24 results on '"Anna-Lisa Doebley"'
Search Results
2. Circulating tumor DNA is readily detectable among Ghanaian breast cancer patients supporting non-invasive cancer genomic studies in Africa
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Samuel Terkper Ahuno, Anna-Lisa Doebley, Thomas U. Ahearn, Joel Yarney, Nicholas Titiloye, Nancy Hamel, Ernest Adjei, Joe-Nat Clegg-Lamptey, Lawrence Edusei, Baffour Awuah, Xiaoyu Song, Verna Vanderpuye, Mustapha Abubakar, Maire Duggan, Daniel G. Stover, Kofi Nyarko, John M. S. Bartlett, Francis Aitpillah, Daniel Ansong, Kevin L. Gardner, Felix Andy Boateng, Anne M. Bowcock, Carlos Caldas, William D. Foulkes, Seth Wiafe, Beatrice Wiafe-Addai, Montserrat Garcia-Closas, Alexander Kwarteng, Gavin Ha, Jonine D. Figueroa, Paz Polak, and the Ghana Breast Health Study Team
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Circulating tumor DNA (ctDNA) sequencing studies could provide novel insights into the molecular pathology of cancer in sub-Saharan Africa. In 15 patient plasma samples collected at the time of diagnosis as part of the Ghana Breast Health Study and unselected for tumor grade and subtype, ctDNA was detected in a majority of patients based on whole- genome sequencing at high (30×) and low (0.1×) depths. Breast cancer driver copy number alterations were observed in the majority of patients.
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- 2021
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3. Author Correction: A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA
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Anna-Lisa Doebley, Minjeong Ko, Hanna Liao, A. Eden Cruikshank, Katheryn Santos, Caroline Kikawa, Joseph B. Hiatt, Robert D. Patton, Navonil De Sarkar, Katharine A. Collier, Anna C. H. Hoge, Katharine Chen, Anat Zimmer, Zachary T. Weber, Mohamed Adil, Jonathan B. Reichel, Paz Polak, Viktor A. Adalsteinsson, Peter S. Nelson, David MacPherson, Heather A. Parsons, Daniel G. Stover, and Gavin Ha
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Science - Published
- 2023
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4. The meiotic phosphatase GSP-2/PP1 promotes germline immortality and small RNA-mediated genome silencing.
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Katherine Kretovich Billmyre, Anna-Lisa Doebley, Maya Spichal, Bree Heestand, Tony Belicard, Aya Sato-Carlton, Stephane Flibotte, Matt Simon, Megan Gnazzo, Ahna Skop, Donald Moerman, Peter Mark Carlton, Peter Sarkies, and Shawn Ahmed
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Genetics ,QH426-470 - Abstract
Germ cell immortality, or transgenerational maintenance of the germ line, could be promoted by mechanisms that could occur in either mitotic or meiotic germ cells. Here we report for the first time that the GSP-2 PP1/Glc7 phosphatase promotes germ cell immortality. Small RNA-induced genome silencing is known to promote germ cell immortality, and we identified a separation-of-function allele of C. elegans gsp-2 that is compromised for germ cell immortality and is also defective for small RNA-induced genome silencing and meiotic but not mitotic chromosome segregation. Previous work has shown that GSP-2 is recruited to meiotic chromosomes by LAB-1, which also promoted germ cell immortality. At the generation of sterility, gsp-2 and lab-1 mutant adults displayed germline degeneration, univalents, histone methylation and histone phosphorylation defects in oocytes, phenotypes that mirror those observed in sterile small RNA-mediated genome silencing mutants. Our data suggest that a meiosis-specific function of GSP-2 ties small RNA-mediated silencing of the epigenome to germ cell immortality. We also show that transgenerational epigenomic silencing at hemizygous genetic elements requires the GSP-2 phosphatase, suggesting a functional link to small RNAs. Given that LAB-1 localizes to the interface between homologous chromosomes during pachytene, we hypothesize that small localized discontinuities at this interface could promote genomic silencing in a manner that depends on small RNAs and the GSP-2 phosphatase.
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- 2019
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5. The effect of Tmem135 overexpression on the mouse heart.
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Sarah Aileen Lewis, Tetsuya Takimoto, Shima Mehrvar, Hitoshi Higuchi, Anna-Lisa Doebley, Giangela Stokes, Nader Sheibani, Sakae Ikeda, Mahsa Ranji, and Akihiro Ikeda
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Medicine ,Science - Abstract
Tissues with high-energy demand including the heart are rich in the energy-producing organelles, mitochondria, and sensitive to mitochondrial dysfunction. While alterations in mitochondrial function are increasingly recognized in cardiovascular diseases, the molecular mechanisms through which changes in mitochondria lead to heart abnormalities have not been fully elucidated. Here, we report that transgenic mice overexpressing a novel regulator of mitochondrial dynamics, transmembrane protein 135 (Tmem135), exhibit increased fragmentation of mitochondria and disease phenotypes in the heart including collagen accumulation and hypertrophy. The gene expression analysis showed that genes associated with ER stress and unfolded protein response, and especially the pathway involving activating transcription factor 4, are upregulated in the heart of Tmem135 transgenic mice. It also showed that gene expression changes in the heart of Tmem135 transgenic mice significantly overlap with those of aged mice in addition to the similarity in cardiac phenotypes, suggesting that changes in mitochondrial dynamics may be involved in the development of heart abnormalities associated with aging. Our study revealed the pathological consequence of overexpression of Tmem135, and suggested downstream molecular changes that may underlie those disease pathologies.
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- 2018
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6. Reduced Insulin/IGF-1 Signaling Restores Germ Cell Immortality to Caenorhabditis elegans Piwi Mutants
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Matt Simon, Peter Sarkies, Kohta Ikegami, Anna-Lisa Doebley, Leonard D. Goldstein, Jacinth Mitchell, Aisa Sakaguchi, Eric A. Miska, and Shawn Ahmed
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Biology (General) ,QH301-705.5 - Abstract
Defects in the Piwi/piRNA pathway lead to transposon desilencing and immediate sterility in many organisms. We found that the C. elegans Piwi mutant prg-1 became sterile after growth for many generations. This phenotype did not occur for RNAi mutants with strong transposon-silencing defects and was separable from the role of PRG-1 in transgene silencing. Brief periods of starvation extended the transgenerational lifespan of prg-1 mutants by stimulating the DAF-16/FOXO longevity transcription factor. Constitutive activation of DAF-16 via reduced daf-2 insulin/IGF-1 signaling immortalized prg-1 strains via RNAi proteins and histone H3 lysine 4 demethylases. In late-generation prg-1 mutants, desilencing of repetitive segments of the genome occurred, and silencing of repetitive loci was restored in prg-1; daf-2 mutants. This study reveals an unexpected interface between aging and transgenerational maintenance of germ cells, where somatic longevity is coupled to a genome-silencing pathway that promotes germ cell immortality in parallel to the Piwi/piRNA system.
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- 2014
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7. denovo-db: a compendium of human de novo variants.
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Tychele Turner, Qian Yi, Niklas Krumm, John Huddleston, Kendra Hoekzema, Holly A. Stessman, Anna-Lisa Doebley, Raphael A. Bernier, Deborah A. Nickerson, and Evan E. Eichler
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- 2017
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8. Supplementary Table S4 from Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes
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Gavin Ha, Peter S. Nelson, Steven Henikoff, Eva Corey, R. Bruce Montgomery, Michael C. Haffner, Kami Ahmad, Matthew L. Freedman, Jacob E. Berchuck, Sylvan C. Baca, Atish D. Choudhury, Colm Morrissey, Michael T. Schweizer, Colin C. Pritchard, Heather M. McClure, Holly M. Nguyen, Talina A. Nunez, Jared M. Lucas, Ruth F. Dumpit, Arnab Bose, Ilsa M. Coleman, Lisa S. Ang, Derek H. Janssens, Michael P. Meers, Sandipan Brahma, Minjeong Ko, Jay F. Sarthy, Adam J. Kreitzman, Mohamed Adil, Brian Hanratty, Anna-Lisa Doebley, Robert D. Patton, and Navonil De Sarkar
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Feature-region combination AUCs and benchmarking Sheet 1: Log2 fold-change, p-value, and q-value between ARPC and NEPC lines for central mean coverage in all queried (338) TFs (two tailed Mann-Whitney U test, Benjamini-Hochberg adjusted). Sheet 2: 100-fold cross-validation AUCs for all region and feature combinations subset by the ‘AR10’ overlapping features (see Methods). Sheet 3: 100-fold cross-validation AUCs for all region and feature combinations subset by the ‘Phenotype 47-defining’ overlapping features. Sheet 4: 100-fold cross-validation AUCs for all region and feature combinations (global). Sheet 5: Predictions scores, tumor fraction, depth of coverage, and subtype for benchmarking admixtures. Sheet 6: AUCs for unsupervised prediction of admixture subtypes grouped by tumor fraction and depth. Sheet 7: NEPC:ARPC ratio, tumor fraction, and ARPC and NEPC fraction predictions for mixed phenotype admixtures using Keraon (see Methods).
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- 2023
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9. Supplementary Figures from Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes
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Gavin Ha, Peter S. Nelson, Steven Henikoff, Eva Corey, R. Bruce Montgomery, Michael C. Haffner, Kami Ahmad, Matthew L. Freedman, Jacob E. Berchuck, Sylvan C. Baca, Atish D. Choudhury, Colm Morrissey, Michael T. Schweizer, Colin C. Pritchard, Heather M. McClure, Holly M. Nguyen, Talina A. Nunez, Jared M. Lucas, Ruth F. Dumpit, Arnab Bose, Ilsa M. Coleman, Lisa S. Ang, Derek H. Janssens, Michael P. Meers, Sandipan Brahma, Minjeong Ko, Jay F. Sarthy, Adam J. Kreitzman, Mohamed Adil, Brian Hanratty, Anna-Lisa Doebley, Robert D. Patton, and Navonil De Sarkar
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Supplementary Figures S1-S18 and Supplementary Table legends.
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- 2023
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10. Nucleosome patterns in circulating tumor DNA reveal transcriptional regulation of advanced prostate cancer phenotypes
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Navonil De Sarkar, Robert D. Patton, Anna-Lisa Doebley, Brian Hanratty, Mohamed Adil, Adam J. Kreitzman, Jay F. Sarthy, Minjeong Ko, Sandipan Brahma, Michael P. Meers, Derek H. Janssens, Lisa S. Ang, Ilsa M. Coleman, Arnab Bose, Ruth F. Dumpit, Jared M. Lucas, Talina A. Nunez, Holly M. Nguyen, Heather M. McClure, Colin C. Pritchard, Michael T. Schweizer, Colm Morrissey, Atish D. Choudhury, Sylvan C. Baca, Jacob E. Berchuck, Matthew L. Freedman, Kami Ahmad, Michael C. Haffner, R. Bruce Montgomery, Eva Corey, Steven Henikoff, Peter S. Nelson, and Gavin Ha
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Oncology - Abstract
Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and GATA2. To distinguish NEPC and ARPC in patient plasma samples, we developed prediction models that achieved accuracies of 97% for dominant phenotypes and 87% for mixed clinical phenotypes. Although phenotype classification is typically assessed by IHC or transcriptome profiling from tumor biopsies, we demonstrate that ctDNA provides comparable results with diagnostic advantages for precision oncology. Significance: This study provides insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. New methods for classification in phenotype mixtures extend the utility of ctDNA beyond assessments of somatic DNA alterations with important implications for molecular classification and precision oncology. This article is highlighted in the In This Issue feature, p. 517
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- 2022
11. Abstract LB298: Molecular phenotype classification of metastatic prostate cancer by cell-free DNA methylation analysis
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Mohamed Adil, Brian Hanratty, Pallabi Mustafi, Ilsa Coleman, Radhika Patel, Anna-Lisa Doebley, Robert Patton, Eden Cruikshank, Patricia Galipeau, Ruth Dumpit, Martine Roudier, Jin-Yih Low, Navonil De Sarkar, Robert Montgomery, Eva Corey, Colm Morrissey, Peter Nelson, Gavin Ha, and Michael Haffner
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Cancer Research ,Oncology - Abstract
Introduction: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease which can be classified into clinically relevant subtypes based on the expression of transcription factors (TF), such as the androgen receptor (AR) and neuroendocrine markers. Neuroendocrine prostate cancer (NEPC), characterized by gain of stem-like and neuroendocrine features and lack of AR expression is a clinically aggressive variant. Due to the absence of adequate biomarkers, NEPC is usually detected at a very advanced stage. There is mounting evidence that molecular subtype changes seen in NEPC are enforced by widespread epigenetic alterations, in particular DNA methylation changes. In this study, we aim to devise a novel DNA methylation-based assay for molecular subtyping and disease monitoring from cell-free DNA (cfDNA). Methods: We analyzed genome wide methylation patterns in 60 prostate cancer patient-derived xenograft (PDX) and 133 mCRPC tumors using array- and sequencing-based assays. We integrated DNA methylation with TF cistrome data to determine the landscape of methylation alterations at key lineage TF binding sites (TFBS). A linear regression model was trained on low-pass Enzymatic Methyl-Seq (EM-seq) cfDNA data derived from PDXs to identify molecular subtype specific DNA methylation changes at these TFBS. The model performance was optimized with in silico admixture experiments. This model was then used to discern tumor molecular phenotypes from cfDNA in three independent cohorts of mCRPC patients using low-pass whole genome bisulfite sequencing and EM-seq. Results: We observed a strong association between TFBS methylation and TF expression. For lineage specific TFs such as AR and ASCL1, we identified core sets of TFBSs whose differential methylation allowed for accurate assay-independent molecular subtype classification in tumor tissues. Applying an optimized quantitative model to mCRPC patients who underwent comprehensive tissue sampling by rapid autopsy we observed perfect subtype prediction from both tissue samples and cfDNA (AUC=1). A similar analytical performance was observed in additional clinical mCRPC cohorts with cfDNA. Conclusions: We show that methylation patterns at TFBSs can determine TF activity and can be used to classify molecular subtypes from both tumor tissue and cfDNA. For prostate cancer, we demonstrate that this approach can accurately detect NEPC by cost-effective low-pass EM-seq. More broadly, this study provides a novel analysis framework for robustly assessing molecular tumor phenotypes in cfDNA with applications in solid and liquid tumor diagnostics. Citation Format: Mohamed Adil, Brian Hanratty, Pallabi Mustafi, Ilsa Coleman, Radhika Patel, Anna-Lisa Doebley, Robert Patton, Eden Cruikshank, Patricia Galipeau, Ruth Dumpit, Martine Roudier, Jin-Yih Low, Navonil De Sarkar, Robert Montgomery, Eva Corey, Colm Morrissey, Peter Nelson, Gavin Ha, Michael Haffner. Molecular phenotype classification of metastatic prostate cancer by cell-free DNA methylation analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB298.
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- 2023
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12. Loss of Chondroitin Sulfate Modification Causes Inflammation and Neurodegeneration in skt Mice
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Nicholas A. Zumwalde, Erik Jessen, Daniel Western, Erika Henningsen, Anna-Lisa Doebley, Akihiro Ikeda, Michael Landowski, Samuel A. Miller, Sakae Ikeda, Nathan P Gruenke, Erica L. Macke, Bikash R. Pattnaik, Jenny E. Gumperz, Wei-Hua Lee, and Che Liu
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Male ,retina ,hippocampus ,retinal pigment epithelium ,Apoptosis ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Chondroitin sulfate synthase 1 ,subretinal space ,Glucuronosyltransferase ,Mice, Knockout ,Neurons ,Genetics ,0303 health sciences ,Chondroitin Sulfates ,Retinal Degeneration ,Neurodegeneration ,Age Factors ,neurodegeneration ,Neurodegenerative Diseases ,Cell biology ,medicine.anatomical_structure ,myeloid cells ,N-Acetylgalactosaminyltransferases ,Female ,medicine.symptom ,Positional cloning ,Inflammation ,Investigations ,Biology ,03 medical and health sciences ,Cellular Genetics ,medicine ,Animals ,Chondroitin ,Chondroitin sulfate ,mouse ,030304 developmental biology ,Retinal pigment epithelium ,aging ,Proteins ,medicine.disease ,Multifunctional Enzymes ,Mice, Inbred C57BL ,chemistry ,chondroitin sulfate synthase ,Chondroitin sulfate proteoglycan ,Mutation ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery - Abstract
One major aspect of the aging process is the onset of chronic, low-grade inflammation that is highly associated with age-related diseases. The molecular mechanisms that regulate these processes have not been fully elucidated. We have identified a spontaneous mutant mouse line, small with kinky tail (skt), that exhibits accelerated aging and age-related disease phenotypes including increased inflammation in the brain and retina, enhanced age-dependent retinal abnormalities including photoreceptor cell degeneration, neurodegeneration in the hippocampus, and reduced lifespan. By positional cloning, we identified a deletion in chondroitin sulfate synthase 1 (Chsy1) that is responsible for these phenotypes in skt mice. CHSY1 is a member of the chondroitin N-acetylgalactosaminyltransferase family that plays critical roles in the biosynthesis of chondroitin sulfate, a glycosaminoglycan (GAG) that is attached to the core protein to form the chondroitin sulfate proteoglycan (CSPG). Consistent with this function, the Chsy1 mutation dramatically decreases chondroitin sulfate GAGs in the retina and hippocampus. In addition, macrophage and neutrophil populations appear significantly altered in the bone marrow and spleen of skt mice, suggesting an important role for CHSY1 in the functioning of these immune cell types. Thus, our study reveals a previously unidentified impact of CHSY1 in the retina and hippocampus. Specifically, chondroitin sulfate (CS) modification of proteins by CHSY1 appears critical for proper regulation of immune cells of the myeloid lineage and for maintaining the integrity of neuronal tissues, since a defect in this gene results in increased inflammation and abnormal phenotypes associated with age-related diseases.
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- 2020
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13. Griffin: Framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA
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C. Kikawa, Peter S. Nelson, Jonathan Reichel, Joseph B. Hiatt, Gavin Ha, M. Ko, Anna C. H. Hoge, Zachary Weber, K. Santos, H. Liao, K. Chen, Paz Polak, R. D. Patton, Heather A. Parsons, A. E. Cruikshank, David MacPherson, Anna-Lisa Doebley, N. De Sarkar, Viktor A. Adalsteinsson, M. Adil, and Daniel G. Stover
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Tumor Subtype ,Whole genome sequencing ,Cell-free fetal DNA ,business.industry ,Medicine ,Nucleosome ,Cancer ,Computational biology ,business ,medicine.disease ,Metastatic breast cancer ,Tumor heterogeneity ,Subtyping - Abstract
Cell-free DNA (cfDNA) has the potential to inform tumor subtype classification and help guide clinical precision oncology. Here we developed Griffin, a new method for profiling nucleosome protection and accessibility from cfDNA to study the phenotype of tumors using as low as 0.1x coverage whole genome sequencing (WGS) data. Griffin employs a novel GC correction procedure tailored to variable cfDNA fragment sizes, which improves the prediction of chromatin accessibility. Griffin achieved excellent performance for detecting tumor cfDNA in early-stage cancer patients (AUC=0.96). Next, we applied Griffin for the first demonstration of estrogen receptor (ER) subtyping in metastatic breast cancer from cfDNA. We analyzed 254 samples from 139 patients and predicted ER subtype with high performance (AUC=0.89), leading to insights about tumor heterogeneity. In summary, Griffin is a framework for accurate clinical subtyping and can be generalizable to other cancer types for precision oncology applications.
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- 2021
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14. A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA
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Anna-Lisa Doebley, Minjeong Ko, Hanna Liao, A. Eden Cruikshank, Katheryn Santos, Caroline Kikawa, Joseph B. Hiatt, Robert D. Patton, Navonil De Sarkar, Katharine A. Collier, Anna C. H. Hoge, Katharine Chen, Anat Zimmer, Zachary T. Weber, Mohamed Adil, Jonathan B. Reichel, Paz Polak, Viktor A. Adalsteinsson, Peter S. Nelson, David MacPherson, Heather A. Parsons, Daniel G. Stover, and Gavin Ha
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Multidisciplinary ,Receptors, Estrogen ,Neoplasms ,General Physics and Astronomy ,Humans ,General Chemistry ,Precision Medicine ,Cell-Free Nucleic Acids ,General Biochemistry, Genetics and Molecular Biology ,Nucleosomes - Abstract
Cell-free DNA (cfDNA) has the potential to inform tumor subtype classification and help guide clinical precision oncology. Here we develop Griffin, a framework for profiling nucleosome protection and accessibility from cfDNA to study the phenotype of tumors using as low as 0.1x coverage whole genome sequencing data. Griffin employs a GC correction procedure tailored to variable cfDNA fragment sizes, which generates a better representation of chromatin accessibility and improves the accuracy of cancer detection and tumor subtype classification. We demonstrate estrogen receptor subtyping from cfDNA in metastatic breast cancer. We predict estrogen receptor subtype in 139 patients with at least 5% detectable circulating tumor DNA with an area under the receive operator characteristic curve (AUC) of 0.89 and validate performance in independent cohorts (AUC = 0.96). In summary, Griffin is a framework for accurate tumor subtyping and can be generalizable to other cancer types for precision oncology applications.
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- 2021
15. Circulating tumor DNA is readily detectable among Ghanaian breast cancer patients supporting non-invasive cancer genomic studies in Africa
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Carlos Caldas, Ernest Adjei, Joe-Nat Clegg Lamptey, Felix Andy Boateng, Beatrice Wiafe-Addai, Lawrence Edusei, John M S Bartlet, Nicholas Titiloye, Máire A. Duggan, Thomas U. Ahearn, Anna-Lisa Doebley, Montserrat Garcia-Closas, Gavin Ha, Joel Yarney, Mustapha Abubakar, Jonine D. Figueroa, Kofi Mensah Nyarko, Xiaoyu Song, Daniel Ansong, Francis Aitpillah, William D. Foulkes, Kevin Gardner, Daniel G. Stover, Seth Wiafe, Verne Vanderpuye, Alexander Kwarteng, Anne M. Bowcock, Samuel Terkper Ahuno, Nancy Hamel, Paz Polak, and Baffour Awuah
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Oncology ,medicine.medical_specialty ,Molecular pathology ,business.industry ,Non invasive ,Cancer ,medicine.disease ,Suspected breast cancer ,Breast cancer ,Circulating tumor DNA ,Internal medicine ,parasitic diseases ,medicine ,business - Abstract
Circulating tumor DNA (ctDNA) sequencing studies could provide novel insights into the molecular pathology of cancer in sub-Saharan Africa. ctDNA was readily detected in 15 blood samples collected in Ghana at the time of suspected breast cancer. Genomic alterations previously associated with unfavorable prognostic outcomes were observed in the majority of patients. This supports the use of liquid biopsies for diagnosis, surveillance and clinical management of breast cancer in Ghana.
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- 2020
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16. Abstract LB022: Griffin: A method for nucleosome profiling and breast cancer subtype prediction from ultra-low pass whole genome sequencing of cell-free DNA
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Paz Polak, Gavin Ha, Anna-Lisa Doebley, Heather A. Parsons, Caroline Kikawa, Viktor A. Adalsteinsson, Eden Cruikshank, Minjeong Ko, Joseph B. Hiatt, Peter S. Nelson, Daniel G. Stover, David MacPherson, Anna C. H. Hoge, Navonil De Sarkar, and Hanna Liao
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Whole genome sequencing ,Cancer Research ,medicine.medical_treatment ,Cancer ,Computational biology ,Biology ,medicine.disease ,Targeted therapy ,Metastasis ,Causes of cancer ,Breast cancer ,Oncology ,Cell-free fetal DNA ,Cancer cell ,medicine - Abstract
Background: Cell-free DNA (cfDNA) is released from dying cells, including tumor cells, and can be isolated from peripheral blood for studying cancer. In the bloodstream, cfDNA is protected from degradation by nucleosomes and other DNA binding proteins, leading to a coverage pattern that reflects the genomic organization in the cells-of-origin. Recent work has shown that it is possible to use this pattern to predict gene and transcription factor activity in cancer cells. This is known as nucleosome profiling. Breast cancer is among the most common causes of cancer, accounting for 23% of cancer diagnoses and 14% of cancer-related deaths among women worldwide. Targeted therapy is guided by tumor subtype, including the expression of three key receptors: ER, PR and HER2. Typically, subtyping involves a tumor biopsy and immunohistochemistry. However, in late-stage cancer, surgical biopsies for disease monitoring are difficult to obtain. Accurate subtype determination is critical to address hormone subtype switches during metastasis or treatment resistance. cfDNA offers an alternative, non-invasive method for identifying tumor subtypes through nucleosome profiling and, to the best of our knowledge, has not been shown for breast cancer. Methods: We developed a method, called Griffin, to examine nucleosome protection and genome accessibility by quantifying cfDNA fragments around accessible sites. Unlike previous methods, Griffin uses fragment length-based GC correction to remove GC biases that obscure signals. We used ATAC-seq data from TCGA to identify differentially accessible sites between ER positive and negative breast cancers. We developed a machine learning classifier that predicts ER subtype based upon the signals at these differentially accessible sites. Results: We then tested Griffin by examining differentially accessible sites in ultra-low pass sequencing (ULP-WGS, 0.1X) of several hundred cfDNA samples from patients with ER positive or negative breast cancer. We found that overall, differential sites were more accessible in the cfDNA of their respective subtypes. Additionally, we found that site accessibility within patient cfDNA samples was correlated to the cfDNA tumor fraction. We built and tested a prediction model with cross-validation, which revealed an accuracy of >80% for correctly classifying tumor status as ER positive or negative from this ULP-WGS dataset. Conclusion: This study has several novel aspects compared to prior nucleosome profiling approaches. First, we use fragment-based GC correction which reduces sample variability and allows us to observe previously obscured signals. Second, we demonstrated that signals are correlated to tumor fraction. And finally, we applied this method to cost-effective and scalable ULP-WGS of breast cancer and demonstrated the ability to predict breast cancer ER subtype in these samples. Citation Format: Anna-Lisa Doebley, Hanna Liao, Caroline Kikawa, Eden Cruikshank, Minjeong Ko, Anna Hoge, Joseph Hiatt, Navonil De Sarkar, Viktor A. Adalsteinsson, Paz Polak, David MacPherson, Peter S. Nelson, Heather A. Parsons, Daniel Stover, Gavin Ha. Griffin: A method for nucleosome profiling and breast cancer subtype prediction from ultra-low pass whole genome sequencing of cell-free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB022.
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- 2021
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17. Abstract 81: Studying Ghanian Cancer Genomes Using Cell-free DNA
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Kevin Gardner, Carlos Caldas, Xiaoyu Song, Daniel Ansong, Verne Vanderpuye, Francis Aitpillah, Wiafe-Addai, Ernest Adjei, Joel Yarney, Kofi Mensah Nyarko, Nicholas Titiloye, Montserrat Garcia-Closas, Gavin Ha, Mustapha Abubakar, Anna-Lisa Doebley, William D. Foulkes, Paz Polak, Baffour Awuah, Joe-Nat Clegg-Lamptey, Alexander Kwarteng, John M S Bartlet, Thomas U. Ahearn, Máire A. Duggan, Samuel Terkper Ahuno, Anne M. Bowcock, Nancy Hamel, Lawrence Edusei, Jonine D. Figueroa, Daniel G. Stover, and Seth Wiafe
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Copy number gain ,Genetics ,Breast cancer ,Oncology ,Cell-free fetal DNA ,Epidemiology ,Concordance ,medicine ,Cancer ,Biology ,medicine.disease ,Genome ,Cancer Etiology - Abstract
Purpose: Analysis of cell free DNA could provide a rapid and non-invasive approach to detect cancer and provide new molecular insights in many African countries where expert pathology is lacking. Hence, we tested whether whole-genome sequencing of cfDNA (WGS-cfDNA) could identify somatic alterations that drive breast cancer. Methods: We conducted a pilot on 15 Ghanaian women (median age 49.5 years) recruited as part of the Ghana Breast Health Study. cfDNA was extracted and subjected to WGS at 30x and 0.1x. ichorCNA software was used to predict copy number alterations and ctDNA fractions. Results: We found extensive amplification and deletion of multiple chromosomal regions including those with oncogenes and tumor suppressor genes associated with breast cancer. Similar copy number alterations for selected breast cancer genes were observed with 0.1x and 30x cfDNA-WGS with increasing concordance between the two instruments as the ctDNA fraction increases. We observed a high frequency (>50%) of copy number gain in 3/5 regions and potential target genes for the amplification (chr8p11-12 [ZNF703] n=8, 53.3%; chr8q24.2 [MYC] n=9, 60%; chr19q12 [CCNE1] n=9, 60%), which were in agreement to previous observations among African-American (AA) ancestry compared to European-American (EA) ancestry in TCGA datasets. Conclusion: Our data provided evidence that ctDNA-based genomic studies are possible and ctDNA analysis could be a tool for future molecular oncology studies in Africa for cancer etiology, surveillance and clinical trials. Citation Format: Samuel Ahuno, Anna-Lisa Doebley, Thomas Ahearn, Joel Yarney, Nicholas Titiloye, Nancy Hamel, Ernest Adjei, Joe-Nat Clegg-Lamptey, Lawrence Edusei, Baffour Awuah, Xiaoyu Song, Verne Vanderpuye, Mustapha Abubakar, Maire Duggan, Daniel Stover, Kofi Nyarko, John Bartlet, Francis Aitpillah, Daniel Ansong, Kevin Gardner, Anne Bowcock, Carlos Caldas, William Foulkes, Seth Wiafe, Wiafe-Addai, Montserrat Garcia-Closas, Alexander Kwarteng, Gavin Ha, Jonine Figueroa, Paz Polak, On Behalf Of Ghana Breast Health Study Team. Studying Ghanian Cancer Genomes Using Cell-free DNA [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 81.
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- 2021
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18. denovo-db: a compendium of humande novovariants
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Anna-Lisa Doebley, Qian Yi, Kendra Hoekzema, Evan E. Eichler, Raphael Bernier, Holly A.F. Stessman, John Huddleston, Deborah A. Nickerson, Tychele N. Turner, and Niklas Krumm
- Subjects
0301 basic medicine ,Genetics ,MEDLINE ,Computational Biology ,Genetic Variation ,Molecular Sequence Annotation ,Disease ,Web Browser ,Biology ,Polymorphism, Single Nucleotide ,Phenotype ,3. Good health ,03 medical and health sciences ,Annotation ,030104 developmental biology ,Germline mutation ,Database Issue ,Humans ,Databases, Nucleic Acid ,Gene ,Exome ,Genetic Association Studies ,Germ-Line Mutation - Abstract
Whole-exome and whole-genome sequencing have facilitated the large-scale discovery of de novo variants in human disease. To date, most de novo discovery through next-generation sequencing focused on congenital heart disease and neurodevelopmental disorders (NDDs). Currently, de novo variants are one of the most significant risk factors for NDDs with a substantial overlap of genes involved in more than one NDD. To facilitate better usage of published data, provide standardization of annotation, and improve accessibility, we created denovo-db (http://denovo-db.gs.washington.edu), a database for human de novo variants. As of July 2016, denovo-db contained 40 different studies and 32,991 de novo variants from 23,098 trios. Database features include basic variant information (chromosome location, change, type); detailed annotation at the transcript and protein levels; severity scores; frequency; validation status; and, most importantly, the phenotype of the individual with the variant. We included a feature on our browsable website to download any query result, including a downloadable file of the full database with additional variant details. denovo-db provides necessary information for researchers to compare their data to other individuals with the same phenotype and also to controls allowing for a better understanding of the biology of de novo variants and their contribution to disease.
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- 2016
- Full Text
- View/download PDF
19. The conserved phosphatase GSP-2/PP1 promotes germline immortality via small RNA-mediated genome silencing during meiosis
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Donald G. Moerman, Peter M. Carlton, Shawn Ahmed, Katherine Kretovich Billmyre, Anna-Lisa Doebley, Peter Sarkies, Bree Heestand, Megan M. Gnazzo, Ahna R. Skop, Aya Sato-Carlton, Matt Simon, Stephane Flibotte, and Tony Belicard
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0303 health sciences ,Small RNA ,Epigenome ,Biology ,Cell biology ,Chromosome segregation ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Meiosis ,Homologous chromosome ,medicine ,Gene silencing ,Mitosis ,030217 neurology & neurosurgery ,Germ cell ,030304 developmental biology - Abstract
Genomic silencing can promote germ cell immortality, or transgenerational maintenance of the germ line, via mechanisms that may occur during mitosis or meiosis. Here we report that thegsp-2PP1/Glc7 phosphatase promotes germ cell immortality. We identified a separation-of-function allele ofC. elegansGSP-2 that caused a meiosis-specific chromosome segregation defect and defects in transgenerational small RNA-induced genome silencing. GSP-2 is recruited to meiotic chromosomes by LAB-1, which also promoted germ cell immortality. Sterilegsp-2andlab-1mutant adults displayed germline degeneration, univalents and histone phosphorylation defects in oocytes, similar to small RNA genome silencing mutants. Epistasis and RNA analysis suggested that GSP-2 functions downstream of small RNAs. We conclude that a meiosis-specific function of GSP-2/LAB-1 ties small RNA-mediated silencing of the epigenome to germ cell immortality. Given that hemizygous genetic elements can drive transgenerational epigenomic silencing, and given that LAB-1 promotes pairing of homologous chromosomes and localizes to the interface between homologous chromosomes during pachytene, we suggest that discontinuities at this interface could promote nuclear silencing in a manner that depends on GSP-2.Author SummaryThe germ line of an organism is considered immortal in its capacity to give rise to an unlimited number of future generations. To protect the integrity of the germ line, mechanisms act to suppress the accumulation of transgenerational damage to the genome or epigenome. Loss of germ cell immortality can result from mutations that disrupt the small RNA-mediated silencing pathway that helps to protect the integrity of the epigenome. Here we report for the first time that theC. elegansprotein phosphatase GSP-2 that promotes core chromosome biology functions during meiosis is also required for germ cell immortality. Specifically, we identified a partial loss of function allele ofgsp-2that exhibits defects in meiotic chromosome segregation and is also dysfunctional for transgenerational small RNA-mediated genome silencing. Our results are consistent with a known role ofDrosophilaProtein Phosphatase 1 in heterochromatin silencing, and point to a meiotic phosphatase function that is relevant to germ cell immortality, conceivably related to its roles in chromosome pairing or sister chromatid cohesion.
- Published
- 2018
- Full Text
- View/download PDF
20. The effect of Tmem135 overexpression on the mouse heart
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Giangela Stokes, Shima Mehrvar, Akihiro Ikeda, Sakae Ikeda, Anna-Lisa Doebley, Nader Sheibani, Hitoshi Higuchi, Mahsa Ranji, Tetsuya Takimoto, and Sarah Lewis
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0301 basic medicine ,Heart malformation ,Gene Expression ,lcsh:Medicine ,Mitochondrion ,Biochemistry ,Mitochondrial Dynamics ,Mitochondria, Heart ,Mice ,0302 clinical medicine ,Gene expression ,Medicine and Health Sciences ,Myocytes, Cardiac ,lcsh:Science ,Energy-Producing Organelles ,Multidisciplinary ,Gene Ontologies ,Heart ,Animal Models ,Genomics ,Immunohistochemistry ,Transmembrane protein ,Cell biology ,Mitochondria ,Experimental Organism Systems ,Hyperexpression Techniques ,Anatomy ,Cellular Structures and Organelles ,Research Article ,Genetically modified mouse ,Heart Diseases ,Transgene ,Mouse Models ,Mice, Transgenic ,Biology ,Bioenergetics ,Research and Analysis Methods ,Mitochondrial Proteins ,03 medical and health sciences ,Model Organisms ,DNA-binding proteins ,Genetics ,Gene Expression and Vector Techniques ,Animals ,Gene Regulation ,Molecular Biology Techniques ,Molecular Biology ,Molecular Biology Assays and Analysis Techniques ,Gene Expression Profiling ,Myocardium ,lcsh:R ,Biology and Life Sciences ,Proteins ,Computational Biology ,Membrane Proteins ,Cell Biology ,Sequence Analysis, DNA ,Genome Analysis ,Regulatory Proteins ,Gene expression profiling ,Disease Models, Animal ,030104 developmental biology ,Unfolded protein response ,Cardiovascular Anatomy ,lcsh:Q ,Collagens ,030217 neurology & neurosurgery ,Biomarkers ,Transcription Factors - Abstract
Tissues with high-energy demand including the heart are rich in the energy-producing organelles, mitochondria, and sensitive to mitochondrial dysfunction. While alterations in mitochondrial function are increasingly recognized in cardiovascular diseases, the molecular mechanisms through which changes in mitochondria lead to heart abnormalities have not been fully elucidated. Here, we report that transgenic mice overexpressing a novel regulator of mitochondrial dynamics, transmembrane protein 135 (Tmem135), exhibit increased fragmentation of mitochondria and disease phenotypes in the heart including collagen accumulation and hypertrophy. The gene expression analysis showed that genes associated with ER stress and unfolded protein response, and especially the pathway involving activating transcription factor 4, are upregulated in the heart of Tmem135 transgenic mice. It also showed that gene expression changes in the heart of Tmem135 transgenic mice significantly overlap with those of aged mice in addition to the similarity in cardiac phenotypes, suggesting that changes in mitochondrial dynamics may be involved in the development of heart abnormalities associated with aging. Our study revealed the pathological consequence of overexpression of Tmem135, and suggested downstream molecular changes that may underlie those disease pathologies.
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- 2018
21. The normal human visual system extracts about 1% of the hues possible from the L, M and S cones compared to a perfect hue encoder
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Maureen Neitz, Jay Neitz, Anna-Lisa Doebley, James A. Kuchenbecker, and Sara S. Patterson
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Ophthalmology ,business.industry ,Human visual system model ,Computer vision ,Artificial intelligence ,business ,Encoder ,Sensory Systems ,Mathematics ,Hue - Published
- 2019
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22. The meiotic phosphatase GSP-2/PP1 promotes germline immortality and small RNA-mediated genome silencing
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Donald G. Moerman, Shawn Ahmed, Anna-Lisa Doebley, Stephane Flibotte, Peter Sarkies, Maya Spichal, Katherine Kretovich Billmyre, Bree Heestand, Peter M. Carlton, Ahna R. Skop, Megan M. Gnazzo, Aya Sato-Carlton, Matt Simon, Tony Belicard, and Medical Research Council
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C. ELEGANS ,Cancer Research ,Small RNA ,Chromosomal Proteins, Non-Histone ,SHUGOSHIN ,PATHWAY ,0302 clinical medicine ,RNA interference ,Chromosome Segregation ,Protein Phosphatase 1 ,Meiotic Prophase I ,RNA, Small Interfering ,Genetics (clinical) ,GENE-EXPRESSION ,Genetics & Heredity ,0303 health sciences ,Genome ,Cell biology ,DROSOPHILA ,Meiosis ,Histone phosphorylation ,medicine.anatomical_structure ,RNA Interference ,Life Sciences & Biomedicine ,STEM-CELLS ,Germ cell ,lcsh:QH426-470 ,21U-RNAS ,Biology ,Methylation ,03 medical and health sciences ,stomatognathic system ,Genetics ,Homologous chromosome ,medicine ,FERTILITY ,Animals ,Gene silencing ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,HISTONE H3 ,Molecular Biology ,Mitosis ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,0604 Genetics ,Science & Technology ,PIWI ,Epigenome ,Phosphoric Monoester Hydrolases ,lcsh:Genetics ,Germ Cells ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Germ cell immortality, or transgenerational maintenance of the germ line, could be promoted by mechanisms that could occur in either mitotic or meiotic germ cells. Here we report for the first time that the GSP-2 PP1/Glc7 phosphatase promotes germ cell immortality. Small RNA-induced genome silencing is known to promote germ cell immortality, and we identified a separation-of-function allele of C. elegans gsp-2 that is compromised for germ cell immortality and is also defective for small RNA-induced genome silencing and meiotic but not mitotic chromosome segregation. Previous work has shown that GSP-2 is recruited to meiotic chromosomes by LAB-1, which also promoted germ cell immortality. At the generation of sterility, gsp-2 and lab-1 mutant adults displayed germline degeneration, univalents, histone methylation and histone phosphorylation defects in oocytes, phenotypes that mirror those observed in sterile small RNA-mediated genome silencing mutants. Our data suggest that a meiosis-specific function of GSP-2 ties small RNA-mediated silencing of the epigenome to germ cell immortality. We also show that transgenerational epigenomic silencing at hemizygous genetic elements requires the GSP-2 phosphatase, suggesting a functional link to small RNAs. Given that LAB-1 localizes to the interface between homologous chromosomes during pachytene, we hypothesize that small localized discontinuities at this interface could promote genomic silencing in a manner that depends on small RNAs and the GSP-2 phosphatase.
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- 2019
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23. Caenorhabditis elegans RSD-2 and RSD-6 promote germ cell immortality by maintaining small interfering RNA populations
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Ashley Hedges, Matt Simon, Leonard D. Goldstein, Eric A. Miska, Aisa Sakaguchi, Jeannine R. LaRocque, Stacy M. Alvares, Anna-Lisa Doebley, Liwei Yang, Shawn Ahmed, Julie Hall, Peter Sarkies, and Kohta Ikegami
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Small interfering RNA ,Transcription, Genetic ,Somatic cell ,Apoptosis ,Nondisjunction, Genetic ,RNA interference ,Stress, Physiological ,Chromosome Segregation ,medicine ,Gene silencing ,RasiRNA ,Animals ,Gene Silencing ,RNA, Small Interfering ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,Spermatogenesis ,Cell Line, Transformed ,Cell Proliferation ,Genetics ,Multidisciplinary ,biology ,Temperature ,biology.organism_classification ,RNA silencing ,medicine.anatomical_structure ,Germ Cells ,PNAS Plus ,Gene Expression Regulation ,Genetic Loci ,Tandem Repeat Sequences ,Infertility ,Mutation ,Germ cell - Abstract
Germ cells are maintained in a pristine non-aging state as they proliferate over generations. Here, we show that a novel function of the Caenorhabditis elegans RNA interference proteins RNAi spreading defective (RSD)-2 and RSD-6 is to promote germ cell immortality at high temperature. rsd mutants cultured at high temperatures became progressively sterile and displayed loss of small interfering RNAs (siRNAs) that target spermatogenesis genes, simple repeats, and transposons. Desilencing of spermatogenesis genes occurred in late-generation rsd mutants, although defective spermatogenesis was insufficient to explain the majority of sterility. Increased expression of repetitive loci occurred in both germ and somatic cells of late-generation rsd mutant adults, suggesting that desilencing of many heterochromatic segments of the genome contributes to sterility. Nuclear RNAi defective (NRDE)-2 promotes nuclear silencing in response to exogenous double-stranded RNA, and our data imply that RSD-2, RSD-6, and NRDE-2 function in a common transgenerational nuclear silencing pathway that responds to endogenous siRNAs. We propose that RSD-2 and RSD-6 promote germ cell immortality at stressful temperatures by maintaining transgenerational epigenetic inheritance of endogenous siRNA populations that promote genome silencing.
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- 2014
24. Genetic modification of corneal neovascularization in Dstncorn1 mice
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Sharolyn V. Kawakami-Schulz, Akihiro Ikeda, Sakae Ikeda, Anna-Lisa Doebley, and Shannon G. Sattler
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genetic structures ,Quantitative Trait Loci ,Locus (genetics) ,Mice, Transgenic ,Biology ,Quantitative trait locus ,Article ,Neovascularization ,Mice ,Cornea ,Genetics ,medicine ,Animals ,Corneal Neovascularization ,Allele ,Genetic Association Studies ,Epistasis, Genetic ,medicine.disease ,Null allele ,Molecular biology ,eye diseases ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Destrin ,Phenotype ,Corneal neovascularization ,sense organs ,medicine.symptom ,Lod Score - Abstract
Mutations in the gene for destrin (Dstn), an actin depolymerizing factor, lead to corneal abnormalities in mice. A null mutation in Dstn, termed Dstn corn1 , isolated and maintained in the A.BY background (A.BY Dstn corn1 ), results in corneal epithelial hyperproliferation, inflammation, and neovascularization. We previously reported that neovascularization in the cornea of Dstn corn1 mice on the C57BL/6 background (B6.A.BY-Dstn corn1 ) is significantly reduced when compared to A.BY Dstn corn1 mice, suggesting the existence of genetic modifier(s). The purpose of this study is to identify the genetic basis of the difference in corneal neovascularization between A.BY Dstn corn1 and B6.A.BY-Dstn corn1 mice. We generated N2 mice for a whole-genome scan by backcrossing F1 progeny (A.BY Dstn corn1 × B6.A.BY-Dstn corn1 ) to B6.A.BY-Dstn corn1 mice. N2 progeny were quantitatively phenotyped for the extent of corneal neovascularization and genotyped for markers across the mouse genome. We identified significant association of variability in corneal neovascularization with a locus on chromosome 3 (Chr3). The validity of the identified quantitative trait locus (QTL) was tested using B6 consomic mice carrying Chr3 from A/J mice. Dstn corn1 mice from F1 and F2 intercrosses (B6.A.BY-Dstn corn1 × C57BL/6J-Chr3A/J/NaJ) were phenotyped for the extent of corneal neovascularization. This analysis showed that mice carrying the A/J allele at the QTL show significantly increased neovascularization. Our results indicate the existence of a modifier that genetically interacts with the Dstn gene. This modifier demonstrates allelic differences between C57BL6 and A.BY or A/J. The modifier is sufficient to increase neovascularization in Dstn corn1 mice.
- Published
- 2013
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