138 results on '"Aakrosh Ratan"'
Search Results
2. 185 Global and local copy number aberration signatures as prognostic and immunotherapeutic predictors
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Xuefeng Wang, Patrick Hwu, Igor Puzanov, Abdul Rafeh Naqash, Ahmad A Tarhini, George J Weiner, Margaret E Gatti-Mays, Howard Colman, Timothy I Shaw, Aakrosh Ratan, Martin D McCarter, John Carpten, Susanne M Arnold, Michelle Churchman, Tingyi Li, William S Dalton, Sijie Yao, and Islam Eljilany
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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3. 151 Genetic heterogeneity between paired primary and metastatic solid tumors and implications for neoantigen-based personalized cancer vaccines
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Xuefeng Wang, Igor Puzanov, Abdul Rafeh Naqash, Paulo C Rodriguez, George J Weiner, Jose Conejo-Garcia, Jamie Teer, Xiaoqing Yu, Margaret E Gatti-Mays, William Dalton, Howard Colman, Aik Choon Tan, Timothy I Shaw, Darwin Chang, Alyssa Obermayer, Dale Hedges, Aakrosh Ratan, Martin D McCarter, John Carpten, Susanne M Arnold, and Michelle Churchman
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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4. Prehistoric human migration between Sundaland and South Asia was driven by sea-level rise
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Hie Lim Kim, Tanghua Li, Namrata Kalsi, Hung Tran The Nguyen, Timothy A. Shaw, Khai C. Ang, Keith C. Cheng, Aakrosh Ratan, W. Richard Peltier, Dhrubajyoti Samanta, Mahesh Pratapneni, Stephan C. Schuster, and Benjamin P. Horton
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Biology (General) ,QH301-705.5 - Abstract
Population genomic analyses and palaeogeographical modelling combine to help infer the ancient migration of humans into South Asia from Sundaland, driven by rapid sea level rises.
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- 2023
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5. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthmaResearch in context
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Kathryn Recto, Priyadarshini Kachroo, Tianxiao Huan, David Van Den Berg, Gha Young Lee, Helena Bui, Dong Heon Lee, Jessica Gereige, Chen Yao, Shih-Jen Hwang, Roby Joehanes, Scott T. Weiss, George T. O’Connor, Daniel Levy, Dawn L. DeMeo, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Nathan Blue, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April P. Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Xiuqing Guo, Namrata Gupta, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yongmei Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Pradeep Natarajan, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi‘a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Scott Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Baojun Wu, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Elad Ziv, Michael Zody, and Sebastian Zoellner
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EWAS ,DNA methylation ,IgE ,Asthma ,RNA-Sequencing ,Mendelian randomization ,Medicine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. Findings: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P
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- 2023
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6. Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program
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Marsha M. Wheeler, Adrienne M. Stilp, Shuquan Rao, Bjarni V. Halldórsson, Doruk Beyter, Jia Wen, Anna V. Mihkaylova, Caitlin P. McHugh, John Lane, Min-Zhi Jiang, Laura M. Raffield, Goo Jun, Fritz J. Sedlazeck, Ginger Metcalf, Yao Yao, Joshua B. Bis, Nathalie Chami, Paul S. de Vries, Pinkal Desai, James S. Floyd, Yan Gao, Kai Kammers, Wonji Kim, Jee-Young Moon, Aakrosh Ratan, Lisa R. Yanek, Laura Almasy, Lewis C. Becker, John Blangero, Michael H. Cho, Joanne E. Curran, Myriam Fornage, Robert C. Kaplan, Joshua P. Lewis, Ruth J. F. Loos, Braxton D. Mitchell, Alanna C. Morrison, Michael Preuss, Bruce M. Psaty, Stephen S. Rich, Jerome I. Rotter, Hua Tang, Russell P. Tracy, Eric Boerwinkle, Goncalo R. Abecasis, Thomas W. Blackwell, Albert V. Smith, Andrew D. Johnson, Rasika A. Mathias, Deborah A. Nickerson, Matthew P. Conomos, Yun Li, Unnur Þorsteinsdóttir, Magnús K. Magnússon, Kari Stefansson, Nathan D. Pankratz, Daniel E. Bauer, Paul L. Auer, and Alex P. Reiner
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Science - Abstract
Most genetic association studies have been done on single nucleotide polymorphisms and small indels, while other types of variants have been less studied. Here, the authors use whole genome sequencing in a diverse population to identify and provide experimental evidence for associations between structural variants and blood-cell traits.
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- 2022
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7. Telomere length is not a main factor for the development of islet autoimmunity and type 1 diabetes in the TEDDY study
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Carina Törn, Xiang Liu, Suna Onengut-Gumuscu, Kevin M. Counts, Jose Leonardo Moreno, Cassandra L. Remedios, Wei-Min Chen, Jonathon LeFaive, Martha D. Butterworth, Beena Akolkar, Jeffrey P. Krischer, Åke Lernmark, Marian Rewers, Jin-Xiong She, Jorma Toppari, Anette-Gabriele Ziegler, Aakrosh Ratan, Albert V. Smith, William A. Hagopian, Stephen S. Rich, Hemang M. Parikh, and The TEDDY Study Group
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Medicine ,Science - Abstract
Abstract The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8676 children, 3–4 months of age, born with HLA-susceptibility genotypes for islet autoimmunity (IA) and type 1 diabetes (T1D). Whole-genome sequencing (WGS) was performed in 1119 children in a nested case–control study design. Telomere length was estimated from WGS data using five tools: Computel, Telseq, Telomerecat, qMotif and Motif_counter. The estimated median telomere length was 5.10 kb (IQR 4.52–5.68 kb) using Computel. The age when the blood sample was drawn had a significant negative correlation with telomere length (P = 0.003). European children, particularly those from Finland (P = 0.041) and from Sweden (P = 0.001), had shorter telomeres than children from the U.S.A. Paternal age (P = 0.019) was positively associated with telomere length. First-degree relative status, presence of gestational diabetes in the mother, and maternal age did not have a significant impact on estimated telomere length. HLA-DR4/4 or HLA-DR4/X children had significantly longer telomeres compared to children with HLA-DR3/3 or HLA-DR3/9 haplogenotypes (P = 0.008). Estimated telomere length was not significantly different with respect to any IA (P = 0.377), IAA-first (P = 0.248), GADA-first (P = 0.248) or T1D (P = 0.861). These results suggest that telomere length has no major impact on the risk for IA, the first step to develop T1D. Nevertheless, telomere length was shorter in the T1D high prevalence populations, Finland and Sweden.
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- 2022
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8. Integrated bioinformatic pipeline using whole-exome and RNAseq data to identify germline variants correlated with cancer
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Divya Sahu, Ajay Chatrath, Aakrosh Ratan, and Anindya Dutta
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Bioinformatics ,Cancer ,Genetics ,Genomics ,Sequencing ,RNAseq ,Science (General) ,Q1-390 - Abstract
Summary: Germline Variants (GVs) are effective in predicting cancer risk and may be relevant in predicting patient outcomes. Here we provide a bioinformatic pipeline to identify GVs from the TCGA lower grade glioma cohort in Genomics Data Commons. We integrate paired whole exome sequences from normal and tumor samples and RNA sequences from tumor samples to determine a patient’s GV status. We then identify the subset of GVs that are predictive of patient outcomes by Cox regression.For complete details on the use and execution of this protocol, please refer to Chatrath et al. (2019) and Chatrath et al. (2020).
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- 2022
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9. Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2
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Kushal Suryamohan, Devan Diwanji, Eric W. Stawiski, Ravi Gupta, Shane Miersch, Jiang Liu, Chao Chen, Ying-Ping Jiang, Frederic A. Fellouse, J. Fah Sathirapongsasuti, Patrick K. Albers, Tanneeru Deepak, Reza Saberianfar, Aakrosh Ratan, Gavin Washburn, Monika Mis, Devi Santhosh, Sneha Somasekar, G. H. Hiranjith, Derek Vargas, Sangeetha Mohan, Sameer Phalke, Boney Kuriakose, Aju Antony, Mart Ustav Jr, Stephan C. Schuster, Sachdev Sidhu, Jagath R. Junutula, Natalia Jura, and Somasekar Seshagiri
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Biology (General) ,QH301-705.5 - Abstract
Suryamohan, Diwanji, Stawiski et al. identify natural ACE2 variants that are predicted to alter virus–host interactions. They find that soluble ACE2 K26R and T92I variants are more effective in blocking the entry of SARS-CoV-2 S-protein pseudotyped virus, compared to wild-type ACE2. This study suggests that ACE2 variants may modulate the host susceptibility to SARS-CoV-2.
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- 2021
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10. Protocol for integrative subtyping of lower-grade gliomas using the SUMO pipeline
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Karolina Sienkiewicz and Aakrosh Ratan
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Bioinformatics ,Cancer ,Health Sciences ,Genomics ,Gene Expression ,Science (General) ,Q1-390 - Abstract
Summary: Grouping patients into subtypes with homogeneous molecular features can guide diagnosis and therapeutic interventions. SUMO is a computational pipeline that uses nonnegative matrix factorization of patient-similarity networks to integrate continuous multi-omic datasets for molecular subtyping of a disease. Here, we present a detailed protocol to demonstrate its use in determining subtypes of lower-grade gliomas by integrating gene expression, DNA methylation, and miRNA expression data from the TCGA-LGG cohort.For complete details on the use and execution of this profile, please refer to Sienkiewicz et al. (2022).
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- 2022
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11. Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation
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Celestia Fang, Zhenjia Wang, Cuijuan Han, Stephanie L. Safgren, Kathryn A. Helmin, Emmalee R. Adelman, Valentina Serafin, Giuseppe Basso, Kyle P. Eagen, Alexandre Gaspar-Maia, Maria E. Figueroa, Benjamin D. Singer, Aakrosh Ratan, Panagiotis Ntziachristos, and Chongzhi Zang
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CTCF ,3D genome organization ,Integrative analysis ,Gene regulation ,Transcription factor ,Enhancer ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Background The three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. As a key regulator of genome organization, CCCTC-binding factor (CTCF) has been characterized as a DNA-binding protein with important functions in maintaining the topological structure of chromatin and inducing DNA looping. Among the prolific binding sites in the genome, several events with altered CTCF occupancy have been reported as associated with effects in physiology or disease. However, hitherto there is no comprehensive survey of genome-wide CTCF binding patterns across different human cancers. Results To dissect functions of CTCF binding, we systematically analyze over 700 CTCF ChIP-seq profiles across human tissues and cancers and identify cancer-specific CTCF binding patterns in six cancer types. We show that cancer-specific lost and gained CTCF binding events are associated with altered chromatin interactions, partially with DNA methylation changes, and rarely with sequence mutations. While lost bindings primarily occur near gene promoters, most gained CTCF binding events exhibit enhancer activities and are induced by oncogenic transcription factors. We validate these findings in T cell acute lymphoblastic leukemia cell lines and patient samples and show that oncogenic NOTCH1 induces specific CTCF binding and they cooperatively activate expression of target genes, indicating transcriptional condensation phenomena. Conclusions Specific CTCF binding events occur in human cancers. Cancer-specific CTCF binding can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer.
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- 2020
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12. The pan-cancer landscape of prognostic germline variants in 10,582 patients
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Ajay Chatrath, Roza Przanowska, Shashi Kiran, Zhangli Su, Shekhar Saha, Briana Wilson, Takaaki Tsunematsu, Ji-Hye Ahn, Kyung Yong Lee, Teressa Paulsen, Ewelina Sobierajska, Manjari Kiran, Xiwei Tang, Tianxi Li, Pankaj Kumar, Aakrosh Ratan, and Anindya Dutta
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Germline variants ,Single nucleotide polymorphism ,Cancer biology ,Pan-cancer ,Survival analysis ,Tumor suppressor ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background While clinical factors such as age, grade, stage, and histological subtype provide physicians with information about patient prognosis, genomic data can further improve these predictions. Previous studies have shown that germline variants in known cancer driver genes are predictive of patient outcome, but no study has systematically analyzed multiple cancers in an unbiased way to identify genetic loci that can improve patient outcome predictions made using clinical factors. Methods We analyzed sequencing data from the over 10,000 cancer patients available through The Cancer Genome Atlas to identify germline variants associated with patient outcome using multivariate Cox regression models. Results We identified 79 prognostic germline variants in individual cancers and 112 prognostic germline variants in groups of cancers. The germline variants identified in individual cancers provide additional predictive power about patient outcomes beyond clinical information currently in use and may therefore augment clinical decisions based on expected tumor aggressiveness. Molecularly, at least 12 of the germline variants are likely associated with patient outcome through perturbation of protein structure and at least five through association with gene expression differences. Almost half of these germline variants are in previously reported tumor suppressors, oncogenes or cancer driver genes with the other half pointing to genomic loci that should be further investigated for their roles in cancers. Conclusions Germline variants are predictive of outcome in cancer patients and specific germline variants can improve patient outcome predictions beyond predictions made using clinical factors alone. The germline variants also implicate new means by which known oncogenes, tumor suppressor genes, and driver genes are perturbed in cancer and suggest roles in cancer for other genes that have not been extensively studied in oncology. Further studies in other cancer cohorts are necessary to confirm that germline variation is associated with outcome in cancer patients as this is a proof-of-principle study.
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- 2020
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13. Genomic Variants Among Threatened Acropora Corals
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Sheila. A. Kitchen, Aakrosh Ratan, Oscar C. Bedoya-Reina, Richard Burhans, Nicole D. Fogarty, Webb Miller, and Iliana B. Baums
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coral ,Caribbean ,single nucleotide polymorphism ,population genomics ,Galaxy ,Genetics ,QH426-470 - Abstract
Genomic sequence data for non-model organisms are increasingly available requiring the development of efficient and reproducible workflows. Here, we develop the first genomic resources and reproducible workflows for two threatened members of the reef-building coral genus Acropora. We generated genomic sequence data from multiple samples of the Caribbean A. cervicornis (staghorn coral) and A. palmata (elkhorn coral), and predicted millions of nucleotide variants among these two species and the Pacific A. digitifera. A subset of predicted nucleotide variants were verified using restriction length polymorphism assays and proved useful in distinguishing the two Caribbean acroporids and the hybrid they form (“A. prolifera”). Nucleotide variants are freely available from the Galaxy server (usegalaxy.org), and can be analyzed there with computational tools and stored workflows that require only an internet browser. We describe these data and some of the analysis tools, concentrating on fixed differences between A. cervicornis and A. palmata. In particular, we found that fixed amino acid differences between these two species were enriched in proteins associated with development, cellular stress response, and the host’s interactions with associated microbes, for instance in the ABC transporters and superoxide dismutase. Identified candidate genes may underlie functional differences in how these threatened species respond to changing environments. Users can expand the presented analyses easily by adding genomic data from additional species, as they become available.
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- 2019
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14. Germline variants predictive of tumor mutational burden and immune checkpoint inhibitor efficacy
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Ajay Chatrath, Aakrosh Ratan, and Anindya Dutta
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Genetics ,Genomics ,Cancer ,Science - Abstract
Summary: High tumor mutational burden (TMB) is associated with response to checkpoint blockade in several cancers. We identify pathogenic germline variants associated with increased TMB (GVITMB). GVITMB were found in 7 genes using a pan-cancer approach (APC, FANCL, SLC25A13, ERCC3, MSH6, PMS2, and TP53) and 38 gene sets (e.g., those involved in DNA repair and programmed cell death). GVITMB were also associated with mutational signatures related to the dysfunction of the gene carrying the variant, somatic mutations that further affect the gene or pathway with the variant, or transcriptomic changes concordant with the expected effect of the variant. In a validation cohort of 140 patients with cutaneous melanoma, we found that patients with GVITMB had prolonged progression-free survival (p = 0.0349, hazard ratio = 0.688) and responded favorably (p = 0.0341, odds = 1.842) when treated with immune checkpoint inhibitors. Our results suggest that germline variants can influence the molecular phenotypes of tumors and predict the response to immune checkpoint inhibitors.
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- 2021
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15. Human endogenous retrovirus-K mRNA expression and genomic alignment data in hepatoblastoma
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David F Grabski, Aakrosh Ratan, Laurie R Gray, Stefan Bekiranov, David Rekosh, Marie-Louise Hammarskjold, and Sara K Rasmussen
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Human endogenous retrovirus-K ,Hepatoblastoma ,Transcriptome analysis ,Genomic alignment ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
Human Endogenous Retroviruses are a class of genomic elements that are the result of ancient retroviral infection of the human germline. Many are biologically active elements that have been implicated in multiple diseases including cancer. The most recent class to invade the human genome is the HERV-K(HML-2) (HERV-K) family. Approximately 90 HERV-K proviruses and many smaller elements have been identified to date in the human genome. Additional proviruses are continually being discovered with the rapid advancement of deep-sequencing and long-read sequencing technologies. HERV-K proviruses are poorly annotated in human transcriptome databases making their analysis in RNA-seq data difficult. To enable analysis, we compiled the sequences of 91 HERV-K proviruses identified in NCBI GenBank (ID JN675007-JN675097) and created a proviral alignment tool for visualizing RNA-seq reads aligned across individual proviruses. This allowed us to analyse publicly available RNA-seq data from 10 hepatoblastoma samples and 3 normal liver controls (GEO Accession ID: GSE89775). This data report includes the raw FASTA sequence files of the HERV-K proviruses from NCBI, a differential gene expression list between hepatoblastoma samples, and genomic alignment figures from 5 HERV-K proviruses identified as differentially expressed in the companion research article “Upregulation of Human Endogenous Retrovirus-K (HML-2) mRNAs in hepatoblastoma: Identification of potential new immunotherapeutic targets and biomarkers [1]. The data provided here are available for other research groups interested in evaluating individual HERV-K proviral expression using RNA-seq data. Furthermore, the data analysis is highly flexible and will accommodate the addition of other HERV-K proviruses.
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- 2020
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16. SVXplorer: Three-tier approach to identification of structural variants via sequential recombination of discordant cluster signatures.
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Kunal Kathuria and Aakrosh Ratan
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Biology (General) ,QH301-705.5 - Abstract
The identification of structural variants using short-read data remains challenging. Most approaches that use discordant paired-end sequences ignore non-trivial signatures presented by variants containing 3 breakpoints, such as those generated by various copy-paste and cut-paste mechanisms. This can result in lower precision and sensitivity in the identification of the more common structural variants such as deletions and duplications. We present SVXplorer, which uses a graph-based clustering approach streamlined by the integration of non-trivial signatures from discordant paired-end alignments, split-reads and read depth information to improve upon existing methods. We show that SVXplorer is more sensitive and precise compared to several existing approaches on multiple real and simulated datasets. SVXplorer is available for download at https://github.com/kunalkathuria/SVXplorer.
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- 2020
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17. Genomic analysis of DNA repair genes and androgen signaling in prostate cancer
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Kasey Jividen, Katarzyna Z Kedzierska, Chun-Song Yang, Karol Szlachta, Aakrosh Ratan, and Bryce M Paschal
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Prostate cancer ,Androgen receptor ,DNA repair and DNA damage response ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The cellular effects of androgen are transduced through the androgen receptor, which controls the expression of genes that regulate biosynthetic processes, cell growth, and metabolism. Androgen signaling also impacts DNA damage signaling through mechanisms involving gene expression and transcription-associated DNA damaging events. Defining the contributions of androgen signaling to DNA repair is important for understanding androgen receptor function, and it also has translational implications. Methods We generated RNA-seq data from multiple prostate cancer lines and used bioinformatic analyses to characterize androgen-regulated gene expression. We compared the results from cell lines with gene expression data from prostate cancer xenografts, and patient samples, to query how androgen signaling and prostate cancer progression influences the expression of DNA repair genes. We performed whole genome sequencing to help characterize the status of the DNA repair machinery in widely used prostate cancer lines. Finally, we tested a DNA repair enzyme inhibitor for effects on androgen-dependent transcription. Results Our data indicates that androgen signaling regulates a subset of DNA repair genes that are largely specific to the respective model system and disease state. We identified deleterious mutations in the DNA repair genes RAD50 and CHEK2. We found that inhibition of the DNA repair enzyme MRE11 with the small molecule mirin inhibits androgen-dependent transcription and growth of prostate cancer cells. Conclusions Our data supports the view that crosstalk between androgen signaling and DNA repair occurs at multiple levels, and that DNA repair enzymes in addition to PARPs, could be actionable targets in prostate cancer.
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- 2018
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18. Data characterizing the chloroplast genomes of extinct and endangered Hawaiian endemic mints (Lamiaceae) and their close relatives
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Andreanna J. Welch, Katherine Collins, Aakrosh Ratan, Daniela I. Drautz-Moses, Stephan C. Schuster, and Charlotte Lindqvist
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Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
These data are presented in support of a plastid phylogenomic analysis of the recent radiation of the Hawaiian endemic mints (Lamiaceae), and their close relatives in the genus Stachys, “The quest to resolve recent radiations: Plastid phylogenomics of extinct and endangered Hawaiian endemic mints (Lamiaceae)” [1]. Here we describe the chloroplast genome sequences for 12 mint taxa. Data presented include summaries of gene content and length for these taxa, structural comparison of the mint chloroplast genomes with published sequences from other species in the order Lamiales, and comparisons of variability among three Hawaiian taxa vs. three outgroup taxa. Finally, we provide a list of 108 primer pairs targeting the most variable regions within this group and designed specifically for amplification of DNA extracted from degraded herbarium material. Keywords: Hawaii, Lamiaceae, Plastid genomes, Genome structure
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- 2016
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19. Giraffe genome sequence reveals clues to its unique morphology and physiology
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Morris Agaba, Edson Ishengoma, Webb C. Miller, Barbara C. McGrath, Chelsea N. Hudson, Oscar C. Bedoya Reina, Aakrosh Ratan, Rico Burhans, Rayan Chikhi, Paul Medvedev, Craig A. Praul, Lan Wu-Cavener, Brendan Wood, Heather Robertson, Linda Penfold, and Douglas R. Cavener
- Subjects
Science - Abstract
Giraffe’s unique anatomy and physiology include its stature and associated cardiovascular adaptation. Here, Douglas Cavener and colleagues provide de novogenome assemblies of giraffe and its closest relative okapi and provide comparative analyses to infer insights into evolution and adaptation.
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- 2016
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20. Elephantid Genomes Reveal the Molecular Bases of Woolly Mammoth Adaptations to the Arctic
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Vincent J. Lynch, Oscar C. Bedoya-Reina, Aakrosh Ratan, Michael Sulak, Daniela I. Drautz-Moses, George H. Perry, Webb Miller, and Stephan C. Schuster
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Biology (General) ,QH301-705.5 - Abstract
Woolly mammoths and living elephants are characterized by major phenotypic differences that have allowed them to live in very different environments. To identify the genetic changes that underlie the suite of woolly mammoth adaptations to extreme cold, we sequenced the nuclear genome from three Asian elephants and two woolly mammoths, and we identified and functionally annotated genetic changes unique to woolly mammoths. We found that genes with mammoth-specific amino acid changes are enriched in functions related to circadian biology, skin and hair development and physiology, lipid metabolism, adipose development and physiology, and temperature sensation. Finally, we resurrected and functionally tested the mammoth and ancestral elephant TRPV3 gene, which encodes a temperature-sensitive transient receptor potential (thermoTRP) channel involved in thermal sensation and hair growth, and we show that a single mammoth-specific amino acid substitution in an otherwise highly conserved region of the TRPV3 channel strongly affects its temperature sensitivity.
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- 2015
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21. Comparison of sequencing platforms for single nucleotide variant calls in a human sample.
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Aakrosh Ratan, Webb Miller, Joseph Guillory, Jeremy Stinson, Somasekar Seshagiri, and Stephan C Schuster
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Medicine ,Science - Abstract
Next-generation sequencings platforms coupled with advanced bioinformatic tools enable re-sequencing of the human genome at high-speed and large cost savings. We compare sequencing platforms from Roche/454(GS FLX), Illumina/HiSeq (HiSeq 2000), and Life Technologies/SOLiD (SOLiD 3 ECC) for their ability to identify single nucleotide substitutions in whole genome sequences from the same human sample. We report on significant GC-related bias observed in the data sequenced on Illumina and SOLiD platforms. The differences in the variant calls were investigated with regards to coverage, and sequencing error. Some of the variants called by only one or two of the platforms were experimentally tested using mass spectrometry; a method that is independent of DNA sequencing. We establish several causes why variants remained unreported, specific to each platform. We report the indel called using the three sequencing technologies and from the obtained results we conclude that sequencing human genomes with more than a single platform and multiple libraries is beneficial when high level of accuracy is required.
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- 2013
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22. Implementation of a Hamming distance-like genomic quantum classifier using inner products on ibmqx2 and ibmq_16_melbourne.
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Kunal Kathuria, Aakrosh Ratan, Michael McConnell, and Stefan Bekiranov
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- 2020
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23. Augmented Interval List: a novel data structure for efficient genomic interval search.
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Jianglin Feng, Aakrosh Ratan, and Nathan C. Sheffield
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- 2019
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24. SONiCS: PCR stutter noise correction in genome-scale microsatellites.
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Katarzyna Z. Kedzierska, Livia Gerber, Daniele Cagnazzi, Michael Krützen, Aakrosh Ratan, and Logan Kistler
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- 2018
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25. Supplementary Figure 6 from Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells
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Bryce M Paschal, David Wotton, Aakrosh Ratan, Tarek Abbas, Justin M Drake, Nicki Abianeh, Sachi B Tengse, Song Yi Bae, Natalia M Dworak, Krzysztof Wierbilowicz, and Chunsong Yang
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Extendend analysis of PARP7 expression in prostate cancer
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- 2023
26. Supplementary Figure 5 from Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells
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Bryce M Paschal, David Wotton, Aakrosh Ratan, Tarek Abbas, Justin M Drake, Nicki Abianeh, Sachi B Tengse, Song Yi Bae, Natalia M Dworak, Krzysztof Wierbilowicz, and Chunsong Yang
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FACS analysis of NCI-H660 cells for detection of necrosis and apoptosis
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- 2023
27. Supplementary Table 1 from Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells
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Bryce M. Paschal, David Wotton, Aakrosh Ratan, Tarek Abbas, Justin M. Drake, Nicki Abianeh, Sachi B. Tengse, Song Yi Bae, Natalia M. Dworak, Krzysztof Wierbiłowicz, and Chunsong Yang
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Supplementary Table 1: RBN2397 growth effects in prostate cencer cell lines
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- 2023
28. Supplementary Figure 4 from Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells
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Bryce M Paschal, David Wotton, Aakrosh Ratan, Tarek Abbas, Justin M Drake, Nicki Abianeh, Sachi B Tengse, Song Yi Bae, Natalia M Dworak, Krzysztof Wierbilowicz, and Chunsong Yang
- Abstract
RBN2397 inhibition of prostate cancer cell growth requires PARP7 over-expression
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- 2023
29. Supplementary Figure 1 from Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells
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Bryce M Paschal, David Wotton, Aakrosh Ratan, Tarek Abbas, Justin M Drake, Nicki Abianeh, Sachi B Tengse, Song Yi Bae, Natalia M Dworak, Krzysztof Wierbilowicz, and Chunsong Yang
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Cell cycle distributions of cell lines treated with RBN2397 plus androgen or plus AHR agonist
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- 2023
30. Supplementary Figure 2 from Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells
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Bryce M Paschal, David Wotton, Aakrosh Ratan, Tarek Abbas, Justin M Drake, Nicki Abianeh, Sachi B Tengse, Song Yi Bae, Natalia M Dworak, Krzysztof Wierbilowicz, and Chunsong Yang
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BBQ and FICZ treatment activates AHR signaling in prostate cancer cells
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- 2023
31. Data from Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells
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Bryce M. Paschal, David Wotton, Aakrosh Ratan, Tarek Abbas, Justin M. Drake, Nicki Abianeh, Sachi B. Tengse, Song Yi Bae, Natalia M. Dworak, Krzysztof Wierbiłowicz, and Chunsong Yang
- Abstract
The ADP-ribosyltransferase PARP7 modulates protein function by conjugating ADP-ribose to the side chains of acceptor amino acids. PARP7 has been shown to affect gene expression in prostate cancer cells and certain other cell types by mechanisms that include transcription factor ADP-ribosylation. Here, we use a recently developed catalytic inhibitor to PARP7, RBN2397, to study the effects of PARP7 inhibition in androgen receptor (AR)-positive and AR-negative prostate cancer cells. We find that RBN2397 has nanomolar potency for inhibiting androgen-induced ADP-ribosylation of the AR. RBN2397 inhibits the growth of prostate cancer cells in culture when cells are treated with ligands that activate the AR, or the aryl hydrocarbon receptor, and induce PARP7 expression. We show that the growth-inhibitory effects of RBN2397 are distinct from its enhancement of IFN signaling recently shown to promote tumor immunogenicity. RBN2397 treatment also induces trapping of PARP7 in a detergent-resistant fraction within the nucleus, which is reminiscent of how inhibitors such as talazoparib affect PARP1 compartmentalization. Because PARP7 is expressed in AR-negative metastatic tumors and RBN2397 can affect cancer cells through multiple mechanisms, PARP7 may be an actionable target in advanced prostate cancer.Significance:RBN2397 is a potent and selective inhibitor of PARP7 that reduces the growth of prostate cancer cells, including a model for treatment-emergent neuroendocrine prostate cancer. RBN2397 induces PARP7 trapping on chromatin, suggesting its mechanism of action might be similar to clinically used PARP1 inhibitors.
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- 2023
32. All Supplementary Figures and Tables from The Germline Variants rs61757955 and rs34988193 Are Predictive of Survival in Lower Grade Glioma Patients
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Anindya Dutta, Aakrosh Ratan, Pankaj Kumar, Manjari Kiran, and Ajay Chatrath
- Abstract
S1. A boxplot representing the percentage of variants called in the whole exome sequenced (WXS) tumor sample that is likely somatic mutations. S2. Correlation between the variant allele frequencies calculated from the four variant sets and the distribution of allele frequencies. S3. Principal components calculated from germline variants from the whole exome sequencing data from the non-tumor samples. S4. Kaplan-Meier plot for the germline variant rs28672782 in BRSK2. Table S1. Quality control checks reveal that somatic mutations and RNA editing did not affect the results of our analysis. Table S2. Correlation between the allele frequencies calculated in our four variant sets and the allele frequencies reported by gnomAD. Table S3. Variants genetically linked to rs61757955 in the European population, the population that is most similar to the TCGA lower grade glioma patient population. Table S4. Results from testing for an association between the germline variant rs34988193 and genomic and histological variables.
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- 2023
33. Structural variation across 138,134 samples in the TOPMed consortium
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Goo Jun, Adam English, Ginger Metcalf, Jianzhi Yang, Mark Chaisson, Nathan Pankratz, Vipin Menon, William Salerno, Olga Krasheninina, Albert Smith, John Lane, Thomas Blackwell, Hyun Min Kang, Sejal Salvi, Qingchang Meng, Hua Shen, Divya Pasham, Sravya Bhamidipati, Kavya Kottapalli, Donna Arnett, Allison Ashley-Koch, Paul Auer, KAthleen Beutel, Joshua Bis, John Blangero, Donald Bowden, Jennifer Brody, Brian Cade, Yii-Der Ida Chen, Michael Cho, Joanne Curran, Myriam Fornage, Barry Frredman, Tasha Fingerlin, Bruce Gelb, Lifang Hou, Yi-Jen Hung, John P Kane, Robert Kaplan, Wonji Kim, Ruth Loos, Gregory Marcus, Rasika Mathias, Stephen McGarvey, Courtney Montgomery, Take Naseri, Seyed Nouraie, Michael Preuss, Nicholette Palmer, Patricia Peyser, Laura Raffield, Aakrosh Ratan, Susan Redline, Muagututia Reupena, Jerome Rotter, Stephen Rich, Michiel Rienstra, Ingo Ruczinski, Vijay Sankaran, David Schwartz, Christine Seidman, Jonathan Seidman, Edwin Silverman, Jennifer Smith, Adrienne Stilp, Kent Taylor, Marilyn Telen, Scott Weiss, L. Keoki Williams, Baojun Wu, Lisa Yanek, Yingze Zhang, Jessica Lasky-Su, Marie-Claude Gingras, Susan Dutcher, Evan Eichler, Stacey Gabriel, Soren Germer, Ryan Kim, Karine Martinez, Deborah Nickerson, James Luo, Alexander Reiner, Richard Gibbs, Eric Boerwinkle, Goncaol Abecasis, and Fritz Sedlazeck
- Subjects
Article - Abstract
Ever larger Structural Variant (SV) catalogs highlighting the diversity within and between populations help researchers better understand the links between SVs and disease. The identification of SVs from DNA sequence data is non-trivial and requires a balance between comprehensiveness and precision. Here we present a catalog of 355,667 SVs (59.34% novel) across autosomes and the X chromosome (50bp+) from 138,134 individuals in the diverse TOPMed consortium. We describe our methodologies for SV inference resulting in high variant quality and >90% allele concordance compared to long-read de-novo assemblies of well-characterized control samples. We demonstrate utility through significant associations between SVs and important various cardio-metabolic and hematologic traits. We have identified 690 SV hotspots and deserts and those that potentially impact the regulation of medically relevant genes. This catalog characterizes SVs across multiple populations and will serve as a valuable tool to understand the impact of SV on disease development and progression.
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- 2023
34. Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease
- Author
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Daniel H. Katz, Usman A. Tahir, Alexander G. Bick, Akhil Pampana, Debby Ngo, Mark D. Benson, Zhi Yu, Jeremy M. Robbins, Zsu-Zsu Chen, Daniel E. Cruz, Shuliang Deng, Laurie Farrell, Sumita Sinha, Alec A. Schmaier, Dongxiao Shen, Yan Gao, Michael E. Hall, Adolfo Correa, Russell P. Tracy, Peter Durda, Kent D. Taylor, Yongmei Liu, W. Craig Johnson, Xiuqing Guo, Jie Yao, Yii-Der Ida Chen, Ani W. Manichaikul, Deepti Jain, Claude Bouchard, Mark A. Sarzynski, Stephen S. Rich, Jerome I. Rotter, Thomas J. Wang, James G. Wilson, Pradeep Natarajan, Robert E. Gerszten, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Namrata Gupta, David M. Haas, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O’Connell, Tim O’Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi’a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Scott T. Weiss, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Michael Zody, and Sebastian Zoellner
- Subjects
Adult ,Male ,Proteomics ,Aging ,Whole genome sequence analysis ,Proteome ,Clinical Sciences ,Black People ,Disease ,Computational biology ,race and ethnicity ,Cardiorespiratory Medicine and Haematology ,Cardiovascular ,Article ,proteomics ,cardiovascular disease ,Physiology (medical) ,Genetics ,2.1 Biological and endogenous factors ,Humans ,Medicine ,Aetiology ,Lung ,Heart Disease - Coronary Heart Disease ,and Blood Institute TOPMed (Trans-Omics for Precision Medicine) Consortium† ,business.industry ,Prevention ,Human Genome ,National Heart ,Genomics ,Blood proteins ,Genetic architecture ,Heart Disease ,Good Health and Well Being ,Cardiovascular System & Hematology ,Cardiovascular Diseases ,Public Health and Health Services ,Female ,Cardiology and Cardiovascular Medicine ,business ,Biotechnology ,Genome-Wide Association Study - Abstract
Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.
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- 2022
35. 54 Prognostic value of T cell immunoscore estimated from transcriptomic data in patients with advanced malignancies treated with immune checkpoint inhibitors
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Ahmad Tarhini, Payman Ghasemi Saghand, Aik Choon Tan, James Chen, Aakrosh Ratan, Martin McCarter, John Carpton, Howard Colman, Alexandra Ikeguchi, Igor Puzanov, Susanne Arnold, Michelle Churchman, Patrick Hwu, Jose Conejo-Garcia, William (Bill) Dalton, George Weiner, and Issam El Naqa
- Published
- 2022
36. 1279 A novel graphical deep neural network learning approach utilizing molecular data for optimizing patient selection for treatment with immune checkpoint inhibitors: An ORIEN pan-cancer study
- Author
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Issam El Naqa, Payman Ghasemi, Aik Choon Tan, James Chen, Aakrosh Ratan, Martin McCarter, John Carpten, Howard Colman, Alexandra Ikeguchi, Igor Puzanov, Susanne Arnold, Michelle Churchman, Patrick Hwu, Jose Conejo-Garcia, William (Bill) Dalton, George Weiner, and Ahmad Tarhini
- Published
- 2022
37. 1147 Differences in co-expression of T cell co-inhibitory and co-stimulatory molecules with PD1 across different human cancers
- Author
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Ahmad Tarhini, Dale Hedges, Aik Choon Tan, Paulo Rodriguez, Vineeth Sukrithan, Aakrosh Ratan, Martin McCarter, John Carpten, Howard Colman, Alexandra Ikeguchi, Igor Puzanov, Susanne Arnold, Michelle Churchman, Patrick Hwu, Jose Conejo-Garcia, William (Bill) Dalton, and George Weiner
- Published
- 2022
38. Identification of indels in next-generation sequencing data.
- Author
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Aakrosh Ratan, Thomas L. Olson, Thomas P. Loughran, and Webb Miller
- Published
- 2015
- Full Text
- View/download PDF
39. Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells
- Author
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Chunsong Yang, Krzysztof Wierbiłowicz, Natalia M. Dworak, Song Yi Bae, Sachi B. Tengse, Nicki Abianeh, Justin M. Drake, Tarek Abbas, Aakrosh Ratan, David Wotton, and Bryce M. Paschal
- Abstract
The ADP-ribosyltransferase PARP7 modulates protein function by conjugating ADP-ribose to the side chains of acceptor amino acids. PARP7 has been shown to affect gene expression in prostate cancer cells and certain other cell types by mechanisms that include transcription factor ADP-ribosylation. Here, we use a recently developed catalytic inhibitor to PARP7, RBN2397, to study the effects of PARP7 inhibition in androgen receptor-positive and androgen receptor-negative prostate cancer cells. We find that RBN2397 has nanomolar potency for inhibiting androgen-induced ADP-ribosylation of the androgen receptor. RBN2397 inhibits the growth of prostate cancer cells in culture when cells are treated with ligands that activate the androgen receptor, or the aryl hydrocarbon receptor, and induce PARP7 expression. We show that the growth inhibitory effects of RBN2397 are distinct from its enhancement of interferon signaling recently shown to promote tumor immunogenicity. RBN2397 treatment also induces trapping of PARP7 in a detergentresistant fraction within the nucleus, which is reminiscent of how inhibitors such as Talazoparib affect PARP1 fractionation. Because PARP7 is expressed in AR negative metastatic tumors and RBN2397 can affect cancer cells through multiple mechanisms, PARP7 may be an actionable target in advanced prostate cancer.SignificanceRBN2397 is a potent and selective inhibitor of PARP7 that reduces the growth of prostate cancer cells, including a model for treatment-emergent neuroendocrine prostate cancer. RBN2397 induces PARP7 trapping on chromatin, suggesting its mechanism of action might be similar to clinically-used PARP1 inhibitors.
- Published
- 2022
40. A Heuristic Algorithm for Reconstructing Ancestral Gene Orders with Duplications.
- Author
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Jian Ma 0004, Aakrosh Ratan, Louxin Zhang, Webb Miller, and David Haussler
- Published
- 2007
- Full Text
- View/download PDF
41. Genetic Variation in Reproductive Investment Across an Ephemerality Gradient in Daphnia pulex
- Author
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Karen B Barnard-Kubow, Dörthe Becker, Connor S Murray, Robert Porter, Grace Gutierrez, Priscilla Erickson, Joaquin C B Nunez, Erin Voss, Kushal Suryamohan, Aakrosh Ratan, Andrew Beckerman, and Alan O Bergland
- Subjects
Male ,Polymorphism, Genetic ,Daphnia ,Reproduction ,Quantitative Trait Loci ,Genetics ,Animals ,Genetic Variation ,Molecular Biology ,Adaptation, Physiological ,Ecology, Evolution, Behavior and Systematics - Abstract
Species across the tree of life can switch between asexual and sexual reproduction. In facultatively sexual species, the ability to switch between reproductive modes is often environmentally dependent and subject to local adaptation. However, the ecological and evolutionary factors that influence the maintenance and turnover of polymorphism associated with facultative sex remain unclear. We studied the ecological and evolutionary dynamics of reproductive investment in the facultatively sexual model species, Daphnia pulex. We found that patterns of clonal diversity, but not genetic diversity varied among ponds consistent with the predicted relationship between ephemerality and clonal structure. Reconstruction of a multi-year pedigree demonstrated the coexistence of clones that differ in their investment into male production. Mapping of quantitative variation in male production using lab-generated and field-collected individuals identified multiple putative quantitative trait loci (QTL) underlying this trait, and we identified a plausible candidate gene. The evolutionary history of these QTL suggests that they are relatively young, and male limitation in this system is a rapidly evolving trait. Our work highlights the dynamic nature of the genetic structure and composition of facultative sex across space and time and suggests that quantitative genetic variation in reproductive strategy can undergo rapid evolutionary turnover.
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- 2022
42. Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias
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Cait E. Hamele, Mariella F. Toro, Emily Farber, Jeffrey C. Xing, Cheryl A. Keller, Kristine C. Olson, Umadevi Paila, Suna Onengut-Gumuscu, Thomas L. Olson, Thomas P. Loughran, Aakrosh Ratan, Yaseswini Neelamraju, Shriram K. Sundararaman, Matt Schmachtenberg, Hee Jin Cheon, David J. Feith, Ross C. Hardison, Bryna C. Shemo, and Francine E. Garrett-Bakelman
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Male ,Lymphocyte ,Immunology ,Bisulfite sequencing ,Mutant ,Biology ,Gene mutation ,medicine.disease_cause ,Biochemistry ,Epigenesis, Genetic ,Dioxygenases ,Pathogenesis ,medicine ,Humans ,Registries ,Mutation ,Lymphoid Neoplasia ,Leukemia ,Lymphoma, T-Cell, Peripheral ,Cell Biology ,Hematology ,medicine.disease ,Neoplasm Proteins ,Killer Cells, Natural ,DNA-Binding Proteins ,Leukemia, Large Granular Lymphocytic ,medicine.anatomical_structure ,Chronic Disease ,Absolute neutrophil count ,Female - Abstract
Chronic natural killer large granular lymphocyte (NK-LGL) leukemia, also referred to as chronic lymphoproliferative disorder of NK cells, is a rare disorder defined by prolonged expansion of clonal NK cells. Similar prevalence of STAT3 mutations in chronic T-LGL and NK-LGL leukemia is suggestive of common pathogenesis. We undertook whole-genome sequencing to identify mutations unique to NK-LGL leukemia. The results were analyzed to develop a resequencing panel that was applied to 58 patients. Phosphatidylinositol 3-kinase pathway gene mutations (PIK3CD/PIK3AP1) and TNFAIP3 mutations were seen in 5% and 10% of patients, respectively. TET2 was exceptional in that mutations were present in 16 (28%) of 58 patient samples, with evidence that TET2 mutations can be dominant and exclusive to the NK compartment. Reduced-representation bisulfite sequencing revealed that methylation patterns were significantly altered in TET2 mutant samples. The promoter of TET2 and that of PTPRD, a negative regulator of STAT3, were found to be methylated in additional cohort samples, largely confined to the TET2 mutant group. Mutations in STAT3 were observed in 19 (33%) of 58 patient samples, 7 of which had concurrent TET2 mutations. Thrombocytopenia and resistance to immunosuppressive agents were uniquely observed in those patients with only TET2 mutation (Games-Howell post hoc test, P = .0074; Fisher’s exact test, P = .00466). Patients with STAT3 mutation, inclusive of those with TET2 comutation, had lower hematocrit, hemoglobin, and absolute neutrophil count compared with STAT3 wild-type patients (Welch’s t test, P ≤ .015). We present the discovery of TET2 mutations in chronic NK-LGL leukemia and evidence that it identifies a unique molecular subtype.
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- 2021
43. Abstract 5703: The immune cell state atlas analysis predicts therapeutic benefits with immune checkpoint inhibitors
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Tingyi Li, Vineeth Sukrithan, Aakrosh Ratan, Martin McCarter, John Carpten, Howard Colman, Alexandra P. Ikeguchi, Igor Puzanov, Susanne Arnold, Michelle Churchman, Patrick Hwu, Paulo C. Rodriguez, William S. Dalton, George J. Weiner, Ahmad Tarhini, and Xuefeng Wang
- Subjects
Cancer Research ,Oncology - Abstract
Introduction: In this study, we investigated the prognostic role of the immune cell state atlas in predicting therapeutic benefits of patients treated with immune checkpoint inhibitors (ICI) within the ORIEN network of 18 collaborating cancer centers under the Total Cancer Care protocol. Methods: We utilized RNA-seq data of 926 samples generated from 875 individuals. Gene expression data were deconvoluted for immune cell states using the Carcinoma EcoTyper software. We then conducted a series of survival analyses to test the association between survival outcomes and predicted cell types and states in five malignant tumors: Genitourinary (GU), Gastrointestinal (GI), Thoracic (THO), Cutaneous (CUT), Head & Neck (H&N). The regularized Cox regression model in R package ‘glmnet’ was then applied to select the complementary pathway signatures (including gene ontology and KEGG pathways) to the immune cell states in predicting survival outcomes. We also explored the immune-related long non-coding RNAs (lncRNA) as potential biomarkers for cell states and patient outcomes. Results: EcoTyper analysis revealed that 692 (~80%) of patients were assigned to the 10 pre-identified Carcinoma Ecotypes (CE1 to CE10) or cell state atlas group. Overall, two immune deficiency ecotype patient groups (CE1 and CE2) pre-identified based on the independent training data were linked to worse survival, while two proinflammatory ecotype groups (CE9 and CE10) were associated with favorable surxvival. Those ecotype groups showed strong prognostic significance in predicting OS in melanoma and H&N. Meanwhile, CE6, a non-neoplastic tissue enriched cell subtype, was also found to be highly associated with longer OS in H&N and GU. CE7, an age-related mutation patient subgroup, contributed to shorter survival in both melanoma and GI. We also found that a subset of activated B cell state and the exhausted/effector CD4 T cell state were significantly associated with patient survival in melanoma and GU, respectively. The penalized Cox regression model revealed that β-catenin signaling pathway, P53 pathway and heme metabolism in the MSigDB Hallmark gene sets are the most complementary pathways to the ecotype scores in multiple cancer types. In additional, multiple pathways in KEGG such as endocytosis were found to jointly contribute to the ecotype-pathway composite prognostic model. In anazlying immune-related lncRNA biomarkers, we highlighted the prognostic role of NKILA in our dataset, which has been studied to promote tumor immune evasion. Conclusion: Our analysis has successfully established the utility of immune cell state atlas in predicting therapeutic benefits with ICIs. We expect that the discovered complementary signatures in the cancer-cell compartment will also lead to a novel spectrum of tumor-based biomarkers to ICI. Citation Format: Tingyi Li, Vineeth Sukrithan, Aakrosh Ratan, Martin McCarter, John Carpten, Howard Colman, Alexandra P. Ikeguchi, Igor Puzanov, Susanne Arnold, Michelle Churchman, Patrick Hwu, Paulo C. Rodriguez, William S. Dalton, George J. Weiner, Ahmad Tarhini, Xuefeng Wang. The immune cell state atlas analysis predicts therapeutic benefits with immune checkpoint inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5703.
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- 2023
44. The Indian cobra reference genome and transcriptome enables comprehensive identification of venom toxins
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Meredith Sagolla, Gus A. Wright, Hiroki Shibata, Ying Jiun J. Chen, Dinesh Velayutham, Meng Wu, Rajadurai Chinnasamy Perumal, Ivan Koludarov, Sangeetha Mohan, Kate Senger, Eric Stawiski, Subhra Chaudhuri, Peter Liu, Brendan Faherty, Aju Antony, Kristen Wiley, Rami N. Hannoush, Matthew Jevit, Oommen K. Mathew, Mandumpala Davis Dixon, Arun Zachariah, Ridhi Goel, Leonard D. Goldstein, Guillermo de la Rosa, Terje Raudsepp, Jeremy Stinson, Sajesh Puthenpurackal Krishnankutty, James Ziai, Zora Modrusan, Donald S. Kirkpatrick, Steffen Durinck, Joseph Guillory, Kushal Suryamohan, Megha Muraleedharan, R. Manjunatha Kini, Aakrosh Ratan, Markus S. Schröder, Miriam Baca, Somasekar Seshagiri, Domagoj Vucic, Boney Kuriakose, and Derek Vargas
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Naja ,Antivenom ,India ,Sequence Homology ,Venom ,Computational biology ,Biology ,ENCODE ,Genome ,complex mixtures ,Article ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,Animals ,Amino Acid Sequence ,DNA sequencing ,Transcriptomics ,030304 developmental biology ,Elapid Venoms ,0303 health sciences ,Gene Expression Profiling ,Naja naja ,Computational Biology ,RNA sequencing ,Genomics ,biology.organism_classification ,Sequence annotation ,Indian cobra ,030217 neurology & neurosurgery ,Reference genome - Abstract
Snakebite envenoming is a serious and neglected tropical disease that kills ~100,000 people annually. High-quality, genome-enabled comprehensive characterization of toxin genes will facilitate development of effective humanized recombinant antivenom. We report a de novo near-chromosomal genome assembly of Naja naja, the Indian cobra, a highly venomous, medically important snake. Our assembly has a scaffold N50 of 223.35 Mb, with 19 scaffolds containing 95% of the genome. Of the 23,248 predicted protein-coding genes, 12,346 venom-gland-expressed genes constitute the ‘venom-ome’ and this included 139 genes from 33 toxin families. Among the 139 toxin genes were 19 ‘venom-ome-specific toxins’ (VSTs) that showed venom-gland-specific expression, and these probably encode the minimal core venom effector proteins. Synthetic venom reconstituted through recombinant VST expression will aid in the rapid development of safe and effective synthetic antivenom. Additionally, our genome could serve as a reference for snake genomes, support evolutionary studies and enable venom-driven drug discovery., Analysis of a near-chromosomal genome assembly and transcriptome profiling of the Indian cobra identifies genes expressed in the venom glands. These data should help develop a new antivenom.
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- 2020
45. DUPCAR: Reconstructing Contiguous Ancestral Regions with Duplications.
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Jian Ma 0004, Aakrosh Ratan, Brian J. Raney, Bernard B. Suh, Louxin Zhang, Webb Miller, and David Haussler
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- 2008
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46. The infinite sites model of genome evolution.
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Jian Ma 0004, Aakrosh Ratan, Brian J. Raney, Bernard B. Suh, Webb Miller, and David Haussler
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- 2008
- Full Text
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47. Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma
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Priyadarshini Kachroo, Julian Hecker, Bo L. Chawes, Tarunveer S. Ahluwalia, Michael H. Cho, Dandi Qiao, Rachel S. Kelly, Su H. Chu, Yamini V. Virkud, Mengna Huang, Kathleen C. Barnes, Esteban G. Burchard, Celeste Eng, Donglei Hu, Juan C. Celedón, Michelle Daya, Albert M. Levin, Hongsheng Gui, L. Keoki Williams, Erick Forno, Angel C.Y. Mak, Lydiana Avila, Manuel E. Soto-Quiros, Michelle M. Cloutier, Edna Acosta-Pérez, Glorisa Canino, Klaus Bønnelykke, Hans Bisgaard, Benjamin A. Raby, Christoph Lange, Scott T. Weiss, Jessica A. Lasky-Su, Namiko Abe, Goncalo Abecasis, Christine Albert, Nicholette (Nichole) Palmer Allred, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Terri Beaty, Diane Becker, Lewis Becker, Rebecca Beer, Ferdouse Begum, Amber Beitelshees, Emelia Benjamin, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Ingrid Borecki, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Esteban Burchard, Jonathan Cardwell, Cara Carty, Richard Casaburi, James Casella, Mark Chaffin, Christy Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sayantan Das, Sean David, Colleen Davis, Mariza de Andrade, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Ron Do, Qing Duan, Ravi Duggirala, Peter Durda, Susan Dutcher, Charles Eaton, Lynette Ekunwe, Patrick Ellinor, Leslie Emery, Charles Farber, Leanna Farnam, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Yan Gao, Margery Gass, Bruce Gelb, Xiaoqi (Priscilla) Geng, Soren Germer, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, C. Charles Gu, Yue Guan, Xiuqing Guo, Jeff Haessler, Michael Hall, Daniel Harris, Nicola Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, John Hokanson, Kramer Holly, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Min A. Jhun, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Sekar Kathiresan, Laura Kaufman, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Greg Kinney, Barbara Konkle, Charles Kooperberg, Stephanie Krauter, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Yun Li, Honghuang Lin, Keng Han Lin, Simin Liu, Yongmei Liu, Ruth Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Michael Mahaney, Barry Make, Ani Manichaikul, JoAnn Manson, Lauren Margolin, Lisa Martin, Susan Mathai, Rasika Mathias, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Hao Mei, Deborah A. Meyers, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton Mitchell, May E. Montasser, Solomon Musani, Stanford Mwasongwe, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Pradeep Natarajan, Sergei Nekhai, Deborah Nickerson, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, James Pankow, George Papanicolaou, Margaret Parker, Afshin Parsa, Sara Penchev, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Sam Phillips, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Dmitry Prokopenko, Bruce Psaty, Pankaj Qasba, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Vasan Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Elizabeth Regan, Alex Reiner, Ken Rice, Stephen Rich, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Phuwanat Sakornsakolpat, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Vijay Sankaran, Christopher Scheller, Ellen Schmidt, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Vivien Sheehan, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Tamar Sofer, Nona Sotoodehnia, Adrienne Stilp, Elizabeth Streeten, Yun Ju Sung, Jessica Su-Lasky, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Lesley Tinker, David Tirschwell, Hemant Tiwari, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Emily Wan, Fei Fei Wang, Karol Watson, Daniel E. Weeks, Bruce Weir, Scott Weiss, Lu-Chen Weng, Cristen Willer, Kayleen Williams, Carla Wilson, James Wilson, Quenna Wong, Huichun Xu, Lisa Yanek, Ivana Yang, Rongze Yang, Norann Zaghloul, Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiuwen Zheng, Degui Zhi, Xiang Zhou, Michael Zody, and Sebastian Zoellner
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Adult ,Costa Rica ,Male ,Pulmonary and Respiratory Medicine ,Adolescent ,Vital Capacity ,Single-nucleotide polymorphism ,Pedigree chart ,Critical Care and Intensive Care Medicine ,Young Adult ,03 medical and health sciences ,FEV1/FVC ratio ,0302 clinical medicine ,Polymorphism (computer science) ,Forced Expiratory Volume ,Humans ,Medicine ,SNP ,030212 general & internal medicine ,Child ,Asthma ,Whole Genome Sequencing ,business.industry ,Middle Aged ,respiratory system ,medicine.disease ,respiratory tract diseases ,Minor allele frequency ,030228 respiratory system ,Genetic epidemiology ,Child, Preschool ,Interferon Regulatory Factors ,Immunology ,Respiratory Physiological Phenomena ,Female ,Cardiology and Cardiovascular Medicine ,business ,Cell Adhesion Molecules - Abstract
BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.
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- 2019
48. The GenomeAsia 100K Project enables genetic discoveries across Asia
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Manjari Deshmukh, Stephan C. Schuster, Jong Il Kim, Venkatesan Radha, Partha P. Majumder, Herawati Sudoyo, Somasekar Seshagiri, John C. Chambers, Kok-Gan Chan, R. Rand Allingham, Vladimir Kharkov, Arkasubhra Ghosh, Ravi Gupta, Changhoon Kim, Keith C. Cheng, Lukas Forer, Thiramsett Sattibabu, Qixin Bei, Jeremy Stinson, Murray P. Cox, J. Stephen Lansing, Joseph Guillory, Akshi Bassi, Purushothaman Natarajan, Vadim Stepanov, George Koki, Markus S. Schröder, Ramesh Menon, Santosh Gopi Krishna Gadde, Elena S. Gusareva, Nidhan K. Biswas, Analabha Basu, Christian Fuchsberger, Michael A. Hauser, Santiago-Turla, Sandhya Nair, Mahesh Pratapneni, Sivasankar Malaichamy, Sebastian Schoenherr, Jonathan S. Friedlaender, Seik-Soon Khor, Jeong-Sun Seo, Aakrosh Ratan, Vivek Gopalan, Jeffrey D. Wall, Madasamy Parani, Tatiana M. Karafet, Viswanathan Mohan, Rikky W. Purbojati, Steffen Durinck, Anjali Verma, Kushal Suryamohan, Vedam L. Ramprasad, Badrul Munir Md-Zain, Phalkek Sameer, Andrew S. Peterson, Jong-Yeon Shin, Hie Lim Kim, Eric Stawiski, Joyner T. George, Michael F. Hammer, Katsushi Tokunaga, Jiani Li, Khai C. Ang, Sam Santhosh, Jennifer Tom, Syed Qasim Mehdi, Belong Cho, Tushar Bhangale, Asian School of the Environment, Lee Kong Chian School of Medicine (LKCMedicine), and Complexity Institute
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Asia ,Genotype ,Population structure ,Population ,Datasets as Topic ,Disease ,Article ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Genetic variation ,Humans ,Medicine [Science] ,education ,Alleles ,030304 developmental biology ,Genetic association ,0303 health sciences ,education.field_of_study ,Multidisciplinary ,Genome, Human ,Geography ,Evolutionary biology ,Genetic Discoveries ,030217 neurology & neurosurgery ,Imputation (genetics) ,Founder effect ,Reference genome ,Genome-Wide Association Study - Abstract
The underrepresentation of non-Europeans in human genetic studies so far has limited the diversity of individuals in genomic datasets and led to reduced medical relevance for a large proportion of the world’s population. Population-specific reference genome datasets as well as genome-wide association studies in diverse populations are needed to address this issue. Here we describe the pilot phase of the GenomeAsia 100K Project. This includes a whole-genome sequencing reference dataset from 1,739 individuals of 219 population groups and 64 countries across Asia. We catalogue genetic variation, population structure, disease associations and founder effects. We also explore the use of this dataset in imputation, to facilitate genetic studies in populations across Asia and worldwide., Using whole-genome sequencing data from 1,739 individuals, the GenomeAsia 100K Project catalogues genetic variation, population structure and disease associations to facilitate genetic studies in Asian populations and increase representation in genetics studies worldwide.
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- 2019
49. Genomic analyses of the metastasis-derived prostate cancer cell lines LNCaP, VCaP, and PC3-AR
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Karolina Sienkiewicz, Chunsong Yang, Bryce M. Paschal, and Aakrosh Ratan
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Male ,Whole Genome Sequencing ,Urology ,Cell Cycle ,Prostatic Neoplasms ,Bone Neoplasms ,Adenocarcinoma ,DNA Mismatch Repair ,Polymorphism, Single Nucleotide ,Article ,Oncology ,Cell Line, Tumor ,Lymphatic Metastasis ,Mutation ,PC-3 Cells ,Humans ,Neoplasm Invasiveness ,Neoplasm Metastasis ,Gene Deletion - Abstract
BACKGROUND: The lymph node metastasis-derived LNCaP, the bone metastasis-derived PC3 (skull), and VCaP (vertebral) cell lines are widely used as preclinical models of human prostate cancer (CaP) and have been described in more than 19,000 publications. Here, we report on short-read whole-genome sequencing and genomic analyses of LNCaP, VCaP, and PC3 cells stably transduced with WT AR (PC3-AR). METHODS: LNCaP, VCaP, and PC3-AR cell lines were sequenced to an average depth of more than 30-fold using Illumina short-read sequencing. Using various computational methods, we identified and compared the single-nucleotide variants, copy-number profiles, and the structural variants observed in the three cell lines. RESULTS: LNCaP cells are composed of multiple subpopulations, which results in nonintegral copy number states and a high mutational load when the data is analyzed in bulk. All three cell lines contain pathogenic mutations and homozygous deletions in genes involved in DNA mismatch repair, along with deleterious mutations in cell-cycle, Wnt signaling, and other critical cellular processes. PC3-AR cells have a truncating mutation in TP53 and do not express the p53 protein. The VCaP cells contain a homozygous gain-of-function mutation in TP53 (p.R248W) that promotes cancer invasion, metastasis, and progression and has also been observed in prostate adenocarcinomas. In addition, we detect the signatures of chromothripsis of the q arms of chromosome 5 in both PC3-AR and VCaP cells, strengthening the association of TP53 inactivation with chromothripsis reported in other systems. CONCLUSIONS: Our work provides a resource for genetic, genomic, and biological studies employing these commonly-used prostate cancer cell lines.
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- 2021
50. Author Correction: Comparative and demographic analysis of orang-utan genomes
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Devin P. Locke, LaDeana W. Hillier, Wesley C. Warren, Kim C. Worley, Lynne V. Nazareth, Donna M. Muzny, Shiaw-Pyng Yang, Zhengyuan Wang, Asif T. Chinwalla, Pat Minx, Makedonka Mitreva, Lisa Cook, Kim D. Delehaunty, Catrina Fronick, Heather Schmidt, Lucinda A. Fulton, Robert S. Fulton, Joanne O. Nelson, Vincent Magrini, Craig Pohl, Tina A. Graves, Chris Markovic, Andy Cree, Huyen H. Dinh, Jennifer Hume, Christie L. Kovar, Gerald R. Fowler, Gerton Lunter, Stephen Meader, Andreas Heger, Chris P. Ponting, Tomas Marques-Bonet, Can Alkan, Lin Chen, Ze Cheng, Jeffrey M. Kidd, Evan E. Eichler, Simon White, Stephen Searle, Albert J. Vilella, Yuan Chen, Paul Flicek, Jian Ma, Brian Raney, Bernard Suh, Richard Burhans, Javier Herrero, David Haussler, Rui Faria, Olga Fernando, Fleur Darré, Domènec Farré, Elodie Gazave, Meritxell Oliva, Arcadi Navarro, Roberta Roberto, Oronzo Capozzi, Nicoletta Archidiacono, Giuliano Della Valle, Stefania Purgato, Mariano Rocchi, Miriam K. Konkel, Jerilyn A. Walker, Brygg Ullmer, Mark A. Batzer, Arian F. A. Smit, Robert Hubley, Claudio Casola, Daniel R. Schrider, Matthew W. Hahn, Victor Quesada, Xose S. Puente, Gonzalo R. Ordoñez, Carlos López-Otín, Tomas Vinar, Brona Brejova, Aakrosh Ratan, Robert S. Harris, Webb Miller, Carolin Kosiol, Heather A. Lawson, Vikas Taliwal, André L. Martins, Adam Siepel, Arindam RoyChoudhury, Xin Ma, Jeremiah Degenhardt, Carlos D. Bustamante, Ryan N. Gutenkunst, Thomas Mailund, Julien Y. Dutheil, Asger Hobolth, Mikkel H. Schierup, Oliver A. Ryder, Yuko Yoshinaga, Pieter J. de Jong, George M. Weinstock, Jeffrey Rogers, Elaine R. Mardis, Richard A. Gibbs, and Richard K. Wilson
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Multidisciplinary - Published
- 2022
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