PLoS Articles
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UNC-authored articles published by the Public Library of Science (PLoS)
Works (2127)
2071. CLAVATA1 controls distinct signaling outputs that buffer shoot stem cell proliferation through a two-step transcriptional compensation loop
- Title Tesim:
- CLAVATA1 controls distinct signaling outputs that buffer shoot stem cell proliferation through a two-step transcriptional compensation loop
- Creator:
- Nimchuk, Zachary L.
- Date of publication:
- 2017
- Abstract Tesim:
- The regulation of stem cell proliferation in plants is controlled by intercellular signaling pathways driven by the diffusible CLAVATA3 (CLV3p) peptide. CLV3p perception is thought to be mediated by an overlapping array of receptors in the stem cell niche including the transmembrane receptor kinase CLV1, Receptor-Like Protein Kinase 2 (RPK2), and a dimer of the receptor-like protein CLV2 and the CORYNE (CRN) pseudokinase. Mutations in these receptors have qualitatively similar effects on stem cell function but it is unclear if this represents common or divergent signaling outputs. Previous work in heterologous systems has suggested that CLV1, RPK2 and CLV2/CRN could form higher order complexes but it is also unclear what relevance these putative complexes have to in vivo receptor functions. Here I use the in vivo regulation of a specific transcriptional target of CLV1 signaling in Arabidopsis to demonstrate that, despite the phenotypic similarities between the different receptor mutants, CLV1 controls distinct signaling outputs in living stem cell niches independent of other receptors. This regulation is separable from stem cell proliferation driven by WUSCHEL, a proposed common transcriptional target of CLV3p signaling. In addition, in the absence of CLV1, CLV1-related receptor kinases are ectopically expressed but also buffer stem cell proliferation through the auto-repression of their own expression. Collectively these data reveal a unique in vivo role for CLV1 separable from other stem cell receptors and provides a framework for dissecting the signaling outputs in stem cell regulation.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Biology
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/wf9m-wm23
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pgen.1006681, Onescience id: 2cb76ef7ce5ff48ecb0e530e1ad761291660f405, PMCID: PMC5371295, and PMID: 28355208
- ISSN:
- 1553-7390 and 1553-7404
- Journal Issue:
- 3
- Journal Title:
- PLoS Genetics
- Journal Volume:
- 13
- Keyword:
- Cell Proliferation, Microscopy, Confocal, BAM1 protein, Arabidopsis, Protein-Serine-Threonine Kinases, Mutation, Gene Expression Regulation, Plant, Stem Cells, Models, Genetic, Plants, Genetically Modified, Receptors, Cell Surface, Arabidopsis, Membrane Proteins, Homeodomain Proteins, Signal Transduction, Arabidopsis Proteins, Plant Shoots, WUSCHEL protein, Arabidopsis, and CLV2 protein, Arabidopsis
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Curriculum in Genetics and Molecular Biology
- Page Start:
- e1006681
- Person:
- Nimchuk, Zachary L.
- Rights Statement Label:
- In Copyright
- Source:
- 6108vh26x
2072. Arabidopsis RAD51, RAD51C and XRCC3 proteins form a complex and facilitate RAD51 localization on chromosomes for meiotic recombination
- Title Tesim:
- Arabidopsis RAD51, RAD51C and XRCC3 proteins form a complex and facilitate RAD51 localization on chromosomes for meiotic recombination
- Creator:
- Ma, Hong, Su, Hang, Copenhaver, Gregory P., Huang, Jiyue, Cheng, Zhihao, Lin, Juan, and Wang, Yingxiang
- Date of publication:
- 2017
- Abstract Tesim:
- Meiotic recombination is required for proper homologous chromosome segregation in plants and other eukaryotes. The eukaryotic RAD51 gene family has seven ancient paralogs with important roles in mitotic and meiotic recombination. Mutations in mammalian RAD51 homologs RAD51C and XRCC3 lead to embryonic lethality. In the model plant Arabidopsis thaliana, RAD51C and XRCC3 homologs are not essential for vegetative development but are each required for somatic and meiotic recombination, but the mechanism of RAD51C and XRCC3 in meiotic recombination is unclear. The non-lethal Arabidopsis rad51c and xrcc3 null mutants provide an opportunity to study their meiotic functions. Here, we show that AtRAD51C and AtXRCC3 are components of the RAD51-dependent meiotic recombination pathway and required for normal AtRAD51 localization on meiotic chromosomes. In addition, AtRAD51C interacts with both AtRAD51 and AtXRCC3 in vitro and in vivo, suggesting that these proteins form a complex (es). Comparison of AtRAD51 foci in meiocytes from atrad51, atrad51c, and atxrcc3 single, double and triple heterozygous mutants further supports an interaction between AtRAD51C and AtXRCC3 that enhances AtRAD51 localization. Moreover, atrad51c-/+atxrcc3-/+ double and atrad51-/+atrad51c-/+atxrcc3-/+ triple heterozygous mutants have defects in meiotic recombination, suggesting the role of the AtRAD51C-AtXRCC3 complex in meiotic recombination is in part AtRAD51-dependent. Together, our results support a model in which direct interactions between the RAD51C-XRCC3 complex and RAD51 facilitate RAD51 localization on meiotic chromosomes and RAD51-dependent meiotic recombination. Finally, we hypothesize that maintenance of RAD51 function facilitated by the RAD51C-XRCC3 complex could be highly conserved in eukaryotes.
- Resource type:
- Article
- Affiliation Label Tesim:
- Integrative Program for Biological and Genome Sciences
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/k8tj-8k59
- Identifier:
- PMID: 28562599, Publisher DOI: https://doi.org/10.1371/journal.pgen.1006827, Onescience id: c1a11cb2b628ee92f4c0b731488e7a32e48611e8, and PMCID: PMC5470734
- ISSN:
- 1553-7404 and 1553-7390
- Journal Issue:
- 5
- Journal Title:
- PLoS Genetics
- Journal Volume:
- 13
- Keyword:
- Arabidopsis, ATRAD51 protein, Arabidopsis, At5g57450 protein, Arabidopsis, Protein Binding, Rad51 Recombinase, AtRAD51C protein, Arabidopsis, Homologous Recombination, Meiosis, and Arabidopsis Proteins
- Language Label:
- English
- ORCID:
- , 0000-0002-7185-4201, and 0000-0001-6085-5615
- Other Affiliation:
- Center for Evolutionary Biology; Institutes of Biomedical Sciences; School of Life Sciences; Fudan University, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center of Genetics and Development; Ministry of Education Key Laboratory of Biodiversity Sciences and Ecological Engineering; Institute of Plant Biology; School of Life Sciences; Fudan University, School of Medicine, and Institute of Banana and Plantain; Chinese Academy of Tropic Agriculture Science
- Page Start:
- e1006827
- Person:
- Ma, Hong, Su, Hang, Copenhaver, Gregory P., Huang, Jiyue, Cheng, Zhihao, Lin, Juan, and Wang, Yingxiang
- Rights Statement Label:
- In Copyright
- Source:
- 8k71np320
2073. Amino acid metabolites that regulate G protein signaling during osmotic stress
- Title Tesim:
- Amino acid metabolites that regulate G protein signaling during osmotic stress
- Creator:
- Morin-Kensicki, Elizabeth, Yin, Guowei, Shellhammer, James P., Campbell, Sharon L., Matson, Jacob P., Mohney, Robert P., Isom, Daniel G., and Dohlman, Henrik G.
- Date of publication:
- 2017
- Abstract Tesim:
- All cells respond to osmotic stress by implementing molecular signaling events to protect the organism. Failure to properly adapt can lead to pathologies such as hypertension and ischemia-reperfusion injury. Mitogen-activated protein kinases (MAPKs) are activated in response to osmotic stress, as well as by signals acting through G protein-coupled receptors (GPCRs). For proper adaptation, the action of these kinases must be coordinated. To identify second messengers of stress adaptation, we conducted a mass spectrometry-based global metabolomics profiling analysis, quantifying nearly 300 metabolites in the yeast S. cerevisiae. We show that three branched-chain amino acid (BCAA) metabolites increase in response to osmotic stress and require the MAPK Hog1. Ectopic addition of these BCAA derivatives promotes phosphorylation of the G protein α subunit and dampens G protein-dependent transcription, similar to that seen in response to osmotic stress. Conversely, genetic ablation of Hog1 activity or the BCAA-regulatory enzymes leads to diminished phosphorylation of Gα and increased transcription. Taken together, our results define a new class of candidate second messengers that mediate cross talk between osmotic stress and GPCR signaling pathways.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Biochemistry and Biophysics and Department of Pharmacology
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/b5xj-qj51
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pgen.1006829, PMCID: PMC5469498, Onescience id: de5532ce6e3106e71a4a09c1e922a89cf1856d1f, and PMID: 28558063
- ISSN:
- 1553-7404 and 1553-7390
- Journal Issue:
- 5
- Journal Title:
- PLoS Genetics
- Journal Volume:
- 13
- Keyword:
- Saccharomyces cerevisiae Proteins, Gene Expression Regulation, Fungal, Mitogen-Activated Protein Kinases, Osmotic Pressure, Amino Acids, HOG1 protein, S cerevisiae, GTP-Binding Protein alpha Subunits, Metabolome, Signal Transduction, and Saccharomyces cerevisiae
- Language Label:
- English
- ORCID:
- and 0000-0003-2669-7160
- Other Affiliation:
- Metabolon; Inc, Attain; LLC, The University of Miami Miller School of Medicine, and Department of Biochemistry and Biophysics
- Page Start:
- e1006829
- Person:
- Morin-Kensicki, Elizabeth, Yin, Guowei, Shellhammer, James P., Campbell, Sharon L., Matson, Jacob P., Mohney, Robert P., Isom, Daniel G., and Dohlman, Henrik G.
- Rights Statement Label:
- In Copyright
- Source:
- 12579z574
2074. Adaptive introgression from distant Caribbean islands contributed to the diversification of a microendemic adaptive radiation of trophic specialist pupfishes
- Title Tesim:
- Adaptive introgression from distant Caribbean islands contributed to the diversification of a microendemic adaptive radiation of trophic specialist pupfishes
- Creator:
- Martin, Christopher H. and Richards, Emilie J.
- Date of publication:
- 2017
- Abstract Tesim:
- Rapid diversification often involves complex histories of gene flow that leave variable and conflicting signatures of evolutionary relatedness across the genome. Identifying the extent and source of variation in these evolutionary relationships can provide insight into the evolutionary mechanisms involved in rapid radiations. Here we compare the discordant evolutionary relationships associated with species phenotypes across 42 whole genomes from a sympatric adaptive radiation of Cyprinodon pupfishes endemic to San Salvador Island, Bahamas and several outgroup pupfish species in order to understand the rarity of these trophic specialists within the larger radiation of Cyprinodon. 82% of the genome depicts close evolutionary relationships among the San Salvador Island species reflecting their geographic proximity, but the vast majority of variants fixed between specialist species lie in regions with discordant topologies. Top candidate adaptive introgression regions include signatures of selective sweeps and adaptive introgression of genetic variation from a single population in the northwestern Bahamas into each of the specialist species. Hard selective sweeps of genetic variation on San Salvador Island contributed 5 times more to speciation of trophic specialists than adaptive introgression of Caribbean genetic variation; however, four of the 11 introgressed regions came from a single distant island and were associated with the primary axis of oral jaw divergence within the radiation. For example, standing variation in a proto-oncogene (ski) known to have effects on jaw size introgressed into one San Salvador Island specialist from an island 300 km away approximately 10 kya. The complex emerging picture of the origins of adaptive radiation on San Salvador Island indicates that multiple sources of genetic variation contributed to the adaptive phenotypes of novel trophic specialists on the island. Our findings suggest that a suite of factors, including rare adaptive introgression, may be necessary for adaptive radiation in addition to ecological opportunity.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Biology
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/p0j3-qt79
- Identifier:
- PMID: 28796803, Onescience id: ec5208c2ad823d0af841af5a8a1548507ceccbba, Publisher DOI: https://doi.org/10.1371/journal.pgen.1006919, and PMCID: PMC5552031
- ISSN:
- 1553-7404 and 1553-7390
- Journal Issue:
- 8
- Journal Title:
- PLoS Genetics
- Journal Volume:
- 13
- Keyword:
- Adaptation, Genetic Speciation, Phylogeny, Genome, West Indies, Gene Flow, Animals, Genetic Variation, Killifishes, Ecosystem, Biological Evolution, Sympatry, and Physiological
- Language Label:
- English
- ORCID:
- 0000-0001-7989-9124 and 0000-0003-2734-6020
- Page Start:
- e1006919
- Person:
- Martin, Christopher H. and Richards, Emilie J.
- Rights Statement Label:
- In Copyright
- Source:
- 9019s719s
2075. A genetic switch controls the production of flagella and toxins in Clostridium difficile
- Title Tesim:
- A genetic switch controls the production of flagella and toxins in Clostridium difficile
- Creator:
- Anjuwon-Foster, Brandon R. and Tamayo, Rita
- Date of publication:
- 2017
- Abstract Tesim:
- In the human intestinal pathogen Clostridium difficile, flagella promote adherence to intestinal epithelial cells. Flagellar gene expression also indirectly impacts production of the glucosylating toxins, which are essential to diarrheal disease development. Thus, factors that regulate the expression of the flgB operon will likely impact toxin production in addition to flagellar motility. Here, we report the identification a “flagellar switch” that controls the phase variable production of flagella and glucosylating toxins. The flagellar switch, located upstream of the flgB operon containing the early stage flagellar genes, is a 154 bp invertible sequence flanked by 21 bp inverted repeats. Bacteria with the sequence in one orientation expressed flagellum and toxin genes, produced flagella, and secreted the toxins (“flg phase ON”). Bacteria with the sequence in the inverse orientation were attenuated for flagellar and toxin gene expression, were aflagellate, and showed decreased toxin secretion (“flg phase OFF”). The orientation of the flagellar switch is reversible during growth in vitro. We provide evidence that gene regulation via the flagellar switch occurs post-transcription initiation and requires a C. difficile-specific regulatory factor to destabilize or degrade the early flagellar gene mRNA when the flagellar switch is in the OFF orientation. Lastly, through mutagenesis and characterization of flagellar phase locked isolates, we determined that the tyrosine recombinase RecV, which catalyzes inversion at the cwpV switch, is also responsible for inversion at the flagellar switch in both directions. Phase variable flagellar motility and toxin production suggests that these important virulence factors have both advantageous and detrimental effects during the course of infection.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Microbiology and Immunology
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/2mrm-a241
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pgen.1006701, PMCID: PMC5386303, PMID: 28346491, and Onescience id: f31743d6d4eb1003aa7adc6d1254556524dde993
- ISSN:
- 1553-7404 and 1553-7390
- Journal Issue:
- 3
- Journal Title:
- PLoS Genetics
- Journal Volume:
- 13
- Keyword:
- Base Sequence, Blotting, Western, Blotting, Northern, Flagella, Intestines, Gene Expression Regulation, Bacterial, Movement, Bacterial Toxins, Operon, Humans, Microscopy, Fluorescence, Clostridium difficile, Bacterial Proteins, and Enterocolitis, Pseudomembranous
- Language Label:
- English
- ORCID:
- 0000-0002-1140-4321 and 0000-0002-3745-3316
- Page Start:
- e1006701
- Person:
- Anjuwon-Foster, Brandon R. and Tamayo, Rita
- Rights Statement Label:
- In Copyright
- Source:
- sb397f326
2076. The Rheumatoid Arthritis Risk Variant CCR6DNP Regulates CCR6 via PARP-1
- Title Tesim:
- The Rheumatoid Arthritis Risk Variant CCR6DNP Regulates CCR6 via PARP-1
- Creator:
- Nigrovic, Peter A., Plenge, Robert M., Cunin, Pierre, Yang, Yu, Wu, Di, Okada, Yukinori, Diogo, Dorothée, and Li, Gang
- Date of publication:
- 2016
- Abstract Tesim:
- Understanding the implications of genome-wide association studies (GWAS) for disease biology requires both identification of causal variants and definition of how these variants alter gene function. The non-coding triallelic dinucleotide polymorphism CCR6DNP is associated with risk for rheumatoid arthritis, and is considered likely causal because allelic variation correlates with expression of the chemokine receptor CCR6. Using transcription activator-like effector nuclease (TALEN) gene editing, we confirmed that CCR6DNP regulates CCR6. To identify the associated transcription factor, we applied a novel assay, Flanking Restriction Enhanced Pulldown (FREP), to identify specific association of poly (ADP-ribose) polymerase 1 (PARP-1) with CCR6DNP consistent with the established allelic risk hierarchy. Correspondingly, manipulation of PARP-1 expression or activity impaired CCR6 expression in several lineages. These findings show that CCR6DNP is a causal variant through which PARP-1 regulates CCR6, and introduce a highly efficient approach to interrogate non-coding genetic polymorphisms associated with human disease.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Periodontology
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/bzcj-sm19
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pgen.1006292, PMCID: PMC5023119, Onescience id: d292336ace43c3f7c7cbcb094fb9a9fa905035ca, and PMID: 27626929
- ISSN:
- 1553-7390 and 1553-7404
- Journal Issue:
- 9
- Journal Title:
- PLoS Genetics
- Journal Volume:
- 12
- Keyword:
- Genetic Loci, Bioengineering, Genetics, Synthetic bioengineering, White Blood Cells, Proteins, Medicine and Health Sciences, Cell Biology, Gene Regulation, Gene Expression, Animal Cells, T Cells, Molecular Biology Techniques, Genome engineering, Immune Cells, Molecular Biology, Immunology, Blood Cells, Biology and Life Sciences, Cloning, Biology and life sciences, DNA-binding proteins, Cellular Types, Biochemistry, and Biotechnology
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Division of Rheumatology; Immunology and Allergy; Brigham and Women’s Hospital, Division of Immunology; Boston Children’s Hospital, Merck Research Laboratories, Centre for Cancer Research; Monash Institute of Medical Research; Monash University, Department of Statistics; Harvard University, Department of Statistical Genetics; Osaka University Graduate School of Medicine, Department of Human Genetics and Disease Diversity; Graduate School of Medical and Dental Sciences; Tokyo Medical and Dental University, Laboratory for Statistical Analysis; RIKEN Center for Integrative Medical Sciences, Program in Medical and Population Genetics; Broad Institute, and Division of Genetics; Brigham and Women's Hospital; Harvard Medical School
- Page Start:
- e1006292
- Person:
- Nigrovic, Peter A., Plenge, Robert M., Cunin, Pierre, Yang, Yu, Wu, Di, Okada, Yukinori, Diogo, Dorothée, and Li, Gang
- Rights Statement Label:
- In Copyright
- Source:
- gf06g8008
2077. The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts
- Title Tesim:
- The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts
- Creator:
- Mieczkowski, Piotr A., Malc, Ewa P., Roberts, Steven A., Fargo, David C., Kaufmann, William K., Dai, Shuangshuang, Cortes-Ciriano, Isidro, Taylor, Jack A., Park, Peter J., Lee, Eunjung, Saini, Natalie, Grimm, Sara A., Chan, Kin, Klimczak, Leszek J., Boyer, Jayne C., Gordenin, Dmitry A., and Schurman, Shepherd H.
- Date of publication:
- 2016
- Abstract Tesim:
- Accumulation of somatic changes, due to environmental and endogenous lesions, in the human genome is associated with aging and cancer. Understanding the impacts of these processes on mutagenesis is fundamental to understanding the etiology, and improving the prognosis and prevention of cancers and other genetic diseases. Previous methods relying on either the generation of induced pluripotent stem cells, or sequencing of single-cell genomes were inherently error-prone and did not allow independent validation of the mutations. In the current study we eliminated these potential sources of error by high coverage genome sequencing of single-cell derived clonal fibroblast lineages, obtained after minimal propagation in culture, prepared from skin biopsies of two healthy adult humans. We report here accurate measurement of genome-wide magnitude and spectra of mutations accrued in skin fibroblasts of healthy adult humans. We found that every cell contains at least one chromosomal rearrangement and 600–13,000 base substitutions. The spectra and correlation of base substitutions with epigenomic features resemble many cancers. Moreover, because biopsies were taken from body parts differing by sun exposure, we can delineate the precise contributions of environmental and endogenous factors to the accrual of genetic changes within the same individual. We show here that UV-induced and endogenous DNA damage can have a comparable impact on the somatic mutation loads in skin fibroblasts.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Genetics, Department of Pathology and Laboratory Medicine, and Department of Environmental Sciences and Engineering
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/0byj-a360
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pgen.1006385, PMID: 27788131, PMCID: PMC5082821, and Onescience id: 6bdc321877f4ca8387b0c67a10382fe2bb458807
- ISSN:
- 1553-7390 and 1553-7404
- Journal Issue:
- 10
- Journal Title:
- PLoS Genetics
- Journal Volume:
- 12
- Keyword:
- Limbs (Anatomy), Fibroblasts, Cell Biology, Connective Tissue Cells, Biological Tissue, Musculoskeletal System, Biopsy, Animal Cells, Mutation, Cloning, Genetics, Anatomy, Gene Identification and Analysis, Connective Tissue, Medicine and Health Sciences, Surgical and Invasive Medical Procedures, Cellular Types, Biology and Life Sciences, Mutation Detection, Molecular Biology Techniques, Arms, Forearms, Molecular Biology, Somatic Mutation, and Oncology
- Language Label:
- English
- ORCID:
- , 0000-0002-3628-5808, 0000-0003-3048-2576, 0000-0001-5132-5428, and 0000-0002-8399-1836
- Other Affiliation:
- School of Molecular Biosciences; Washington State University, Integrative Bioinformatics Support Group; National Institute of Environmental Health Sciences; US National Institutes of Health, Department of Biomedical Informatics; Harvard Medical School, Epidemiology Branch; National Institute of Environmental Health Sciences; US National Institutes of Health, Division of Genetics; Brigham and Women’s Hospital, Genome Integrity and Structural Biology Laboratory; National Institute of Environmental Health Sciences; US National Institutes of Health, and Clinical Research Unit; National Institute of Environmental Health Sciences; US National Institutes of Health
- Page Start:
- e1006385
- Person:
- Mieczkowski, Piotr A., Malc, Ewa P., Roberts, Steven A., Fargo, David C., Kaufmann, William K., Dai, Shuangshuang, Cortes-Ciriano, Isidro, Taylor, Jack A., Park, Peter J., Lee, Eunjung, Saini, Natalie, Grimm, Sara A., Chan, Kin, Klimczak, Leszek J., Boyer, Jayne C., Gordenin, Dmitry A., and Schurman, Shepherd H.
- Rights Statement Label:
- In Copyright
- Source:
- 79408327p
2078. Recombination Rate Heterogeneity within Arabidopsis Disease Resistance Genes
- Title Tesim:
- Recombination Rate Heterogeneity within Arabidopsis Disease Resistance Genes
- Creator:
- Hardcastle, Thomas J., Choi, Kyuha, Jackson, Matthew, Ziolkowski, Piotr A., Griffin, Catherine, Reinhard, Carsten, McVean, Gil, Zhao, Xiaohui, Underwood, Charles J., Copenhaver, Gregory P., Yelina, Nataliya E., Henderson, Ian R., Serra, Heïdi, and Mézard, Christine
- Date of publication:
- 2016
- Abstract Tesim:
- Meiotic crossover frequency varies extensively along chromosomes and is typically concentrated in hotspots. As recombination increases genetic diversity, hotspots are predicted to occur at immunity genes, where variation may be beneficial. A major component of plant immunity is recognition of pathogen Avirulence (Avr) effectors by resistance (R) genes that encode NBS-LRR domain proteins. Therefore, we sought to test whether NBS-LRR genes would overlap with meiotic crossover hotspots using experimental genetics in Arabidopsis thaliana. NBS-LRR genes tend to physically cluster in plant genomes; for example, in Arabidopsis most are located in large clusters on the south arms of chromosomes 1 and 5. We experimentally mapped 1,439 crossovers within these clusters and observed NBS-LRR gene associated hotspots, which were also detected as historical hotspots via analysis of linkage disequilibrium. However, we also observed NBS-LRR gene coldspots, which in some cases correlate with structural heterozygosity. To study recombination at the fine-scale we used high-throughput sequencing to analyze ~1,000 crossovers within the RESISTANCE TO ALBUGO CANDIDA1 (RAC1) R gene hotspot. This revealed elevated intragenic crossovers, overlapping nucleosome-occupied exons that encode the TIR, NBS and LRR domains. The highest RAC1 recombination frequency was promoter-proximal and overlapped CTT-repeat DNA sequence motifs, which have previously been associated with plant crossover hotspots. Additionally, we show a significant influence of natural genetic variation on NBS-LRR cluster recombination rates, using crosses between Arabidopsis ecotypes. In conclusion, we show that a subset of NBS-LRR genes are strong hotspots, whereas others are coldspots. This reveals a complex recombination landscape in Arabidopsis NBS-LRR genes, which we propose results from varying coevolutionary pressures exerted by host-pathogen relationships, and is influenced by structural heterozygosity.
- Resource type:
- Article
- Affiliation Label Tesim:
- Integrative Program for Biological and Genome Sciences
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/6r18-vv55
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pgen.1006179, PMCID: PMC4945094, PMID: 27415776, and Onescience id: e1294c747a482f15418a11b77455ea66b0a3b3e1
- ISSN:
- 1553-7390 and 1553-7404
- Journal Issue:
- 7
- Journal Title:
- PLoS Genetics
- Journal Volume:
- 12
- Keyword:
- Arabidopsis, Arabidopsis Proteins, Plant Diseases, Heterozygote, Recombination, Genetic, Disease Resistance, Multigene Family, Crosses, Genetic, Nucleic Acid Hybridization, Genes, Plant, Meiosis, Linkage Disequilibrium, Pollen, Alleles, Genetic Variation, and RAC1 protein, Arabidopsis
- Language Label:
- English
- ORCID:
- 0000-0002-9328-5011, , 0000-0001-8862-1386, 0000-0001-9922-2815, 0000-0001-5730-6279, and 0000-0002-7962-3862
- Other Affiliation:
- Department of Plant Sciences; University of Cambridge, Department of Biotechnology; Adam Mickiewicz University, The Wellcome Trust Centre for Human Genetics; University of Oxford, Watson School of Biological Sciences; Cold Spring Harbor Laboratory; Cold Spring Harbor, School of Medicine, and Institut Jean-Pierre Bourgin; INRA; AgroParisTech; CNRS; Université Paris-Saclay; RD10
- Page Start:
- e1006179
- Person:
- Hardcastle, Thomas J., Choi, Kyuha, Jackson, Matthew, Ziolkowski, Piotr A., Griffin, Catherine, Reinhard, Carsten, McVean, Gil, Zhao, Xiaohui, Underwood, Charles J., Copenhaver, Gregory P., Yelina, Nataliya E., Henderson, Ian R., Serra, Heïdi, and Mézard, Christine
- Rights Statement Label:
- In Copyright
- Source:
- m613n3526
2079. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis
- Title Tesim:
- Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis
- Creator:
- Hart, Deborah J., Rivadeneira, Fernando, Lane, Nancy E., Muir, Kenneth, Evangelou, Evangelos, Doherty, Sally, Castaño-Betancourt, Martha C., Meulenbelt, Ingrid, Boer, Cindy G., Styrkarsdottir, Unnur, Uitterlinden, Andre G., Doherty, Michael, Maciewicz, Rose A., Metrustry, Sarah, Evans, Dan S., den Hollander, Wouter, Barrett-Connor, Elizabeth, Jordan, Joanne M., Kloppenburg, Margreet, van Meurs, Joyce B. J., Lafeber, Floris, Slagboom, Eline P., Nelissen, Rob G. H. H., Yau, Michelle S., Mitchell, Braxton D., Nevitt, Michael C., Ramos, Yolande F. M., Liu, Youfang, Kraaij, Robert, Hofman, Albert, Valdes, Ana M., van Rooij, Jeroen, Kraus, Virginia B., Arden, Nigel, Zeggini, Eleftheria, Zhang, Weiya, and Spector, Tim D.
- Date of publication:
- 2016
- Abstract Tesim:
- Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.
- Resource type:
- Article
- Affiliation Label Tesim:
- Thurston Arthritis Research Center
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/ayp9-a134
- Identifier:
- Onescience id: 30a2c4e0d724b1238defbacf6a6a919b42275a48, PMCID: PMC5049763, PMID: 27701424, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1006260
- ISSN:
- 1553-7390 and 1553-7404
- Journal Issue:
- 10
- Journal Title:
- PLoS Genetics
- Journal Volume:
- 12
- Keyword:
- Hip, Genome Analysis, Joints (Anatomy), Cartilage, Cancer Research, Genetic Loci, 0604 Genetics, Molecular Biology, Genetics(clinical), Computational Biology, Biology and Life Sciences, Anatomy, Rheumatology, Research Article, Pelvis, Arthritis, Phenotypes, Genome-Wide Association Studies, QH426-470, Gene Expression, Medicine and Health Sciences, Genetics, Human Genetics, Genomics, and Ecology, Evolution, Behavior and Systematics
- Language Label:
- English
- ORCID:
- , 0000-0003-4809-0044, and 0000-0001-9754-073X
- Other Affiliation:
- Department of Twins Research and Genetic Epidemiology Unit; King’s College London, Department of Internal Medicine; Erasmus Medical Center, School of Medicine; University of California, University of California at San Francisco, Health Sciences Research Institute; University of Warwick, Department of Epidemiology and Biostatistics; School of Public Health; Imperial College London, Department of Hygiene & Epidemiology; University of Ioannina School of Medicine, School of Medicine; University of Nottingham, Department of Medical Statistics and Bioinformatics; Section Molecular Epidemiology; Leiden University Medical Center, Decode Genetics, Department of Epidemiology; Erasmus Medical Center, Respiratory; Inflammation; Autoimmunity Innovative Medicines, California Pacific Medical Center Research Institute, Epidemiology Division; Family Medicine and Public Health Department; University of California, Department of Rheumatology and Department of Clinical Epidemiology; Leiden University Medical Center, University Medical Center Utrecht, Department of Orthopaedics; Leiden University Medical Center, Departments of Medicine and Epidemiology & Public Health; University of Maryland School of Medicine, Geriatrics Research and Education Clinical Center; Baltimore Veterans Administration Medical Center, Department of Epidemiology; Harvard T.H. School of Public Health, Duke Molecular Physiology Institute and Division of Rheumatology; Duke University School of Medicine, Nuffield Department of Orthopaedics; Rheumatology and musculoskeletal sciences; University of Oxford, and Wellcome Trust Sanger Institute
- Page Start:
- e1006260
- Person:
- Hart, Deborah J., Rivadeneira, Fernando, Lane, Nancy E., Muir, Kenneth, Evangelou, Evangelos, Doherty, Sally, Castaño-Betancourt, Martha C., Meulenbelt, Ingrid, Boer, Cindy G., Styrkarsdottir, Unnur, Uitterlinden, Andre G., Doherty, Michael, Maciewicz, Rose A., Metrustry, Sarah, Evans, Dan S., den Hollander, Wouter, Barrett-Connor, Elizabeth, Jordan, Joanne M., Kloppenburg, Margreet, van Meurs, Joyce B. J., Lafeber, Floris, Slagboom, Eline P., Nelissen, Rob G. H. H., Yau, Michelle S., Mitchell, Braxton D., Nevitt, Michael C., Ramos, Yolande F. M., Liu, Youfang, Kraaij, Robert, Hofman, Albert, Valdes, Ana M., van Rooij, Jeroen, Kraus, Virginia B., Arden, Nigel, Zeggini, Eleftheria, Zhang, Weiya, and Spector, Tim D.
- Rights Statement Label:
- In Copyright
- Source:
- d791sn278
2080. Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome
- Title Tesim:
- Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome
- Creator:
- Zhao, Xinyu, Li, Ronghui, Dong, Qiping, Zeng, Xin, Wang, Zefeng, Yuan, Xinni, Keles, Sunduz, Chiao, Cassandra, Gao, Yu, Chang, Qiang, and Li, Hongda
- Date of publication:
- 2016
- Abstract Tesim:
- Mutations in the human MECP2 gene cause Rett syndrome (RTT), a severe neurodevelopmental disorder that predominantly affects girls. Despite decades of work, the molecular function of MeCP2 is not fully understood. Here we report a systematic identification of MeCP2-interacting proteins in the mouse brain. In addition to transcription regulators, we found that MeCP2 physically interacts with several modulators of RNA splicing, including LEDGF and DHX9. These interactions are disrupted by RTT causing mutations, suggesting that they may play a role in RTT pathogenesis. Consistent with the idea, deep RNA sequencing revealed misregulation of hundreds of splicing events in the cortex of Mecp2 knockout mice. To reveal the functional consequence of altered RNA splicing due to the loss of MeCP2, we focused on the regulation of the splicing of the flip/flop exon of Gria2 and other AMPAR genes. We found a significant splicing shift in the flip/flop exon toward the flop inclusion, leading to a faster decay in the AMPAR gated current and altered synaptic transmission. In summary, our study identified direct physical interaction between MeCP2 and splicing factors, a novel MeCP2 target gene, and established functional connection between a specific RNA splicing change and synaptic phenotypes in RTT mice. These results not only help our understanding of the molecular function of MeCP2, but also reveal potential drug targets for future therapies.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Pharmacology
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/y94a-yk43
- Identifier:
- PMCID: PMC4924826, Publisher DOI: https://doi.org/10.1371/journal.pgen.1006129, PMID: 27352031, and Onescience id: 1318c01af29ecbf3eccbe4df80d48bf52a4da735
- ISSN:
- 1553-7390 and 1553-7404
- Journal Issue:
- 6
- Journal Title:
- PLoS Genetics
- Journal Volume:
- 12
- Keyword:
- PSIP1, High-Throughput Nucleotide Sequencing, Gria2, MECP2, Genes, DHX9, Homo sapiens, Synaptic Transmission, Mecp2, Alternative Splicing, RNA Splicing, Exons, Rett Syndrome, GRIA2, Mutation, Phenotype, Methyl-CpG-Binding Protein 2, Dhx9, Mus musculus, Brain, and Therapeutics
- Language Label:
- English
- ORCID:
- 0000-0002-5128-4424, , and 0000-0003-4186-0667
- Other Affiliation:
- Waisman Center; University of Wisconsin-Madison, CMB Training Program; University of Wisconsin-Madison, Department of Statistics; University of Wisconsin-Madison, Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology; CAS-MPG Partner Institute for Computational Biology, Department of Biostatistics and Medical Informatics; University of Wisconsin-Madison, Genetics Training Program; University of Wisconsin-Madison, and Departments of Medical Genetics and Neurology; University of Wisconsin-Madison
- Page Start:
- e1006129
- Person:
- Zhao, Xinyu, Li, Ronghui, Dong, Qiping, Zeng, Xin, Wang, Zefeng, Yuan, Xinni, Keles, Sunduz, Chiao, Cassandra, Gao, Yu, Chang, Qiang, and Li, Hongda
- Rights Statement Label:
- In Copyright
- Source:
- gt54kt14f
Collection Details
- Total items
-
2127
- Size
-
unknown
- Date created
-
February 2, 2022