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1رسالة جامعية
المؤلفون: Coulton, Alexander
المساهمون: Edwards, Keith, Barker, Gary
الوصف: Wheat's wide-ranging distribution, in addition to its vast levels of production and consumption make it an essential component of global food security. Ever-increasing population sizes necessitate an increase in global wheat yields to match. This thesis aims to contribute to this goal by addressing a broad range of seemingly disparate themes: evolution, recombination and segregation distortion. What unites these themes is their methodological underpinnings - the use of high-density genotyping arrays, which have undergone considerable development in the past decade. The genetic diversity of wheat is limited by bottlenecks that have occurred in its evolutionary history, both through polyploidization and domestication. This limitation presents difficulties for future yield increases, potentially increasing wheat's susceptibility to pathogens. One area of interest is the rate of novel polymorphism formation overtime. The results presented here indicate that this question will be difficult to answer using molecular clock methodology. Another route to increasing wheat yield may be the manipulation of wheat recombination distribution, removing large areas of linkage drag in the central regions of chromosomes. Previous work in barley suggests that an increase in environmental temperature could shift recombination distribution inwards. The results presented here suggest that whilst this might be the case for some chromosomes in wheat, for the majority of chromosomes, recombination distribution is unaffected by changes in temperature. Segregation distortion, a deviation from Mendelian ratios in progeny of a cross, is also investigated here, with a focus on current practices of detection in the literature. My results indicate that many studies have been using inappropriate methods for the detection of segregation distortion. Also presented in this thesis are novel methods and tools for wheat research, such as the AutoCloner gene-cloning pipeline, allowing researchers to efficiently clone large numbers of genes in previously unsequenced varieties.
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2دورية أكاديمية
المؤلفون: Spain, Lavinia, Coulton, Alexander, Lobon, Irene, Rowan, Andrew, Schnidrig, Desiree, Shepherd, Scott T C, Shum, Benjamin, Byrne, Fiona, Goicoechea, Maria, Piperni, Elisa, Au, Lewis, Edmonds, Kim, Carlyle, Eleanor, Hunter, Nikki, Renn, Alexandra, Messiou, Christina, Hughes, Peta, Nobbs, Jaime, Foijer, Floris, van den Bos, Hilda, Wardenaar, Rene, Spierings, Diana C J, Spencer, Charlotte, Schmitt, Andreas M, Tippu, Zayd, Lingard, Karla, Grostate, Lauren, Peat, Kema, Kelly, Kayleigh, Sarker, Sarah, Vaughan, Sarah, Mangwende, Mary, Terry, Lauren, Kelly, Denise, Biano, Jennifer, Murra, Aida, Korteweg, Justine, Lewis, Charlotte, O'Flaherty, Molly, Cattin, Anne-Laure, Emmerich, Max, Gerard, Camille L, Pallikonda, Husayn Ahmed, Lynch, Joanna, Mason, Robert, Rogiers, Aljosja, Xu, Hang, Huebner, Ariana, McGranahan, Nicholas, Al Bakir, Maise, Turajlic, Samra
المصدر: PEACE Consortium , Spain , L , Coulton , A , Lobon , I , Rowan , A , Schnidrig , D , Shepherd , S T C , Shum , B , Byrne , F , Goicoechea , M , Piperni , E , Au , L , Edmonds , K , Carlyle , E , Hunter , N , Renn , A , Messiou , C , Hughes , P , Nobbs , J , Foijer , F , van den Bos , H , Wardenaar , R , Spierings , D C J , Spencer , ....
مصطلحات موضوعية: Humans, Melanoma/pathology, Mutation, Evolution, Molecular, Brain Neoplasms, DNA
الوصف: Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.
وصف الملف: application/pdf
الإتاحة: https://doi.org/10.1158/2159-8290.CD-22-1427Test
https://hdl.handle.net/11370/2217fb24-bc44-4e6c-825d-c7918e5510ddTest
https://research.rug.nl/en/publications/2217fb24-bc44-4e6c-825d-c7918e5510ddTest
https://pure.rug.nl/ws/files/701838639/1364.pdfTest -
3دورية أكاديمية
المؤلفون: Coulton, Alexander, Murai, Jun, Qian, Danwen, Thakkar, Krupa, Lewis, Claire E., Litchfield, Kevin
المصدر: Nature Communications; 7/6/2024, Vol. 15 Issue 1, p1-14, 14p
مصطلحات موضوعية: MACROPHAGES, T cells, IMMUNE checkpoint proteins, REFERENCE sources, TUMORS
مستخلص: The paradigm for macrophage characterization has evolved from the simple M1/M2 dichotomy to a more complex model that encompasses the broad spectrum of macrophage phenotypic diversity, due to differences in ontogeny and/or local stimuli. We currently lack an in-depth pan-cancer single cell RNA-seq (scRNAseq) atlas of tumour-associated macrophages (TAMs) that fully captures this complexity. In addition, an increased understanding of macrophage diversity could help to explain the variable responses of cancer patients to immunotherapy. Our atlas includes well established macrophage subsets as well as a number of additional ones. We associate macrophage composition with tumour phenotype and show macrophage subsets can vary between primary and metastatic tumours growing in sites like the liver. We also examine macrophage-T cell functional cross talk and identify two subsets of TAMs associated with T cell activation. Analysis of TAM signatures in a large cohort of immune checkpoint inhibitor-treated patients (CPI1000 +) identify multiple TAM subsets associated with response, including the presence of a subset of TAMs that upregulate collagen-related genes. Finally, we demonstrate the utility of our data as a resource and reference atlas for mapping of novel macrophage datasets using projection. Overall, these advances represent an important step in both macrophage classification and overcoming resistance to immunotherapies in cancer. Single cell sequencing can be used to examine tumour associated macrophages (TAM) and comparison between studies has been a challenge. Here the authors show a comparison tool to compare and contrast TAMs from different human tumour types and how these cells associate with T cells exploring further macrophage heterogeneity. [ABSTRACT FROM AUTHOR]
: Copyright of Nature Communications is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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4دورية أكاديمية
المؤلفون: Coulton, Alexander, Turajlic, Samra
المصدر: Cancer Cell ; volume 40, issue 2, page 134-135 ; ISSN 1535-6108
مصطلحات موضوعية: Cancer Research, Oncology
الإتاحة: https://doi.org/10.1016/j.ccell.2022.01.011Test
https://api.elsevier.com/content/article/PII:S1535610822000137?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1535610822000137?httpAccept=text/plainTest -
5دورية أكاديمية
المؤلفون: Coulton, Alexander, Przewieslik-Allen, Alexandra M., Burridge, Amanda J., Shaw, Daniel S., Edwards, Keith J., Barker, Gary L. A.
المصدر: Coulton , A , Przewieslik-Allen , A M , Burridge , A J , Shaw , D S , Edwards , K J & Barker , G L A 2020 , ' Segregation distortion: Utilizing simulated genotyping data to evaluate statistical methods ' , PLoS ONE , vol. 15 , no. 2 , e0228951 , pp. e0228951 . https://doi.org/10.1371/journal.pone.0228951Test
مصطلحات موضوعية: /dk/atira/pure/subjectarea/asjc/1300, name=Biochemistry, Genetics and Molecular Biology(all), /dk/atira/pure/subjectarea/asjc/1100, name=Agricultural and Biological Sciences(all), /dk/atira/pure/subjectarea/asjc/1000, name=General
الوصف: Segregation distortion is the phenomenon in which genotypes deviate from expected Mendelian ratios in the progeny of a cross between two varieties or species. There is not currently a widely used consensus for the appropriate statistical test, or more specifically the multiple testing correction procedure, used to detect segregation distortion for high-density single-nucleotide polymorphism (SNP) data. Here we examine the efficacy of various multiple testing procedures, including chi-square test with no correction for multiple testing, false-discovery rate correction and Bonferroni correction using an in-silico simulation of a biparental mapping population. We find that the false discovery rate correction best approximates the traditional p-value threshold of 0.05 for high-density marker data. We also utilize this simulation to test the effect of segregation distortion on the genetic mapping process, specifically on the formation of linkage groups during marker clustering. Only extreme segregation distortion was found to effect genetic mapping. In addition, we utilize replicate empirical mapping populations of wheat varieties Avalon and Cadenza to assess how often segregation distortion conforms to the same pattern between closely related wheat varieties.
الإتاحة: https://doi.org/10.1371/journal.pone.0228951Test
https://researchportal.bath.ac.uk/en/publications/90143c5e-913d-4567-824c-196023bbe094Test
http://www.scopus.com/inward/record.url?scp=85079605271&partnerID=8YFLogxKTest -
6دورية أكاديمية
المؤلفون: Coulton, Alexander, Burridge, Amanda J, Edwards, Keith J
المصدر: Coulton , A , Burridge , A J & Edwards , K J 2020 , ' Examining the effects of temperature on recombination in wheat ' , Frontiers in Plant Science , vol. 11 , 230 . https://doi.org/10.3389/fpls.2020.00230Test
مصطلحات موضوعية: recombination, temperature, meiosis, wheat, genotyping
الوصف: Meiotic recombination plays a crucial role in the generation of new varieties. The effectiveness of recombination is limited by the distribution of crossover events, which in wheat and many other crops is skewed towards the distal regions of the chromosomes. Whole-genome sequencing of wheat has revealed that there are numerous important genes in the pericentromeric regions, which are inaccessible to manipulation due to the lack of crossover events. Studies in barley have shown that the distribution of recombination events can be shifted towards the centromeres by increasing temperature during meiosis. Here we present an analysis of the effects of temperature on the distribution and frequency of recombination events in wheat. Our data show that although increased temperature during meiosis does cause an inward shift in recombination distribution for some chromosomes, its overall utility is limited, with many genes remaining highly linked.
وصف الملف: application/pdf
الإتاحة: https://doi.org/10.3389/fpls.2020.00230Test
https://hdl.handle.net/1983/96b3ad49-ea9a-4211-a335-8c2205091034Test
https://research-information.bris.ac.uk/en/publications/96b3ad49-ea9a-4211-a335-8c2205091034Test
https://research-information.bris.ac.uk/ws/files/224284899/fpls_11_00230.pdfTest -
7دورية أكاديمية
المؤلفون: Coulton, Alexander, Edwards, Keith J.
المساهمون: Biotechnology and Biological Sciences Research Council
المصدر: BMC Bioinformatics ; volume 21, issue 1 ; ISSN 1471-2105
مصطلحات موضوعية: Applied Mathematics, Computer Science Applications, Molecular Biology, Biochemistry, Structural Biology
الوصف: Background Polyploid organisms such as wheat complicate even the simplest of procedures in molecular biology. Whilst knowledge of genomic sequences in crops is increasing rapidly, the scientific community is still a long way from producing a full pan-genome for every species. Polymerase chain reaction and Sanger sequencing therefore remain widely used as methods for characterizing gene sequences in many varieties of crops. High sequence similarity between genomes in polyploids means that if primers are not homeologue-specific via the incorporation of a SNP at the 3’ tail, sequences other than the target sequence will also be amplified. Current consensus for gene cloning in wheat is to manually perform many steps in a long bioinformatics pipeline. Results Here we present AutoCloner ( www.autocloner.com ), a fully automated pipeline for crop gene cloning that includes a free-to-use web interface for users. AutoCloner takes a sequence of interest from the user and performs a basic local alignment search tool (BLAST) search against the genome assembly for their particular polyploid crop. Homologous sequences are then compiled with the input sequence into a multiple sequence alignment which is mined for single-nucleotide polymorphisms (SNPs). Various combinations of potential primers that cover the entire gene of interest are then created and evaluated by Primer3; the set of primers with the highest score, as well as all possible primers at every SNP location, are then returned to the user for polymerase chain reaction (PCR). We have successfully used AutoCloner to clone various genes of interest in the Apogee wheat variety, which has no current genome sequence. In addition, we have successfully run the pipeline on ~ 80,000 high-confidence gene models from a wheat genome assembly. Conclusion AutoCloner is the first tool to fully-automate primer design for gene cloning in polyploids, where previously the consensus within the wheat community was to perform this process manually. The web interface for ...
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المؤلفون: Coulton, Alexander, Murai, Jun, Qian, Danwen, Thakkar, Krupa, Lewis, Claire E., Litchfield, Kevin
الوصف: Included is the TAM atlas associated with the publication "Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response". The atlas is a Seurat (v 4.2.0) object stored as a .rds file, which can be loaded in R (v 4.2.2). Note this atlas does not include raw count data as these can be download from the original sources, but does include log-normalized count data, SCTransformed data and integrated data via RPCA. The data can be loaded into R as follows: mac.atlas <- readRDS('mac.atlas.zenodo.200524.rds') ...
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