G × E variation and characterize polymorphisms associated with plasticity. Genomic regions putatively selected during modern temperate maize breeding explain less variability for yield G × E than unselected regions, indicating that improvement by breeding may have reduced G × E of modern temperate cultivars. Trends in genomic position of variants associated with stability reveal fewer genic associations and enrichment of variants 0–5000 base pairs upstream of genes, hypothetically due to control of plasticity by short-range regulatory elements
The preclinical pharmacology of the high affinity anti-IL-6R Nanobody (R) ALX-0061 supports its clinical development in rheumatoid arthritis
Introduction: The pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody (R) with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin. We describe here the relevant aspects of its in vitro and in vivo pharmacology. Methods: ALX-0061 is composed of an affinity-matured IL-6R-targeting domain fused to an albumin-binding domain representing a minimized two-domain structure. A panel of different in vitro assays was used to characterize the biological activities of ALX-0061. The pharmacological properties of ALX-0061 were examined in cynomolgus monkeys, using plasma levels of total soluble (s)IL-6R as pharmacodynamic marker. Therapeutic effect was evaluated in a human IL-6-induced acute phase response model in the same species, and in a collagen-induced arthritis (CIA) model in rhesus monkeys, using tocilizumab as positive control. Results: ALX-0061 was designed to confer the desired pharmacological properties. A 200-fold increase of target affinity was obtained through affinity maturation of the parental domain. The high affinity for sIL-6R (0.19 pM) translated to a concentration-dependent and complete neutralization of sIL-6R in vitro. In cynomolgus monkeys, ALX-0061 showed a dose-dependent and complete inhibition of hIL-6-induced inflammatory parameters, including plasma levels of C-reactive protein (CRP), fibrinogen and platelets. An apparent plasma half-life of 6.6 days was observed after a single intravenous administration of 10 mg/kg ALX-0061 in cynomolgus monkeys, similar to the estimated expected half-life of serum albumin. ALX-0061 and tocilizumab demonstrated a marked decrease in serum CRP levels in a non-human primate CIA model. Clinical effect was confirmed in animals with active drug exposure throughout the study duration. Conclusions: ALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA
The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis
Breeding for high yield in common bean
The traditional empirical approach to selection for yield in common bean has met with modest success. Breeding based on the concepts of ideotype, or for specific combinations of physiological traits, and/or for combining ability based on specific genotypic combinations, have not been universally useful. These approaches have been limited mainly by the procedures being deployed and the restrictions imposed by the type of germplasm available to the breeder. Breeding common bean for yield can only be accomplished successfully within the framework of very specific constraints of growth habit, seed size, maturity and gene pools. Therefore, yield relative to a specific production system is critical. A functional breeding system that could more effectively exploit the strategies of ideotype, physiology and/or combining ability is proposed within the framework of the major constraints that restrict progress in traditional breeding programs. Bean breeding programs need to be designed to accomplish the objective of improving yield while not neglecting the other non-yield related traits which dictate acceptance and which can limit progress. A program structured on a three-tiered breeding pyramid is proposed. The approach to yield breeding would be different at each level of the pyramid. The utilization and maintenance of diversity would be optimized at the lower level while uniformity and yield performance of elite lines would be maximized at the apex of the breeding pyramid. Activities at the intermediate level would involve adapted material more commercially acceptable than the lower tier but not considered elite. Materials developed at the lower levels would be designed to move upwards sequentially or be maintained for additional improvement and further introgression. Although breeding methods will differ at each level, breeders must recognize that a strong continuity between all three levels of the breeding pyramid is required. The breeding pyramid affords flexibility to permit the deployment of different breeding strategies needed to exploit the major genotypic and physiological differences between bean germplasm from diverse races and gene pools. Proven strategies for yield improvement based on the concepts of ideotype, physiology and combining ability, would be differentially utilized at each level of the breeding pyramid. Methods to improve efficiency in breeding for yield, at each level within the breeding pyramid, will be discussed in detail. Since breeders with limited resources struggle over the amount of effort to expend at each level of the breeding pyramid, suggestions will be offered based on experience with breeding for yield in other grain legumes
Selection Mapping of Loci for Quantitative Disease Resistance in a Diverse Maize Population
The selection response of a complex maize population improved primarily for quantitative disease resistance to northern leaf blight (NLB) and secondarily for common rust resistance and agronomic phenotypes was investigated at the molecular genetic level. A tiered marker analysis with 151 simple sequence repeat (SSR) markers in 90 individuals of the population indicated that on average six alleles per locus were available for selection. An improved test statistic for selection mapping was developed, in which quantitative trait loci (QTL) are identified through the analysis of allele-frequency shifts at mapped multiallelic loci over generations of selection. After correcting for the multiple tests performed, 25 SSR loci showed evidence of selection. Many of the putatively selected loci were unlinked and dispersed across the genome, which was consistent with the diffuse distribution of previously published QTL for NLB resistance. Compelling evidence for selection was found on maize chromosome 8, where several putatively selected loci colocalized with published NLB QTL and a race-specific resistance gene. Analysis of F2 populations derived from the selection mapping population suggested that multiple linked loci in this chromosomal segment were, in part, responsible for the selection response for quantitative resistance to NLB
Maize Introgression Library Provides Evidence for the Involvement of liguleless1 in Resistance to Northern Leaf Blight
Plant disease resistance is largely governed by complex genetic architecture. In maize, few disease resistance loci have been characterized. Near-isogenic lines are a powerful genetic tool to dissect quantitative trait loci. We analyzed an introgression library of maize (Zea mays) near-isogenic lines, termed a nested near-isogenic line library for resistance to northern leaf blight caused by the fungal pathogen Setosphaeria turcica. The population was comprised of 412 BC5F4 near-isogenic lines that originated from 18 diverse donor parents and a common recurrent parent, B73. Single nucleotide polymorphisms identified through genotyping by sequencing were used to define introgressions and for association analysis. Near-isogenic lines that conferred resistance and susceptibility to northern leaf blight were comprised of introgressions that overlapped known northern leaf blight quantitative trait loci. Genome-wide association analysis and stepwise regression further resolved five quantitative trait loci regions, and implicated several candidate genes, including Liguleless1, a key determinant of leaf architecture in cereals. Two independently-derived mutant alleles of liguleless1 inoculated with S. turcica showed enhanced susceptibility to northern leaf blight. In the maize nested association mapping population, leaf angle was positively correlated with resistance to northern leaf blight in five recombinant inbred line populations, and negatively correlated with northern leaf blight in four recombinant inbred line populations. This study demonstrates the power of an introgression library combined with high density marker coverage to resolve quantitative trait loci. Furthermore, the role of liguleless1 in leaf architecture and in resistance to northern leaf blight has important applications in crop improvement