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Warner, D.

Publications and source records attributed to Warner, D..

5 recordsLinked to original sources

Increased grain weight conferred by GW2 mutations in wheat does not translate into yield gains in multi-year field trials of near-isogenic lines

Multiple studies have identified genes affecting grain morphology, yet their capacity to deliver yield gains under field conditions remains unclear. We performed a multiyear, multilocation factorial evaluation of GRAIN WIDTH2 (TaGW2) mutants in hexaploid wheat using BC4 near-isogenic lines, sowing-density treatments and semi-dwarfing RHT1 backgrounds. Loss-of-function mutations in TaGW2 increased grain size and thousand grain weight (TGW) additively; with the aaBBDD single mutant showing the most stable singlelocus effect, while the aabbdd triple mutant achieved ~20% higher TGW across twelve field trials. However, overall grain yield remained unchanged or slightly reduced, reflecting a compensatory trade-off with grain number. Spike phenotyping of both main and secondary tillers showed comparable increases in TGW and spike yield despite fewer grains per spike, indicating that limited yield gain primarily reflects reduced spike number per unit area rather than decreased spike-level productivity. Effects were stable across sowing densities, whereas interactions with semi-dwarfing alleles were allele-specific: RHT-B1b partially suppressed TGW gains and accentuated yield penalties, whereas RHT-D1b maintained the large-grain phenotype and productivity. Across experiments, the TaGW2-A1D1 double mutant increased TGW (~14%) while maintaining yield stability, identifying it as a promising genotype for breeding. We conclude that TaGW2 is a reliable modifier of grain size but not yield in isolation.

plant biology↗

AVITI sequencing of a four-generation CEPH/Utah pedigree confirms low mutation rates at homopolymer loci despite their low sequence complexity

BackgroundShort tandem repeats (STRs) and homopolymers are among the most mutable loci in the human genome. Despite their presumed mutability owing to replication slippage, homopolymer loci exhibit lower mutation rates and minimal paternal age effects compared to other STRs. This paradox questions if technical limitations, rather than biological mechanisms, explain these observations. ResultsWe used the Element Biosciences AVITI platform to sequence the genomes of a 48-member, four-generation CEPH/Utah pedigree. As the AVITI platform reduces error rates at repetitive sequences compared to Illumina, this design enabled accurate mutation discovery at 90% of assayed homopolymers and a 1.7-fold increase in discoverable mutations compared to Illumina. We identified a median of 35 de novo homopolymer mutations per trio and a mutation rate of 5.28 x 10-5 DNMs per locus per generation, confirming a lower rate than dinucleotides (1.94 x 10-4). Most DNMs were single base-pair expansions or contractions. Despite comprising <1% of homopolymer loci, G/C homopolymers showed 18-fold higher mutation rates than A/T homopolymers; in contrast, the high dinucleotide mutation rate is not driven by a particular motif class. Parent-of-origin analysis revealed 78% of homopolymer mutations are paternal in origin, but no significant paternal age effect was observed. ConclusionsThis study confirms that homopolymers exhibit lower mutation rates and lack strong paternal age effects compared to other STRs, likely owing to the combination of a lower propensity to form slippage-causing secondary structures and more efficient mismatch repair. Our set of high-quality mutations suggest these phenomena are biological rather than technical in nature. Finally, we demonstrate that AVITI sequencing unlocks previously intractable regions of the genome and will be a powerful tool for continued investigation of repeat mutation.

genomics↗

An aphid resistant wheat variety reduces the transmission of Barley Yellow Dwarf Virus (BYDV) by Rhopalosiphum padi (L.)

INTRODUCTIONRhopalosiphum padi (L.) is a vector of Barley Yellow Dwarf Virus (BYDV) infecting major cereals including wheat. Recently, a winter wheat variety (G1) was identified as exhibiting significant aphid resistance through antixenosis and antibiosis. This study compares resistance to viruliferous aphids, and BYDV transmission, in G1 with RGT Wolverine and RGT Illustrious, a BYDV resistant and susceptible wheat varieties, respectively. We aimed to define how aphid resistance affects BYDV transmission, infection and spread. RESULTSSeedling choice and olfactometer bioassays using wheat volatile organic compounds revealed that G1 emits an aphid repellent compound, identified as 2-tridecanone using GC-MS. Electrical penetration graph recordings showed restricted phloem access and salivation of viruliferous R. padi in G1, associated with lower BYDV transmission efficiency. Quantitative RT-PCR revealed a three-fold reduction in BYDV gene expression ratio on G1 transmission leaves compared to RGT Wolverine or RGT Illustrious. In contrast, reduced systemic infection in RGT Wolverine implied a BYDV resistance mechanism of limiting viral replication and/or movement. Rearing aphids on the aphid or BYDV resistant varieties modified their host selection behaviours suggesting vector conditioning with implications for viral transmission and spread on susceptible hosts. CONCLUSIONThis study demonstrates that the aphid resistance in G1 reduced BYDV transmission. Contrastingly, RGT Wolverine appeared to limit systemic viral infection despite high transmission efficiency. Combining these two distinct resistance mechanisms by breeding offers valuable strategy against both the aphid and the virus. To further define aphid and BYDV defence responses in G1, transcriptomic and metabolomic studies will be required.

plant biology↗

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

The majority of human breast cancers are dependent on hormone-stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap-independent and mTOR inhibitor insensitive, but dependent on 5 UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short-lived targets of ER such as cyclin D1 and other components of the cyclin D-CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand-independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant--an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial (NCT04092673) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer.

cancer biology↗

Multi-Platform Assessment of DNA Sequencing Performance using Human and Bacterial Reference Genomes in the ABRF Next-Generation Sequencing Study

Massively parallel DNA sequencing is a critical tool for genomics research and clinical diagnostics. Here, we describe the Association of Biomolecular Resource Facilities (ABRF) Next-Generation Sequencing Phase II Study to measure quality and reproducibility of DNA sequencing. Replicates of human and bacterial reference DNA samples were generated across multiple sequencing platforms, including well-established technologies such as Illumina, ThermoFisher Ion Torrent, and Pacific Biosciences, as well as emerging technologies such as BGI, Genapsys, and Oxford Nanopore. A total of 202 datasets were generated to investigate the performance of a total of 16 sequencing platforms, including mappability of reads, coverage and error rates in difficult genomic regions, and detection of small-scale polymorphisms and large-scale structural variants. This study provides a comprehensive baseline resource for continual benchmarking as chemistries, methods, and platforms evolve for DNA sequencing.

genomics↗