Biology subjects

Gardner, K.

Publications and source records attributed to Gardner, K..

7 recordsLinked to original sources

bioRxiv2023

NSD2 maintains lineage plasticity and castration-resistance in neuroendocrine prostate cancer

The clinical use of potent androgen receptor (AR) inhibitors has promoted the emergence of novel subtypes of metastatic castration-resistant prostate cancer (mCRPC), including neuroendocrine prostate cancer (CRPC-NE), which is highly aggressive and lethal1. These mCRPC subtypes display increased lineage plasticity and often lack AR expression2-5. Here we show that neuroendocrine differentiation and castration-resistance in CRPC-NE are maintained by the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2)6, which catalyzes histone H3 lysine 36 dimethylation (H3K36me2). We find that organoid lines established from genetically-engineered mice7 recapitulate key features of human CRPC-NE, and can display transdifferentiation to neuroendocrine states in culture. CRPC-NE organoids express elevated levels of NSD2 and H3K36me2 marks, but relatively low levels of H3K27me3, consistent with antagonism of EZH2 activity by H3K36me2. Human CRPC-NE but not primary NEPC tumors expresses high levels of NSD2, consistent with a key role for NSD2 in lineage plasticity, and high NSD2 expression in mCRPC correlates with poor survival outcomes. Notably, CRISPR/Cas9 targeting of NSD2 or expression of a dominant-negative oncohistone H3.3K36M mutant results in loss of neuroendocrine phenotypes and restores responsiveness to the AR inhibitor enzalutamide in mouse and human CRPC-NE organoids and grafts. Our findings indicate that NSD2 inhibition can reverse lineage plasticity and castration-resistance, and provide a potential new therapeutic target for CRPC-NE.

cancer biology↗

bioRxiv2022

ENVIROME-WIDE ASSOCIATIONS ENHANCE MULTI-YEAR GENOME-BASED PREDICTION OF HISTORICAL WHEAT BREEDING DATA

Linking high-throughput environmental data (enviromics) into genomic prediction (GP) is a cost-effective strategy for increasing selection intensity under genotype-by-environment interactions (GxE). This study developed a data-driven approach based on Environment-Phenotype Associations (EPA) aimed at recycling important GxE information from historical breeding data. EPA was developed in two applications: (1) scanning a secondary source of genetic variation, weighted from the shared reaction-norms of past-evaluated genotypes; (2) pinpointing weights of the similarity among trial-sites (locations), given the historical impact of each envirotyping data variable for a given site. Then, the EPA outcomes were integrated into multi-environment GP models through a new single-step GBLUP. The wheat trial data used included 36 locations, 8 years and 3 target populations of environments (TPE) in India. Four prediction scenarios and 6 kernel-models within/across TPEs were tested. Our results suggest that the conventional GBLUP, without enviromic data or when omitting EPA, is inefficient in predicting the performance of wheat lines in future years. However, when EPA was introduced as an intermediary learning step to reduce the dimensionality of the GxE kernels while connecting phenotypic and environmental-wide variation, a significant enhancement of GxE prediction accuracy was evident. EPA revealed that the effect of seasonality makes strategies such as "covariable selection" unfeasible because GxE is year-germplasm specific. We propose that the EPA effectively serves as a "reinforcement learner" algorithm capable of uncovering the effect of seasonality over the reaction-norms, with the benefits of better forecasting the similarities between past and future trialing sites. EPA combines the benefits of dimensionality reduction while reducing the uncertainty of genotype-by-year predictions and increasing the resolution of GP for the genotype-specific level.

genetics↗

bioRxiv2022

Overexpression of the WAPO-A1 gene increases the number of spikelets per spike in bread wheat

Two homoeologous QTLs for number of spikelets per spike (SPS) were mapped on chromosomes 7AL and 7BL using two wheat MAGIC populations. Sets of lines contrasting for the QTL on 7AL were developed which allowed for the validation and fine mapping of the 7AL QTL and for the identification of a previously described candidate gene, WHEAT ORTHOLOG OF APO1 (WAPO1). Using transgenic overexpression in both a low and a high SPS line, we provide a functional validation for the role of this gene in determining SPS also in hexaploid wheat. We show that the expression levels of this gene positively correlate with SPS in multiple MAGIC founder lines under field conditions as well as in transgenic lines grown in the greenhouse. This work highlights the potential use of WAPO1 in hexaploid wheat for further yield increases. The impact of WAPO1 and SPS on yield depends on other genetic and environmental factors, hence, will require a finely balanced expression level to avoid the development of detrimental pleiotropic phenotypes.

plant biology↗

bioRxiv2021

Wheat EARLY FLOWERING3 is a dawn-expressed circadian oscillator component that regulates heading date

Using an eight-parent Multiparent Advanced Generation Inter-Cross (MAGIC) population we investigated how variation at circadian clock-associated genes contributes to the regulation of heading date in UK and European winter wheat varieties. We identified homoeologues of EARLY FLOWERING 3 (ELF3) as candidates for the Earliness per se (Eps) D1 and B1 loci in field conditions. We confirmed that a SNP within the coding region of TaELF3-B1 is a candidate polymorphism underlying the Eps-B1 locus. We found that a reported deletion at the Eps-D1 locus encompassing TaELF3-D1, is instead a novel allele that lies within an introgression region containing an inversion relative to the Chinese Spring D genome. Using T. turgidum cv. Kronos carrying loss of function alleles of TtELF3 we show that ELF3 does regulate heading by demonstrating that the loss of a single ELF3 homoeologue was sufficient to alter heading date. These studies demonstrated that ELF3 forms part of the circadian oscillator but loss of all homoeologues was required to affect circadian rhythms. Similarly, loss of functional LUX ARRHYTHMO (LUX) in T. aestivum, an orthologue of a protein partner of Arabidopsis ELF3, severely disrupted circadian rhythms. ELF3 and LUX transcripts are not co-expressed at dusk suggesting the structure of the wheat circadian oscillator might differ to that of Arabidopsis. Our demonstration that alteration to ELF3 homoeologues can affect heading date separate from effects on the circadian oscillator suggests a role for ELF3 in cereal photoperiodic responses that could be selected for, without pleiotropic deleterious alterations to circadian rhythms.

plant biology↗

bioRxiv2021

Trend, Population Structure And Trait Mapping From 15 Years Of National Varietal Trials Of UK Winter Wheat

There are now a rich variety of genomic and genotypic resources available to wheat researchers and breeders. However, the generation of high-quality and field-relevant phenotyping data which is required to capture the complexities of gene x environment interactions remains a major bottleneck. Historical datasets from national variety performance trials (NVPT) provide sufficient dimensions, in terms of numbers of years and locations, to examine phenotypic trends and study gene x environment interactions. Using NVPT for winter wheat varieties grown in the UK between 2002 - 2017, we examined temporal trends for eight traits related to yield, adaptation, and grain quality performance. We show a non-stationary linear trend for yield, grain protein content, HFN and days to ripening. Our data also show high environmental stability for yield, grain protein content and specific weight in UK winter wheat varieties and high environmental sensitivity for Hagberg Falling Number. Using the historical NVPT data in a genome-wide association analysis, we uncovered a significant marker-trait association peak on wheat chromosome 6A spanning the NAM-A1 gene that have been previously associated with early senescence. Together our results show the value of utilizing the data routinely collected during variety evaluation process for examining breeding progress and the genetic architecture of important traits.

plant biology↗

bioRxiv2020

Limited haplotype diversity underlies polygenic trait architecture across 70 years of wheat breeding

BackgroundBreeding has helped improve bread wheat yield significantly over the last century. Understanding the potential for future crop improvement depends on relating segregating genetic variation to agronomic traits. ResultsWe bred NIAB Diverse MAGIC population, comprising over 500 recombinant inbred lines, descended from sixteen bread wheat varieties released between 1935-2004. We sequenced the founders exomes and promotors by capture. Despite being highly representative of North-West European wheat and capturing 73% of global polymorphism, we found 89% of genes contained no more than three haplotypes. We sequenced each line with 0.3x coverage whole-genome sequencing, and imputed 1.1M high-quality SNPs that were over 99% concordant with array genotypes. Imputation accuracy remained high at coverage as low as 0.076x, with or without the use of founder genomes as reference panels. We created a genotype-phenotype map for 47 traits over two years. We found 136 genome-wide significant associations, concentrated at 42 genetic loci with large and often pleiotropic effects. Outside of these loci most traits are polygenic, as revealed by multi-locus shrinkage modelling. ConclusionsHistorically, wheat breeding has reshuffled a limited palette of haplotypes; continued improvement will require selection at dozens of loci of diminishing effect, as most of the major loci we mapped are known. Breeding to optimise one trait generates correlated trait changes, exemplified by the negative trade-off between yield and protein content, unless selection and recombination can break critical unfavourable trait-trait associations. Finally, low coverage whole genome sequencing of bread wheat populations is an economical and accurate genotyping strategy.

genomics↗

bioRxiv2018

Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy

Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here we perform a genome-wide prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.

cancer biology↗