1,063 results on '"Pachter, Lior"'
Search Results
2. Biophysically interpretable inference of cell types from multimodal sequencing data
- Author
-
Chari, Tara, Gorin, Gennady, and Pachter, Lior
- Published
- 2024
- Full Text
- View/download PDF
3. Biophysical modeling with variational autoencoders for bimodal, single-cell RNA sequencing data
- Author
-
Carilli, Maria, Gorin, Gennady, Choi, Yongin, Chari, Tara, and Pachter, Lior
- Published
- 2024
- Full Text
- View/download PDF
4. The virial theorem and the Price equation
- Author
-
Liorsdóttir, Steinunn and Pachter, Lior
- Subjects
Physics - Biological Physics ,Quantitative Biology - Quantitative Methods - Abstract
We observe that the time averaged continuous Price equation is identical to the positive momentum virial theorem, and we discuss the applications and implications of this connection., Comment: 8 pages
- Published
- 2023
5. PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial
- Author
-
Dorff, Tanya B., Blanchard, M. Suzette, Adkins, Lauren N., Luebbert, Laura, Leggett, Neena, Shishido, Stephanie N., Macias, Alan, Del Real, Marissa M., Dhapola, Gaurav, Egelston, Colt, Murad, John P., Rosa, Reginaldo, Paul, Jinny, Chaudhry, Ammar, Martirosyan, Hripsime, Gerdts, Ethan, Wagner, Jamie R., Stiller, Tracey, Tilakawardane, Dileshni, Pal, Sumanta, Martinez, Catalina, Reiter, Robert E., Budde, Lihua E., D’Apuzzo, Massimo, Kuhn, Peter, Pachter, Lior, Forman, Stephen J., and Priceman, Saul J.
- Published
- 2024
- Full Text
- View/download PDF
6. Data-Driven Approaches to Searches for the Technosignatures of Advanced Civilizations
- Author
-
Lazio, T. Joseph W., Djorgovski, S. G., Howard, Andrew, Cutler, Curt, Sheikh, Sofia Z., Cavuoti, Stefano, Herzing, Denise, Wagstaff, Kiri, Wright, Jason T., Gajjar, Vishal, Hand, Kevin, Rebbapragada, Umaa, Allen, Bruce, Cartmill, Erica, Foster, Jacob, Gelino, Dawn, Graham, Matthew J., Longo, Giuseppe, Mahabal, Ashish A., Pachter, Lior, Ravi, Vikram, and Sussman, Gerald
- Subjects
Astrophysics - Instrumentation and Methods for Astrophysics ,Astrophysics - Earth and Planetary Astrophysics ,Physics - Popular Physics - Abstract
Humanity has wondered whether we are alone for millennia. The discovery of life elsewhere in the Universe, particularly intelligent life, would have profound effects, comparable to those of recognizing that the Earth is not the center of the Universe and that humans evolved from previous species. There has been rapid growth in the fields of extrasolar planets and data-driven astronomy. In a relatively short interval, we have seen a change from knowing of no extrasolar planets to now knowing more potentially habitable extrasolar planets than there are planets in the Solar System. In approximately the same interval, astronomy has transitioned to a field in which sky surveys can generate 1 PB or more of data. The Data-Driven Approaches to Searches for the Technosignatures of Advanced Civilizations_ study at the W. M. Keck Institute for Space Studies was intended to revisit searches for evidence of alien technologies in light of these developments. Data-driven searches, being able to process volumes of data much greater than a human could, and in a reproducible manner, can identify *anomalies* that could be clues to the presence of technosignatures. A key outcome of this workshop was that technosignature searches should be conducted in a manner consistent with Freeman Dyson's "First Law of SETI Investigations," namely "every search for alien civilizations should be planned to give interesting results even when no aliens are discovered." This approach to technosignatures is commensurate with NASA's approach to biosignatures in that no single observation or measurement can be taken as providing full certainty for the detection of life. Areas of particular promise identified during the workshop were (*) Data Mining of Large Sky Surveys, (*) All-Sky Survey at Far-Infrared Wavelengths, (*) Surveys with Radio Astronomical Interferometers, and (*) Artifacts in the Solar System., Comment: Final Report prepared for the W. M. Keck Institute for Space Studies (KISS), http://kiss.caltech.edu/workshops/technosignatures/technosignatures.html ; eds. Lazio, Djorgovski, Howard, & Cutler; The study leads gratefully acknowledge the outstanding support of Michele Judd, KISS Executive Director, and her dedicated staff, who made the study experience invigorating and enormously productive
- Published
- 2023
- Full Text
- View/download PDF
7. Direct androgen receptor control of sexually dimorphic gene expression in the mammalian kidney
- Author
-
Xiong, Lingyun, Liu, Jing, Han, Seung Yub, Koppitch, Kari, Guo, Jin-Jin, Rommelfanger, Megan, Miao, Zhen, Gao, Fan, Hallgrimsdottir, Ingileif B, Pachter, Lior, Kim, Junhyong, MacLean, Adam L, and McMahon, Andrew P
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Kidney Disease ,Biotechnology ,Prevention ,Estrogen ,Underpinning research ,2.1 Biological and endogenous factors ,Aetiology ,1.1 Normal biological development and functioning ,Renal and urogenital ,androgen receptor regulation ,kidney ,multiomic ,proximal tubule ,sexual dimorphism ,single nuclear ,Medical and Health Sciences ,Developmental Biology ,Biochemistry and cell biology - Abstract
Mammalian organs exhibit distinct physiology, disease susceptibility, and injury responses between the sexes. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments. Bulk RNA sequencing (RNA-seq) data demonstrated that sex differences were established from 4 and 8 weeks after birth under gonadal control. Hormone injection studies and genetic removal of androgen and estrogen receptors demonstrated androgen receptor (AR)-mediated regulation of gene activity in PT cells as the regulatory mechanism. Interestingly, caloric restriction feminizes the male kidney. Single-nuclear multiomic analysis identified putative cis-regulatory regions and cooperating factors mediating PT responses to AR activity in the mouse kidney. In the human kidney, a limited set of genes showed conserved sex-linked regulation, whereas analysis of the mouse liver underscored organ-specific differences in the regulation of sexually dimorphic gene expression. These findings raise interesting questions on the evolution, physiological significance, disease, and metabolic linkage of sexually dimorphic gene activity.
- Published
- 2023
8. A decade of molecular cell atlases
- Author
-
Pachter, Lior
- Subjects
Quantitative Biology - Other Quantitative Biology - Abstract
The recent opinion article "A decade of molecular cell atlases" by Stephen Quake narrates the incredible single-cell genomics technology advances that have taken place over the last decade, and how they have translated to increasingly resolved cell atlases. However the sequence of events described is inaccurate and contains several omissions and errors. The errors are corrected in this note.
- Published
- 2022
9. Spectral neural approximations for models of transcriptional dynamics
- Author
-
Gorin, Gennady, Carilli, Maria, Chari, Tara, and Pachter, Lior
- Published
- 2024
- Full Text
- View/download PDF
10. Author Correction: Principles of open source bioinstrumentation applied to the poseidon syringe pump system
- Author
-
Booeshaghi, A. Sina, Beltrame, Eduardo da Veiga, Bannon, Dylan, Gehring, Jase, and Pachter, Lior
- Published
- 2023
- Full Text
- View/download PDF
11. Assessing Markovian and Delay Models for Single-Nucleus RNA Sequencing
- Author
-
Gorin, Gennady, Yoshida, Shawn, and Pachter, Lior
- Published
- 2023
- Full Text
- View/download PDF
12. Analytic solution of chemical master equations involving gene switching. I: Representation theory and diagrammatic approach to exact solution
- Author
-
Vastola, John J., Gorin, Gennady, Pachter, Lior, and Holmes, William R.
- Subjects
Quantitative Biology - Subcellular Processes ,Quantitative Biology - Molecular Networks ,Quantitative Biology - Quantitative Methods - Abstract
The chemical master equation (CME), which describes the discrete and stochastic molecule number dynamics associated with biological processes like transcription, is difficult to solve analytically. It is particularly hard to solve for models involving bursting/gene switching, a biological feature that tends to produce heavy-tailed single cell RNA counts distributions. In this paper, we present a novel method for computing exact and analytic solutions to the CME in such cases, and use these results to explore approximate solutions valid in different parameter regimes, and to compute observables of interest. Our method leverages tools inspired by quantum mechanics, including ladder operators and Feynman-like diagrams, and establishes close formal parallels between the dynamics of bursty transcription, and the dynamics of bosons interacting with a single fermion. We focus on two problems: (i) the chemical birth-death process coupled to a switching gene/the telegraph model, and (ii) a model of transcription and multistep splicing involving a switching gene and an arbitrary number of downstream splicing steps. We work out many special cases, and exhaustively explore the special functionology associated with these problems. This is Part I in a two-part series of papers; in Part II, we explore an alternative solution approach that is more useful for numerically solving these problems, and apply it to parameter inference on simulated RNA counts data., Comment: 108 pages, 12 figures
- Published
- 2021
13. A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex
- Author
-
Yao, Zizhen, Liu, Hanqing, Xie, Fangming, Fischer, Stephan, Adkins, Ricky S, Aldridge, Andrew I, Ament, Seth A, Bartlett, Anna, Behrens, M Margarita, Van den Berge, Koen, Bertagnolli, Darren, de Bézieux, Hector Roux, Biancalani, Tommaso, Booeshaghi, A Sina, Bravo, Héctor Corrada, Casper, Tamara, Colantuoni, Carlo, Crabtree, Jonathan, Creasy, Heather, Crichton, Kirsten, Crow, Megan, Dee, Nick, Dougherty, Elizabeth L, Doyle, Wayne I, Dudoit, Sandrine, Fang, Rongxin, Felix, Victor, Fong, Olivia, Giglio, Michelle, Goldy, Jeff, Hawrylycz, Mike, Herb, Brian R, Hertzano, Ronna, Hou, Xiaomeng, Hu, Qiwen, Kancherla, Jayaram, Kroll, Matthew, Lathia, Kanan, Li, Yang Eric, Lucero, Jacinta D, Luo, Chongyuan, Mahurkar, Anup, McMillen, Delissa, Nadaf, Naeem M, Nery, Joseph R, Nguyen, Thuc Nghi, Niu, Sheng-Yong, Ntranos, Vasilis, Orvis, Joshua, Osteen, Julia K, Pham, Thanh, Pinto-Duarte, Antonio, Poirion, Olivier, Preissl, Sebastian, Purdom, Elizabeth, Rimorin, Christine, Risso, Davide, Rivkin, Angeline C, Smith, Kimberly, Street, Kelly, Sulc, Josef, Svensson, Valentine, Tieu, Michael, Torkelson, Amy, Tung, Herman, Vaishnav, Eeshit Dhaval, Vanderburg, Charles R, van Velthoven, Cindy, Wang, Xinxin, White, Owen R, Huang, Z Josh, Kharchenko, Peter V, Pachter, Lior, Ngai, John, Regev, Aviv, Tasic, Bosiljka, Welch, Joshua D, Gillis, Jesse, Macosko, Evan Z, Ren, Bing, Ecker, Joseph R, Zeng, Hongkui, and Mukamel, Eran A
- Subjects
Human Genome ,Neurosciences ,Genetics ,Bioengineering ,Biotechnology ,1.1 Normal biological development and functioning ,Underpinning research ,Neurological ,Animals ,Atlases as Topic ,Datasets as Topic ,Epigenesis ,Genetic ,Epigenomics ,Female ,Gene Expression Profiling ,Male ,Mice ,Motor Cortex ,Neurons ,Organ Specificity ,Reproducibility of Results ,Single-Cell Analysis ,Transcriptome ,General Science & Technology - Abstract
Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain1-3. With the proliferation of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of cell-type organization. Here we generated transcriptomes and epigenomes from more than 500,000 individual cells in the mouse primary motor cortex, a structure that has an evolutionarily conserved role in locomotion. We developed computational and statistical methods to integrate multimodal data and quantitatively validate cell-type reproducibility. The resulting reference atlas-containing over 56 neuronal cell types that are highly replicable across analysis methods, sequencing technologies and modalities-is a comprehensive molecular and genomic account of the diverse neuronal and non-neuronal cell types in the mouse primary motor cortex. The atlas includes a population of excitatory neurons that resemble pyramidal cells in layer 4 in other cortical regions4. We further discovered thousands of concordant marker genes and gene regulatory elements for these cell types. Our results highlight the complex molecular regulation of cell types in the brain and will directly enable the design of reagents to target specific cell types in the mouse primary motor cortex for functional analysis.
- Published
- 2021
14. A multimodal cell census and atlas of the mammalian primary motor cortex
- Author
-
Callaway, Edward M, Dong, Hong-Wei, Ecker, Joseph R, Hawrylycz, Michael J, Huang, Z Josh, Lein, Ed S, Ngai, John, Osten, Pavel, Ren, Bing, Tolias, Andreas Savas, White, Owen, Zeng, Hongkui, Zhuang, Xiaowei, Ascoli, Giorgio A, Behrens, M Margarita, Chun, Jerold, Feng, Guoping, Gee, James C, Ghosh, Satrajit S, Halchenko, Yaroslav O, Hertzano, Ronna, Lim, Byung Kook, Martone, Maryann E, Ng, Lydia, Pachter, Lior, Ropelewski, Alexander J, Tickle, Timothy L, Yang, X William, Zhang, Kun, Bakken, Trygve E, Berens, Philipp, Daigle, Tanya L, Harris, Julie A, Jorstad, Nikolas L, Kalmbach, Brian E, Kobak, Dmitry, Li, Yang Eric, Liu, Hanqing, Matho, Katherine S, Mukamel, Eran A, Naeemi, Maitham, Scala, Federico, Tan, Pengcheng, Ting, Jonathan T, Xie, Fangming, Zhang, Meng, Zhang, Zhuzhu, Zhou, Jingtian, Zingg, Brian, Armand, Ethan, Yao, Zizhen, Bertagnolli, Darren, Casper, Tamara, Crichton, Kirsten, Dee, Nick, Diep, Dinh, Ding, Song-Lin, Dong, Weixiu, Dougherty, Elizabeth L, Fong, Olivia, Goldman, Melissa, Goldy, Jeff, Hodge, Rebecca D, Hu, Lijuan, Keene, C Dirk, Krienen, Fenna M, Kroll, Matthew, Lake, Blue B, Lathia, Kanan, Linnarsson, Sten, Liu, Christine S, Macosko, Evan Z, McCarroll, Steven A, McMillen, Delissa, Nadaf, Naeem M, Nguyen, Thuc Nghi, Palmer, Carter R, Pham, Thanh, Plongthongkum, Nongluk, Reed, Nora M, Regev, Aviv, Rimorin, Christine, Romanow, William J, Savoia, Steven, Siletti, Kimberly, Smith, Kimberly, Sulc, Josef, Tasic, Bosiljka, Tieu, Michael, Torkelson, Amy, Tung, Herman, van Velthoven, Cindy TJ, Vanderburg, Charles R, Yanny, Anna Marie, Fang, Rongxin, Hou, Xiaomeng, Lucero, Jacinta D, Osteen, Julia K, Pinto-Duarte, Antonio, and Poirion, Olivier
- Subjects
Genetics ,Neurosciences ,Human Genome ,Biotechnology ,Underpinning research ,1.1 Normal biological development and functioning ,Neurological ,Animals ,Atlases as Topic ,Callithrix ,Epigenomics ,Female ,Gene Expression Profiling ,Glutamates ,Humans ,In Situ Hybridization ,Fluorescence ,Male ,Mice ,Motor Cortex ,Neurons ,Organ Specificity ,Phylogeny ,Single-Cell Analysis ,Species Specificity ,Transcriptome ,BRAIN Initiative Cell Census Network ,General Science & Technology - Abstract
Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1-5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
- Published
- 2021
15. Special Function Methods for Bursty Models of Transcription
- Author
-
Gorin, Gennady and Pachter, Lior
- Subjects
Statistics - Methodology ,Quantitative Biology - Molecular Networks ,Quantitative Biology - Quantitative Methods - Abstract
We explore a Markov model used in the analysis of gene expression, involving the bursty production of pre-mRNA, its conversion to mature mRNA, and its consequent degradation. We demonstrate that the integration used to compute the solution of the stochastic system can be approximated by the evaluation of special functions. Furthermore, the form of the special function solution generalizes to a broader class of burst distributions. In light of the broader goal of biophysical parameter inference from transcriptomics data, we apply the method to simulated data, demonstrating effective control of precision and runtime. Finally, we suggest a non-Bayesian approach to reducing the computational complexity of parameter inference to linear order in state space size and number of candidate parameters., Comment: Body: 15 pages, 2 figures, 2 tables. Supplement: 10 pages, 1 figure
- Published
- 2020
- Full Text
- View/download PDF
16. Massively scaled-up testing for SARS-CoV-2 RNA via next-generation sequencing of pooled and barcoded nasal and saliva samples.
- Author
-
Bloom, Joshua, Sathe, Laila, Munugala, Chetan, Jones, Eric, Gasperini, Molly, Lubock, Nathan, Yarza, Fauna, Thompson, Erin, Kovary, Kyle, Park, Jimin, Marquette, Dawn, Kay, Stephania, Lucas, Mark, Love, TreQuan, Sina Booeshaghi, A, Brandenberg, Oliver, Guo, Longhua, Boocock, James, Hochman, Myles, Simpkins, Scott, Lin, Isabella, LaPierre, Nathan, Hong, Duke, Zhang, Yi, Oland, Gabriel, Choe, Bianca, Chandrasekaran, Sukantha, Hilt, Evann, Butte, Manish, Damoiseaux, Robert, Kravit, Clifford, Cooper, Aaron, Yin, Yi, Pachter, Lior, Garner, Omai, Flint, Jonathan, Eskin, Eleazar, Luo, Chongyuan, Kosuri, Sriram, Kruglyak, Leonid, and Arboleda, Valerie
- Subjects
High-Throughput Nucleotide Sequencing ,Humans ,RNA ,Viral ,SARS-CoV-2 ,Saliva ,Sensitivity and Specificity - Abstract
Frequent and widespread testing of members of the population who are asymptomatic for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential for the mitigation of the transmission of the virus. Despite the recent increases in testing capacity, tests based on quantitative polymerase chain reaction (qPCR) assays cannot be easily deployed at the scale required for population-wide screening. Here, we show that next-generation sequencing of pooled samples tagged with sample-specific molecular barcodes enables the testing of thousands of nasal or saliva samples for SARS-CoV-2 RNA in a single run without the need for RNA extraction. The assay, which we named SwabSeq, incorporates a synthetic RNA standard that facilitates end-point quantification and the calling of true negatives, and that reduces the requirements for automation, purification and sample-to-sample normalization. We used SwabSeq to perform 80,000 tests, with an analytical sensitivity and specificity comparable to or better than traditional qPCR tests, in less than two months with turnaround times of less than 24 h. SwabSeq could be rapidly adapted for the detection of other pathogens.
- Published
- 2021
17. Studying stochastic systems biology of the cell with single-cell genomics data
- Author
-
Gorin, Gennady, Vastola, John J., and Pachter, Lior
- Published
- 2023
- Full Text
- View/download PDF
18. Swab-Seq: A high-throughput platform for massively scaled up SARS-CoV-2 testing
- Author
-
Bloom, Joshua, Sathe, Laila, Munugala, Chetan, Jones, Eric, Gasperini, Molly, Lubock, Nathan, Yarza, Fauna, Thompson, Erin, Kovary, Kyle, Park, Jimin, Marquette, Dawn, Kay, Stephania, Lucas, Mark, Love, TreQuan, Booeshaghi, Sina, Brandenberg, Oliver, Guo, Longhua, Boocock, James, Hochman, Myles, Simpkins, Scott, Lin, Isabella, LaPierre, Nathan, Hong, Duke, Zhang, Yi, Oland, Gabriel, Choe, Bianca Judy, Chandrasekaran, Sukantha, Hilt, Evann, Butte, Manish, Damoiseaux, Robert, Kravit, Clifford, Cooper, Aaron, Yin, Yi, Pachter, Lior, Garner, Omai, Flint, Jonathan, Eskin, Eleazar, Luo, Chongyuan, Kosuri, Sriram, Kruglyak, Leonid, and Arboleda, Valerie
- Subjects
Genetics ,Biodefense ,Prevention ,Lung ,Biotechnology ,Pneumonia & Influenza ,Pneumonia ,Emerging Infectious Diseases ,Infectious Diseases ,Clinical Research ,Vaccine Related ,Infection - Abstract
ABSTRACT The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is due to the high rates of transmission by individuals who are asymptomatic at the time of transmission 1, 2 . Frequent, widespread testing of the asymptomatic population for SARS-CoV-2 is essential to suppress viral transmission. Despite increases in testing capacity, multiple challenges remain in deploying traditional reverse transcription and quantitative PCR (RT-qPCR) tests at the scale required for population screening of asymptomatic individuals. We have developed SwabSeq, a high-throughput testing platform for SARS-CoV-2 that uses next-generation sequencing as a readout. SwabSeq employs sample-specific molecular barcodes to enable thousands of samples to be combined and simultaneously analyzed for the presence or absence of SARS-CoV-2 in a single run. Importantly, SwabSeq incorporates an in vitro RNA standard that mimics the viral amplicon, but can be distinguished by sequencing. This standard allows for end-point rather than quantitative PCR, improves quantitation, reduces requirements for automation and sample-to-sample normalization, enables purification-free detection, and gives better ability to call true negatives. After setting up SwabSeq in a high-complexity CLIA laboratory, we performed more than 80,000 tests for COVID-19 in less than two months, confirming in a real world setting that SwabSeq inexpensively delivers highly sensitive and specific results at scale, with a turn-around of less than 24 hours. Our clinical laboratory uses SwabSeq to test both nasal and saliva samples without RNA extraction, while maintaining analytical sensitivity comparable to or better than traditional RT-qPCR tests. Moving forward, SwabSeq can rapidly scale up testing to mitigate devastating spread of novel pathogens.
- Published
- 2020
19. Odd-paired is a pioneer-like factor that coordinates with Zelda to control gene expression in embryos.
- Author
-
Koromila, Theodora, Gao, Fan, Iwasaki, Yasuno, He, Peng, Pachter, Lior, Gergen, J, and Stathopoulos, Angelike
- Subjects
ATAC-seq ,ChIP-seq ,D. melanogaster ,RNA-seq ,Zelda ,developmental biology ,genetics ,genomics ,maternal-to-zygotic transition (MZT) ,odd-paired ,Animals ,Drosophila ,Drosophila Proteins ,Drosophila melanogaster ,Gene Expression Regulation ,Developmental ,Homeodomain Proteins ,Nuclear Proteins ,Transcription Factors - Abstract
Pioneer factors such as Zelda (Zld) help initiate zygotic transcription in Drosophila early embryos, but whether other factors support this dynamic process is unclear. Odd-paired (Opa), a zinc-finger transcription factor expressed at cellularization, controls the transition of genes from pair-rule to segmental patterns along the anterior-posterior axis. Finding that Opa also regulates expression through enhancer sog_Distal along the dorso-ventral axis, we hypothesized Opas role is more general. Chromatin-immunoprecipitation (ChIP-seq) confirmed its in vivo binding to sog_Distal but also identified widespread binding throughout the genome, comparable to Zld. Furthermore, chromatin assays (ATAC-seq) demonstrate that Opa, like Zld, influences chromatin accessibility genome-wide at cellularization, suggesting both are pioneer factors with common as well as distinct targets. Lastly, embryos lacking opa exhibit widespread, late patterning defects spanning both axes. Collectively, these data suggest Opa is a general timing factor and likely late-acting pioneer factor that drives a secondary wave of zygotic gene expression.
- Published
- 2020
20. Fast and accurate diagnostics from highly multiplexed sequencing assays
- Author
-
Booeshaghi, Sina, Lubock, Nathan, Cooper, Aaron, Simpkins, Scott, Bloom, Joshua, Gehring, Jase, Luebbert, Laura, Kosuri, Sriram, and Pachter, Lior
- Abstract
Scalable, inexpensive, accurate, and secure testing for SARS-CoV-2 infection is crucial for control of the novel coronavirus pandemic. Recently developed highly multiplexed sequencing assays that rely on high-throughput sequencing (HMSAs) can, in principle, meet these demands, and present promising alternatives to currently used RT-qPCR-based tests. However, the analysis and interpretation of HMSAs requires overcoming several computational and statistical challenges. Using recently acquired experimental data, we present and validate an accurate and fast computational testing workflow based on kallisto and bustools, that utilize robust statistical methods and fast, memory efficient algorithms for processing high-throughput sequencing data. We show that our workflow is effective at processing data from all recently proposed SARS-CoV-2 sequencing based diagnostic tests, and is generally applicable to any diagnostic HMSAs.
- Published
- 2020
21. Fast and accurate diagnostics from highly multiplexed sequencing assays
- Author
-
Booeshaghi, A Sina, Lubock, Nathan B, Cooper, Aaron R, Simpkins, Scott W, Bloom, Joshua S, Gehring, Jase, Luebbert, Laura, Kosuri, Sri, and Pachter, Lior
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Prevention ,Emerging Infectious Diseases ,Biotechnology ,Networking and Information Technology R&D (NITRD) ,Pneumonia & Influenza ,Bioengineering ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,4.2 Evaluation of markers and technologies ,Infection ,Good Health and Well Being - Abstract
Scalable, inexpensive, accurate, and secure testing for SARS-CoV-2 infection is crucial for control of the novel coronavirus pandemic. Recently developed highly multiplexed sequencing assays that rely on high-throughput sequencing (HMSAs) can, in principle, meet these demands, and present promising alternatives to currently used RT-qPCR-based tests. However, the analysis and interpretation of HMSAs requires overcoming several computational and statistical challenges. Using recently acquired experimental data, we present and validate an accurate and fast computational testing workflow based on kallisto and bustools, that utilize robust statistical methods and fast, memory efficient algorithms for processing high-throughput sequencing data. We show that our workflow is effective at processing data from all recently proposed SARS-CoV-2 sequencing based diagnostic tests, and is generally applicable to any diagnostic HMSAs.
- Published
- 2020
22. Museum of spatial transcriptomics
- Author
-
Moses, Lambda and Pachter, Lior
- Published
- 2022
- Full Text
- View/download PDF
23. A Python library for probabilistic analysis of single-cell omics data
- Author
-
Gayoso, Adam, Lopez, Romain, Xing, Galen, Boyeau, Pierre, Valiollah Pour Amiri, Valeh, Hong, Justin, Wu, Katherine, Jayasuriya, Michael, Mehlman, Edouard, Langevin, Maxime, Liu, Yining, Samaran, Jules, Misrachi, Gabriel, Nazaret, Achille, Clivio, Oscar, Xu, Chenling, Ashuach, Tal, Gabitto, Mariano, Lotfollahi, Mohammad, Svensson, Valentine, da Veiga Beltrame, Eduardo, Kleshchevnikov, Vitalii, Talavera-López, Carlos, Pachter, Lior, Theis, Fabian J., Streets, Aaron, Jordan, Michael I., Regier, Jeffrey, and Yosef, Nir
- Published
- 2022
- Full Text
- View/download PDF
24. Interpretable and tractable models of transcriptional noise for the rational design of single-molecule quantification experiments
- Author
-
Gorin, Gennady, Vastola, John J., Fang, Meichen, and Pachter, Lior
- Published
- 2022
- Full Text
- View/download PDF
25. A latent variable model for survival time prediction with censoring and diverse covariates
- Author
-
McCurdy, Shannon R., Molinaro, Annette, and Pachter, Lior
- Subjects
Statistics - Applications - Abstract
Fulfilling the promise of precision medicine requires accurately and precisely classifying disease states. For cancer, this includes prediction of survival time from a surfeit of covariates. Such data presents an opportunity for improved prediction, but also a challenge due to high dimensionality. Furthermore, disease populations can be heterogeneous. Integrative modeling is sensible, as the underlying hypothesis is that joint analysis of multiple covariates provides greater explanatory power than separate analyses. We propose an integrative latent variable model that combines factor analysis for various data types and an exponential Cox proportional hazards model for continuous survival time with informative censoring. The factor and Cox models are connected through low-dimensional latent variables that can be interpreted and visualized to identify subpopulations. We use this model to predict survival time. We demonstrate this model's utility in simulation and on four Cancer Genome Atlas datasets: diffuse lower-grade glioma, glioblastoma multiforme, lung adenocarcinoma, and lung squamous cell carcinoma. These datasets have small sample sizes, high-dimensional diverse covariates, and high censorship rates. We compare the predictions from our model to two alternative models. Our model outperforms in simulation and is competitive on real datasets. Furthermore, the low-dimensional visualization for diffuse lower-grade glioma displays known subpopulations.
- Published
- 2017
26. Accurate design of translational output by a neural network model of ribosome distribution.
- Author
-
Tunney, Robert, McGlincy, Nicholas, Graham, Monica, Naddaf, Nicki, Pachter, Lior, and Lareau, Liana
- Subjects
Bacterial Proteins ,Codon ,Genes ,Fungal ,Kinetics ,Luminescent Proteins ,Models ,Biological ,Models ,Genetic ,Neural Networks ,Computer ,Peptide Chain Elongation ,Translational ,Protein Biosynthesis ,RNA Stability ,RNA ,Messenger ,Recombinant Proteins ,Ribosomes ,Saccharomyces cerevisiae - Abstract
Synonymous codon choice can have dramatic effects on ribosome speed and protein expression. Ribosome profiling experiments have underscored that ribosomes do not move uniformly along mRNAs. Here, we have modeled this variation in translation elongation by using a feed-forward neural network to predict the ribosome density at each codon as a function of its sequence neighborhood. Our approach revealed sequence features affecting translation elongation and characterized large technical biases in ribosome profiling. We applied our model to design synonymous variants of a fluorescent protein spanning the range of translation speeds predicted with our model. Levels of the fluorescent protein in budding yeast closely tracked the predicted translation speeds across their full range. We therefore demonstrate that our model captures information determining translation dynamics in vivo; that this information can be harnessed to design coding sequences; and that control of translation elongation alone is sufficient to produce large quantitative differences in protein output.
- Published
- 2018
27. A machine-readable specification for genomics assays
- Author
-
Booeshaghi, Ali Sina, primary, Chen, Xi, additional, and Pachter, Lior, additional
- Published
- 2024
- Full Text
- View/download PDF
28. Algorithms for a Commons Cell Atlas
- Author
-
Booeshaghi, A. Sina, primary, Galvez-Merchán, Ángel, additional, and Pachter, Lior, additional
- Published
- 2024
- Full Text
- View/download PDF
29. Fast and scalable querying of eukaryotic linear motifs with gget elm
- Author
-
Luebbert, Laura, primary, Hoang, Chi, additional, Kumar, Manjeet, additional, and Pachter, Lior, additional
- Published
- 2024
- Full Text
- View/download PDF
30. Isoform cell-type specificity in the mouse primary motor cortex
- Author
-
Booeshaghi, A. Sina, Yao, Zizhen, van Velthoven, Cindy, Smith, Kimberly, Tasic, Bosiljka, Zeng, Hongkui, and Pachter, Lior
- Published
- 2021
- Full Text
- View/download PDF
31. Estimating intrinsic and extrinsic noise from single-cell gene expression measurements
- Author
-
Fu, Audrey and Pachter, Lior
- Subjects
Quantitative Biology - Quantitative Methods ,Statistics - Methodology - Abstract
Gene expression is stochastic and displays variation ("noise") both within and between cells. Intracellular (intrinsic) variance can be distinguished from extracellular (extrinsic) variance by applying the law of total variance to data from two-reporter assays that probe expression of identical gene pairs in single-cells. We examine established formulas for the estimation of intrinsic and extrinsic noise and provide interpretations of them in terms of a hierarchical model. This allows us to derive corrections that minimize the mean squared error, an objective that may be important when sample sizes are small. The statistical framework also highlights the need for quantile normalization, and provides justification for the use of the sample correlation between the two reporter expression levels to estimate the percent contribution of extrinsic noise to the total noise. Finally, we provide a geometric interpretation of these results that clarifies the current interpretation.
- Published
- 2016
32. PROBer Provides a General Toolkit for Analyzing Sequencing-Based Toeprinting Assays
- Author
-
Li, Bo, Tambe, Akshay, Aviran, Sharon, and Pachter, Lior
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Human Genome ,Genetics ,2.5 Research design and methodologies (aetiology) ,Aetiology ,Generic health relevance ,Algorithms ,Animals ,Computational Biology ,High-Throughput Nucleotide Sequencing ,Humans ,Models ,Statistical ,Protein Isoforms ,RNA ,RNA Processing ,Post-Transcriptional ,Sequence Analysis ,RNA ,Software ,Transcriptome ,RNA structure probing ,RNA-protein interactions ,bioinformatics ,post-transcriptional modification of RNA nucleotides ,post-transcriptional regulation ,toeprinting by high-throughput sequencing ,Biochemistry and Cell Biology ,Biochemistry and cell biology - Abstract
A number of sequencing-based transcriptase drop-off assays have recently been developed to probe post-transcriptional dynamics of RNA-protein interaction, RNA structure, and RNA modification. Although these assays survey a diverse set of epitranscriptomic marks, we use the term toeprinting assays since they share methodological similarities. Their interpretation is predicated on addressing a similar computational challenge: how to learn isoform-specific chemical modification profiles in the face of complex read multi-mapping. We introduce PROBer, a statistical model and associated software, that addresses this challenge for the analysis of toeprinting assays. PROBer takes sequencing data as input and outputs estimated transcript abundances and isoform-specific modification profiles. Results on both simulated and biological data demonstrate that PROBer significantly outperforms individual methods tailored for specific toeprinting assays. Since the space of toeprinting assays is ever expanding and these assays are likely to be performed and analyzed together, we believe PROBer's unified data analysis solution will be valuable to the RNA community.
- Published
- 2017
33. Modular, efficient and constant-memory single-cell RNA-seq preprocessing
- Author
-
Melsted, Páll, Booeshaghi, A. Sina, Liu, Lauren, Gao, Fan, Lu, Lambda, Min, Kyung Hoi (Joseph), da Veiga Beltrame, Eduardo, Hjörleifsson, Kristján Eldjárn, Gehring, Jase, and Pachter, Lior
- Published
- 2021
- Full Text
- View/download PDF
34. Pseudoalignment for metagenomic read assignment
- Author
-
Schaeffer, Lorian, Pimentel, Harold, Bray, Nicolas, Melsted, Páll, and Pachter, Lior
- Subjects
Quantitative Biology - Quantitative Methods ,Quantitative Biology - Genomics - Abstract
We explore connections between metagenomic read assignment and the quantification of transcripts from RNA-Seq data. In particular, we show that the recent idea of pseudoalignment introduced in the RNA-Seq context is suitable in the metagenomics setting. When coupled with the Expectation-Maximization (EM) algorithm, reads can be assigned far more accurately and quickly than is currently possible with state of the art software., Comment: Replaced accidentally duplicated figure with correct version; fixed some issues with figure generation and labeling; fixed problem with some missing genomes from database; added link to GitHub repo containing analysis code; included assessment of aggregate sensitivity and precision; clarified assessment metrics used
- Published
- 2015
35. Keep Me Around: Intron Retention Detection and Analysis
- Author
-
Pimentel, Harold, Conboy, John G., and Pachter, Lior
- Subjects
Quantitative Biology - Genomics - Abstract
We present a tool, keep me around (kma), a suite of python scripts and an R package that finds retained introns in RNA-Seq experiments and incorporates biological replicates to reduce the number of false positives when detecting retention events. kma uses the results of existing quantification tools that probabilistically assign multi-mapping reads, thus interfacing easily with transcript quantification pipelines. The data is represented in a convenient, database style format that allows for easy aggregation across introns, genes, samples, and conditions to allow for further exploratory analysis.
- Published
- 2015
36. Near-optimal RNA-Seq quantification
- Author
-
Bray, Nicolas, Pimentel, Harold, Melsted, Páll, and Pachter, Lior
- Subjects
Quantitative Biology - Quantitative Methods ,Computer Science - Computational Engineering, Finance, and Science ,Computer Science - Data Structures and Algorithms ,Quantitative Biology - Genomics - Abstract
We present a novel approach to RNA-Seq quantification that is near optimal in speed and accuracy. Software implementing the approach, called kallisto, can be used to analyze 30 million unaligned paired-end RNA-Seq reads in less than 5 minutes on a standard laptop computer while providing results as accurate as those of the best existing tools. This removes a major computational bottleneck in RNA-Seq analysis., Comment: - Added some results (paralog analysis, allele specific expression analysis, alignment comparison, accuracy analysis with TPMs) - Switched bootstrap analysis to human sample from SEQC-MAQCIII - Provided link to a snakefile that allows for reproducibility of all results and figures in the paper
- Published
- 2015
37. Identifying RNA contacts from SHAPE-MaP by partial correlation analysis
- Author
-
Tambe, Akshay, Doudna, Jennifer, and Pachter, Lior
- Subjects
Quantitative Biology - Quantitative Methods ,Quantitative Biology - Biomolecules - Abstract
In a recent paper Siegfried et al. published a new sequence-based structural RNA assay that utilizes mutational profiling to detect base pairing (MaP). Output from MaP provides information about both pairing (via reactivities) and contact (via correlations). Reactivities can be coupled to partition function folding models for structural inference, while correlations can reveal pairs of sites that may be in structural proximity. The possibility for inference of 3D contacts via MaP suggests a novel approach to structural prediction for RNA analogous to covariance structural prediction for proteins. We explore this approach and show that partial correlation analysis outperforms na\"ive correlation analysis. Our results should be applicable to a wide range of high-throughput sequencing based RNA structural assays that are under development.
- Published
- 2014
38. Flexible parsing, interpretation, and editing of technical sequences with splitcode.
- Author
-
Sullivan, Delaney K and Pachter, Lior
- Subjects
- *
NUCLEOTIDE sequencing , *EDITING , *BAR codes - Abstract
Motivation Next-generation sequencing libraries are constructed with numerous synthetic constructs such as sequencing adapters, barcodes, and unique molecular identifiers. Such sequences can be essential for interpreting results of sequencing assays, and when they contain information pertinent to an experiment, they must be processed and analyzed. Results We present a tool called splitcode , that enables flexible and efficient parsing, interpreting, and editing of sequencing reads. This versatile tool facilitates simple, reproducible preprocessing of reads from libraries constructed for a large array of single-cell and bulk sequencing assays. Availability and implementation The splitcode program is available at http://github.com/pachterlab/splitcode. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
39. A Novel Approach to Comparative RNA-Seq Does Not Support a Conserved Set of Orthologs Underlying Animal Regeneration.
- Author
-
Sierra, Noémie C, Olsman, Noah, Yi, Lynn, Pachter, Lior, Goentoro, Lea, and Gold, David A
- Subjects
COMPARATIVE method ,REGENERATION (Biology) ,RNA sequencing ,BIG data ,GENE expression - Abstract
Molecular studies of animal regeneration typically focus on conserved genes and signaling pathways that underlie morphogenesis. To date, a holistic analysis of gene expression across animals has not been attempted, as it presents a suite of problems related to differences in experimental design and gene homology. By combining orthology analyses with a novel statistical method for testing gene enrichment across large data sets, we are able to test whether tissue regeneration across animals shares transcriptional regulation. We applied this method to a meta-analysis of six publicly available RNA-Seq data sets from diverse examples of animal regeneration. We recovered 160 conserved orthologous gene clusters, which are enriched in structural genes as opposed to those regulating morphogenesis. A breakdown of gene presence/absence provides limited support for the conservation of pathways typically implicated in regeneration, such as Wnt signaling and cell pluripotency pathways. Such pathways are only conserved if we permit large amounts of paralog switching through evolution. Overall, our analysis does not support the hypothesis that a shared set of ancestral genes underlie regeneration mechanisms in animals. After applying the same method to heat shock studies and getting similar results, we raise broader questions about the ability of comparative RNA-Seq to reveal conserved gene pathways across deep evolutionary relationships. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
40. Transcript Abundance Estimation and the Laminar Packing Problem
- Author
-
Rahman, Atif, Pachter, Lior, Hutchison, David, Editorial Board Member, Kanade, Takeo, Editorial Board Member, Kittler, Josef, Editorial Board Member, Kleinberg, Jon M., Editorial Board Member, Mattern, Friedemann, Editorial Board Member, Mitchell, John C., Editorial Board Member, Naor, Moni, Editorial Board Member, Pandu Rangan, C., Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Terzopoulos, Demetri, Editorial Board Member, Tygar, Doug, Editorial Board Member, Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Holmes, Ian, editor, Martín-Vide, Carlos, editor, and Vega-Rodríguez, Miguel A., editor
- Published
- 2019
- Full Text
- View/download PDF
41. A dynamic intron retention program enriched in RNA processing genes regulates gene expression during terminal erythropoiesis
- Author
-
Pimentel, Harold, Parra, Marilyn, Gee, Sherry L, Mohandas, Narla, Pachter, Lior, and Conboy, John G
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Underpinning research ,1.1 Normal biological development and functioning ,Cation Transport Proteins ,Cell Differentiation ,Cell Nucleus ,Cells ,Cultured ,Cluster Analysis ,Codon ,Nonsense ,Erythroblasts ,Erythropoiesis ,Exons ,Gene Expression Regulation ,Humans ,Introns ,Microfilament Proteins ,Mitochondrial Proteins ,Nonsense Mediated mRNA Decay ,Phosphoproteins ,RNA Splice Sites ,RNA Splicing Factors ,Ribonucleoprotein ,U2 Small Nuclear ,Spectrin ,Environmental Sciences ,Information and Computing Sciences ,Developmental Biology ,Biological sciences ,Chemical sciences ,Environmental sciences - Abstract
Differentiating erythroblasts execute a dynamic alternative splicing program shown here to include extensive and diverse intron retention (IR) events. Cluster analysis revealed hundreds of developmentally-dynamic introns that exhibit increased IR in mature erythroblasts, and are enriched in functions related to RNA processing such as SF3B1 spliceosomal factor. Distinct, developmentally-stable IR clusters are enriched in metal-ion binding functions and include mitoferrin genes SLC25A37 and SLC25A28 that are critical for iron homeostasis. Some IR transcripts are abundant, e.g. comprising ∼50% of highly-expressed SLC25A37 and SF3B1 transcripts in late erythroblasts, and thereby limiting functional mRNA levels. IR transcripts tested were predominantly nuclear-localized. Splice site strength correlated with IR among stable but not dynamic intron clusters, indicating distinct regulation of dynamically-increased IR in late erythroblasts. Retained introns were preferentially associated with alternative exons with premature termination codons (PTCs). High IR was observed in disease-causing genes including SF3B1 and the RNA binding protein FUS. Comparative studies demonstrated that the intron retention program in erythroblasts shares features with other tissues but ultimately is unique to erythropoiesis. We conclude that IR is a multi-dimensional set of processes that post-transcriptionally regulate diverse gene groups during normal erythropoiesis, misregulation of which could be responsible for human disease.
- Published
- 2016
42. Quantifying orthogonal barcodes for sequence census assays
- Author
-
Booeshaghi, A Sina, primary, Min, Kyung Hoi (Joseph), additional, Gehring, Jase, additional, and Pachter, Lior, additional
- Published
- 2023
- Full Text
- View/download PDF
43. Efficient and accurate detection of viral sequences at single-cell resolution reveals novel viruses perturbing host gene expression
- Author
-
Luebbert, Laura, primary, Sullivan, Delaney K, additional, Carilli, Maria, additional, Eldjarn Hjorleifsson, Kristjan, additional, Winnett, Alexander Viloria, additional, Chari, Tara, additional, and Pachter, Lior, additional
- Published
- 2023
- Full Text
- View/download PDF
44. kallisto, bustools, and kb-python for quantifying bulk, single-cell, and single-nucleus RNA-seq
- Author
-
Sullivan, Delaney K, primary, Min, Kyung Hoi (Joseph), additional, Hjörleifsson, Kristján Eldjárn, additional, Luebbert, Laura, additional, Holley, Guillaume, additional, Moses, Lambda, additional, Gustafsson, Johan, additional, Bray, Nicolas L, additional, Pimentel, Harold, additional, Booeshaghi, A. Sina, additional, Melsted, Páll, additional, and Pachter, Lior, additional
- Published
- 2023
- Full Text
- View/download PDF
45. Fast and scalable querying of eukaryotic linear motifs withgget elm
- Author
-
Luebbert, Laura, primary, Hoang, Chi, additional, Kumar, Manjeet, additional, and Pachter, Lior, additional
- Published
- 2023
- Full Text
- View/download PDF
46. The NIH BD2K center for big data in translational genomics
- Author
-
Paten, Benedict, Diekhans, Mark, Druker, Brian J, Friend, Stephen, Guinney, Justin, Gassner, Nadine, Guttman, Mitchell, Kent, W James, Mantey, Patrick, Margolin, Adam A, Massie, Matt, Novak, Adam M, Nothaft, Frank, Pachter, Lior, Patterson, David, Smuga-Otto, Maciej, Stuart, Joshua M, Veer, Laura Van’t, Wold, Barbara, and Haussler, David
- Subjects
Distributed Computing and Systems Software ,Information and Computing Sciences ,Human Genome ,Networking and Information Technology R&D (NITRD) ,Genetics ,Biotechnology ,Generic health relevance ,Good Health and Well Being ,Computational Biology ,Datasets as Topic ,Genomics ,Humans ,Knowledge Bases ,National Institutes of Health (U.S.) ,Translational Research ,Biomedical ,United States ,computational genomics ,genomics ,big data ,APIs ,genome informatics ,Engineering ,Medical and Health Sciences ,Medical Informatics ,Biomedical and clinical sciences ,Health sciences ,Information and computing sciences - Abstract
The world's genomics data will never be stored in a single repository - rather, it will be distributed among many sites in many countries. No one site will have enough data to explain genotype to phenotype relationships in rare diseases; therefore, sites must share data. To accomplish this, the genetics community must forge common standards and protocols to make sharing and computing data among many sites a seamless activity. Through the Global Alliance for Genomics and Health, we are pioneering the development of shared application programming interfaces (APIs) to connect the world's genome repositories. In parallel, we are developing an open source software stack (ADAM) that uses these APIs. This combination will create a cohesive genome informatics ecosystem. Using containers, we are facilitating the deployment of this software in a diverse array of environments. Through benchmarking efforts and big data driver projects, we are ensuring ADAM's performance and utility.
- Published
- 2015
47. BUTTERFLY: addressing the pooled amplification paradox with unique molecular identifiers in single-cell RNA-seq
- Author
-
Gustafsson, Johan, Robinson, Jonathan, Nielsen, Jens, and Pachter, Lior
- Published
- 2021
- Full Text
- View/download PDF
48. Highly multiplexed single-cell RNA-seq by DNA oligonucleotide tagging of cellular proteins
- Author
-
Gehring, Jase, Hwee Park, Jong, Chen, Sisi, Thomson, Matthew, and Pachter, Lior
- Published
- 2020
- Full Text
- View/download PDF
49. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas
- Author
-
Brat, Daniel J, Verhaak, Roel GW, Aldape, Kenneth D, Yung, WK Alfred, Salama, Sofie R, Cooper, Lee AD, Rheinbay, Esther, Miller, C Ryan, Vitucci, Mark, Morozova, Olena, Robertson, A Gordon, Noushmehr, Houtan, Laird, Peter W, Cherniack, Andrew D, Akbani, Rehan, Huse, Jason T, Ciriello, Giovanni, Poisson, Laila M, Barnholtz-Sloan, Jill S, Berger, Mitchel S, Brennan, Cameron, Colen, Rivka R, Colman, Howard, Flanders, Adam E, Giannini, Caterina, Grifford, Mia, Iavarone, Antonio, Jain, Rajan, Joseph, Isaac, Kim, Jaegil, Kasaian, Katayoon, Mikkelsen, Tom, Murray, Bradley A, O'Neill, Brian Patrick, Pachter, Lior, Parsons, Donald W, Sougnez, Carrie, Sulman, Erik P, Vandenberg, Scott R, Van Meir, Erwin G, von Deimling, Andreas, Zhang, Hailei, Crain, Daniel, Lau, Kevin, Mallery, David, Morris, Scott, Paulauskis, Joseph, Penny, Robert, Shelton, Troy, Sherman, Mark, Yena, Peggy, Black, Aaron, Bowen, Jay, Dicostanzo, Katie, Gastier-Foster, Julie, Leraas, Kristen M, Lichtenberg, Tara M, Pierson, Christopher R, Ramirez, Nilsa C, Taylor, Cynthia, Weaver, Stephanie, Wise, Lisa, Zmuda, Erik, Davidsen, Tanja, Demchok, John A, Eley, Greg, Ferguson, Martin L, Hutter, Carolyn M, Mills Shaw, Kenna R, Ozenberger, Bradley A, Sheth, Margi, Sofia, Heidi J, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean Claude, Ayala, Brenda, Baboud, Julien, Chudamani, Sudha, Jensen, Mark A, Liu, Jia, Pihl, Todd, Raman, Rohini, Wan, Yunhu, Wu, Ye, Ally, Adrian, Auman, J Todd, Balasundaram, Miruna, Balu, Saianand, Baylin, Stephen B, Beroukhim, Rameen, Bootwalla, Moiz S, Bowlby, Reanne, Bristow, Christopher A, Brooks, Denise, Butterfield, Yaron, Carlsen, Rebecca, Carter, Scott, Chin, Lynda, and Chu, Andy
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Human Genome ,Brain Cancer ,Rare Diseases ,Neurosciences ,Biotechnology ,Cancer Genomics ,Genetics ,Cancer ,Brain Disorders ,Adolescent ,Adult ,Aged ,Chromosomes ,Human ,Pair 1 ,Chromosomes ,Human ,Pair 19 ,Cluster Analysis ,DNA ,Neoplasm ,Female ,Genes ,p53 ,Glioblastoma ,Glioma ,Humans ,Kaplan-Meier Estimate ,Male ,Middle Aged ,Mutation ,Neoplasm Grading ,Proportional Hazards Models ,Sequence Analysis ,DNA ,Signal Transduction ,Cancer Genome Atlas Research Network ,Medical and Health Sciences ,General & Internal Medicine ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundDiffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.MethodsWe performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.ResultsUnsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.ConclusionsThe integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).
- Published
- 2015
50. Rational experiment design for sequencing-based RNA structure mapping
- Author
-
Aviran, Sharon and Pachter, Lior
- Subjects
Human Genome ,Biotechnology ,Genetics ,Bioengineering ,Generic health relevance ,Good Health and Well Being ,Computational Biology ,DNA ,Complementary ,Genomics ,High-Throughput Nucleotide Sequencing ,Nucleic Acid Conformation ,Sequence Analysis ,RNA ,Transcriptome ,next-generation sequencing ,RNA structure ,structure mapping ,genomic big data ,high-throughput genomics ,Biochemistry and Cell Biology ,Developmental Biology - Abstract
Structure mapping is a classic experimental approach for determining nucleic acid structure that has gained renewed interest in recent years following advances in chemistry, genomics, and informatics. The approach encompasses numerous techniques that use different means to introduce nucleotide-level modifications in a structure-dependent manner. Modifications are assayed via cDNA fragment analysis, using electrophoresis or next-generation sequencing (NGS). The recent advent of NGS has dramatically increased the throughput, multiplexing capacity, and scope of RNA structure mapping assays, thereby opening new possibilities for genome-scale, de novo, and in vivo studies. From an informatics standpoint, NGS is more informative than prior technologies by virtue of delivering direct molecular measurements in the form of digital sequence counts. Motivated by these new capabilities, we introduce a novel model-based in silico approach for quantitative design of large-scale multiplexed NGS structure mapping assays, which takes advantage of the direct and digital nature of NGS readouts. We use it to characterize the relationship between controllable experimental parameters and the precision of mapping measurements. Our results highlight the complexity of these dependencies and shed light on relevant tradeoffs and pitfalls, which can be difficult to discern by intuition alone. We demonstrate our approach by quantitatively assessing the robustness of SHAPE-Seq measurements, obtained by multiplexing SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) chemistry in conjunction with NGS. We then utilize it to elucidate design considerations in advanced genome-wide approaches for probing the transcriptome, which recently obtained in vivo information using dimethyl sulfate (DMS) chemistry.
- Published
- 2014
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.