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6. RNA Binding Protein CELF2 Regulates Signal-Induced Alternative Polyadenylation by Competing with Enhancers of the Polyadenylation Machinery

Author

Chatrikhi, Rakesh, Mallory, Michael J, Gazzara, Matthew R, Agosto, Laura M, Zhu, Wandi S, Litterman, Adam J, Ansel, K Mark, and Lynch, Kristen W

Subjects
Biochemistry and Cell Biology, Biological Sciences, Human Genome, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, 3' Untranslated Regions, CELF Proteins, Cell Line, Tumor, Cleavage And Polyadenylation Specificity Factor, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Introns, Nerve Tissue Proteins, Polyadenylation, Protein Binding, RNA Splicing Factors, RNA-Binding Proteins, RNA-Seq, Repressor Proteins, Signal Transduction, Splicing Factor U2AF, Transcriptome, 3′ UTR, APA, CELF2, CFIm25, CstF64, polyadenylation, Medical Physiology, Biological sciences
Abstract

The 3' UTR (UTR) of human mRNAs plays a critical role in controlling protein expression and function. Importantly, 3' UTRs of human messages are not invariant for each gene but rather are shaped by alternative polyadenylation (APA) in a cell state-dependent manner, including in response to T cell activation. However, the proteins and mechanisms driving APA regulation remain poorly understood. Here we show that the RNA-binding protein CELF2 controls APA of its own message in a signal-dependent manner by competing with core enhancers of the polyadenylation machinery for binding to RNA. We further show that CELF2 binding overlaps with APA enhancers transcriptome-wide, and almost half of 3' UTRs that undergo T cell signaling-induced APA are regulated in a CELF2-dependent manner. These studies thus reveal CELF2 to be a critical regulator of 3' UTR identity in T cells and demonstrate an additional mechanism for CELF2 in regulating polyadenylation site choice.

Published
2019

7. An anciently diverged family of RNA binding proteins maintain correct splicing of a class of ultra-long exons through cryptic splice site repression.

Author

Siachisumo, Chileleko, Luzzi, Sara, Aldalaqan, Saad, Hysenaj, Gerald, Dalgliesh, Caroline, Cheung, Kathleen, Gazzara, Matthew R., Yonchev, Ivaylo D., James, Katherine, Chadegani, Mahsa Kheirollahi, Ehrmann, Ingrid E., Smith, Graham R., Cockell, Simon J., Munkley, Jennifer, Wilson, Stuart A., Barash, Yoseph, and Elliott, David J.

Published
2024
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8. CYP11B1 variants influence skeletal maturation via alternative splicing

Author

Grgic, Olja, Gazzara, Matthew R., Chesi, Alessandra, Medina-Gomez, Carolina, Cousminer, Diana L., Mitchell, Jonathan A., Prijatelj, Vid, de Vries, Jard, Shevroja, Enisa, McCormack, Shana E., Kalkwarf, Heidi J., Lappe, Joan M., Gilsanz, Vicente, Oberfield, Sharon E., Shepherd, John A., Kelly, Andrea, Mahboubi, Soroosh, Faucz, Fabio R., Feelders, Richard A., de Jong, Frank H., Uitterlinden, Andre G., Visser, Jenny A., Ghanem, Louis R., Wolvius, Eppo B., Hofland, Leo J., Stratakis, Constantine A., Zemel, Babette S., Barash, Yoseph, Grant, Struan F. A., and Rivadeneira, Fernando

Published
2021
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9. Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19

Author

Asnani, Mukta, Hayer, Katharina E., Naqvi, Ammar S., Zheng, Sisi, Yang, Scarlett Y., Oldridge, Derek, Ibrahim, Fadia, Maragkakis, Manolis, Gazzara, Matthew R., Black, Kathryn L., Bagashev, Asen, Taylor, Deanne, Mourelatos, Zissimos, Grupp, Stephan A., Barrett, David, Maris, John M., Sotillo, Elena, Barash, Yoseph, and Thomas-Tikhonenko, Andrei

Published
2020
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10. Extensible benchmarking of methods that identify and quantify polyadenylation sites from RNA-seq data

Author

Bryce-Smith, Sam, primary, Burri, Dominik, additional, Gazzara, Matthew R, additional, Herrmann, Christina J, additional, Danecka, Weronika, additional, Fitzsimmons, Christina M, additional, Wan, Yuk Kei, additional, Zhuang, Farica, additional, Fansler, Mervin M, additional, Fernández, José M, additional, Ferret, Meritxell, additional, Gonzalez-Uriarte, Asier, additional, Haynes, Samuel, additional, Herdman, Chelsea, additional, Kanitz, Alexander, additional, Katsantoni, Maria, additional, Marini, Federico, additional, McDonnel, Euan, additional, Nicolet, Benoit P, additional, Poon, Chi-Lam, additional, Rot, Gregor, additional, Schärfen, Leonard, additional, Wu, Pin-Jou, additional, Yoon, Yoseop, additional, Barash, Yoseph, additional, and Zavolan, Mihaela, additional

Published
2023
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11. An anciently diverged family of RNA binding proteins maintain correct splicing of ultra-long exons through cryptic splice site repression

Author

Siachisumo, Chileleko, primary, Luzzi, Sara, additional, Aldalaqan, Saad, additional, Hysenaj, Gerald, additional, Dalgliesh, Caroline, additional, Cheung, Kathleen, additional, Gazzara, Matthew R, additional, Yonchev, Ivaylo D, additional, James, Katherine, additional, Chadegani, Mahsa Kheirollahi, additional, Ehrmann, Ingrid, additional, Smith, Graham R, additional, Cockell, Simon J, additional, Munkley, Jennifer, additional, Wilson, Stuart A, additional, Barash, Yoseph, additional, and Elliott, David J, additional

Published
2023
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13. Supplementary Figures 1 - 2 from Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy

Author

Sotillo, Elena, primary, Barrett, David M., primary, Black, Kathryn L., primary, Bagashev, Asen, primary, Oldridge, Derek, primary, Wu, Glendon, primary, Sussman, Robyn, primary, Lanauze, Claudia, primary, Ruella, Marco, primary, Gazzara, Matthew R., primary, Martinez, Nicole M., primary, Harrington, Colleen T., primary, Chung, Elaine Y., primary, Perazzelli, Jessica, primary, Hofmann, Ted J., primary, Maude, Shannon L., primary, Raman, Pichai, primary, Barrera, Alejandro, primary, Gill, Saar, primary, Lacey, Simon F., primary, Melenhorst, Jan J., primary, Allman, David, primary, Jacoby, Elad, primary, Fry, Terry, primary, Mackall, Crystal, primary, Barash, Yoseph, primary, Lynch, Kristen W., primary, Maris, John M., primary, Grupp, Stephan A., primary, and Thomas-Tikhonenko, Andrei, primary

Published
2023
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14. Data from Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy

Author

Sotillo, Elena, primary, Barrett, David M., primary, Black, Kathryn L., primary, Bagashev, Asen, primary, Oldridge, Derek, primary, Wu, Glendon, primary, Sussman, Robyn, primary, Lanauze, Claudia, primary, Ruella, Marco, primary, Gazzara, Matthew R., primary, Martinez, Nicole M., primary, Harrington, Colleen T., primary, Chung, Elaine Y., primary, Perazzelli, Jessica, primary, Hofmann, Ted J., primary, Maude, Shannon L., primary, Raman, Pichai, primary, Barrera, Alejandro, primary, Gill, Saar, primary, Lacey, Simon F., primary, Melenhorst, Jan J., primary, Allman, David, primary, Jacoby, Elad, primary, Fry, Terry, primary, Mackall, Crystal, primary, Barash, Yoseph, primary, Lynch, Kristen W., primary, Maris, John M., primary, Grupp, Stephan A., primary, and Thomas-Tikhonenko, Andrei, primary

Published
2023
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15. Supplementary Tables 1 - 9 from Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy

Author

Sotillo, Elena, primary, Barrett, David M., primary, Black, Kathryn L., primary, Bagashev, Asen, primary, Oldridge, Derek, primary, Wu, Glendon, primary, Sussman, Robyn, primary, Lanauze, Claudia, primary, Ruella, Marco, primary, Gazzara, Matthew R., primary, Martinez, Nicole M., primary, Harrington, Colleen T., primary, Chung, Elaine Y., primary, Perazzelli, Jessica, primary, Hofmann, Ted J., primary, Maude, Shannon L., primary, Raman, Pichai, primary, Barrera, Alejandro, primary, Gill, Saar, primary, Lacey, Simon F., primary, Melenhorst, Jan J., primary, Allman, David, primary, Jacoby, Elad, primary, Fry, Terry, primary, Mackall, Crystal, primary, Barash, Yoseph, primary, Lynch, Kristen W., primary, Maris, John M., primary, Grupp, Stephan A., primary, and Thomas-Tikhonenko, Andrei, primary

Published
2023
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16. Extensible benchmarking of methods that identify and quantify polyadenylation sites from RNA-seq data

Author

Barcelona Supercomputing Center, Bryce-Smith, Sam, Burri, Dominik, Gazzara, Matthew R., Herrmann, Christina J., Danecka, Weronika, Feranandez, José M., Ferret, Meritxell, Gonzalez Uriarte, Asier, Barcelona Supercomputing Center, Bryce-Smith, Sam, Burri, Dominik, Gazzara, Matthew R., Herrmann, Christina J., Danecka, Weronika, Feranandez, José M., Ferret, Meritxell, and Gonzalez Uriarte, Asier

Abstract

The tremendous rate with which data is generated and analysis methods emerge makes it increasingly difficult to keep track of their domain of applicability, assumptions, limitations, and consequently, of the efficacy and precision with which they solve specific tasks. Therefore, there is an increasing need for benchmarks, and for the provision of infrastructure for continuous method evaluation. APAeval is an international community effort, organized by the RNA Society in 2021, to benchmark tools for the identification and quantification of the usage of alternative polyadenylation (APA) sites from short-read, bulk RNA-sequencing (RNA-seq) data. Here, we reviewed 17 tools and benchmarked eight on their ability to perform APA identification and quantification, using a comprehensive set of RNA-seq experiments comprising real, synthetic, and matched 3′-end sequencing data. To support continuous benchmarking, we have incorporated the results into the OpenEBench online platform, which allows for continuous extension of the set of methods, metrics, and challenges. We envisage that our analyses will assist researchers in selecting the appropriate tools for their studies, while the containers and reproducible workflows could easily be deployed and extended to evaluate new methods or data sets., We thank the RNA Society for making the hackathon possible and bringing together people from various disciplines. We thank the OpenEBench platform (https://openebench.bsc.es/) for hosting the APAeval benchmark. We thank OEB members Anna Redondo, Laura Portell, Laura Rodriguez-Navas, and Salvador Capella for help and contributions. We thank Seqera Labs (https://seqera.io/) for kindly hosting a workshop regarding the use of Nextflow and Nextflow Tower during the RNA Society 2021 meeting, and Amazon Web Services for providing us with credits for the use of their cloud platform. We are grateful to host the source code on the iRNA COSI (https://irnacosi.org/) GitHub account. S.B.-S. was supported by a UK Motor Neurone Disease Association and Masonic Charitable Foundation PhD Studentship (893-792). C.M.F. was partially supported by a postdoctoral fellowship from the American Cancer Society (PF-19-157-01-RMC). M.R.G. was supported by the Blavatnik Family Fellowship in Biomedical Research and by NHLBI of the National Institutes of Health (NIH) under award number F31 HL162546. A.G.-U. was supported by the The Emerging Human Brain Cluster (Clúster Emergent del Cervell Humà – CECH) project, number 001-P-001682, 50% cofunded by the European Regional Development Fund of the European Union (Programa Operatiu FEDER Catalunya 2014–2020), with the support of the Catalan Government. Y.K.W. was supported by the Singapore International Graduate Award. OpenEBench is partly funded by the Horizon 2020 ELIXIR-CONVERGE programme, grant agreement number 871075. The work of Y.B. was supported by R01 GM128096, R01 GM147739, and R01 LM013437. D.B. and C.J.H. were partially supported by the Swiss National Science Foundation grant number 310030_189063 to M.Z., Peer Reviewed, "Article signat per 26 autors/es: Sam Bryce-Smith, Dominik Burri, Matthew R. Gazzara, Christina J. Herrmann, Weronika Danecka, Christina M. Fitzsimmons, Yuk Kei Wan, Farica Zhuang, Mervin M. Fansler, José M. Fernández, Meritxell Ferret, Asier Gonzalez-Uriarte, Samuel Haynes, Chelsea Herdman, Alexander Kanitz, Maria Katsantoni, Federico Marini, Euan McDonnel, Ben Nicolet, Chi-Lam Poon, Gregor Rot, Leonard Schärfen, Pin-Jou Wu, Yoseop Yoon, Yoseph Barash and Mihaela Zavolan", Postprint (author's final draft)

Published
2023

17. Supplementary Data for RNA splicing analysis using heterogeneous and large RNA-seq datasets

Author

Vaquero-Garcia, Jorge, Aicher, Joseph K., Jewell, San, Gazzara, Matthew R., Radens, Caleb M., Jha, Anupama, Green, Christopher J., Norton, Scorr S., Lahens, Nicholas F., Grant, Gregory R., and Barash, Yoseph

Abstract

This is a supplementary data set for the publication, the abstract of which follows. The ubiquity of RNA-seq has led to many methods that use RNA-seq data to analyze variations in RNA splicing. However, available methods are not well suited for handling heterogeneous and large datasets. Such datasets scale to thousands of samples across dozens of experimental conditions, exhibit increased variability compared to biological replicates, and involve thousands of unannotated splice variants resulting in increased transcriptome complexity. We describe here a suite of algorithms and tools implemented in the MAJIQ v2 package to address challenges in detection, quantification, and visualization of splicing variations from such datasets. Using both large scale synthetic data and GTEx v8 as benchmark datasets, we demonstrate that the approaches in MAJIQ v2 outperform existing methods. We then apply MAJIQ v2 package to analyze differential splicing across 2,335 samples from 13 brain subregions, demonstrating its ability to offer new insights into brain subregion-specific splicing regulation.

Published
2023
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23. Analysis of ISCB honorees and keynotes reveals disparities

Author

Le, Trang T., Himmelstein, Daniel S., Hippen Anderson, Ariel A., Gazzara, Matthew R., and Greene, Casey S.

Subjects
Geography, Library science, Professional association, Pace
Abstract

Professional societies and their conferences provide an important venue for disseminating scientific knowledge. Delivering a keynote for or being named a fellow by an international society is a major recognition. Do such recognitions reflect the composition of the field of bioinformatics? We compiled a list of 412 International Society for Computational Biology honorees (75 fellows and 337 keynote speakers). To assess the composition of senior researchers in the field, we analyze the names and affliations of corresponding authors in leading bioinformatics journals. Comparing to the distribution based on names and affliations of honorees, we looked for disparities in gender, country of affliation, race, and name-origin. Name-origin predictions were created using a neural network trained on 700,000 name-nationality pairs mined from Wikipedia. The proportion of female honorees has kept pace with increasing levels of female authorship, but neither has yet to reach gender parity. However, we noticed a striking geographic disparity where the proportion of honorees with an affliation in the United States was 1.6-fold greater compared to field-specific senior authors. In total, we estimate the U.S. received 85 more honorees than would be expected from randomly selecting honorees from senior authors. Almost half of the excess in U.S. honorees was accounted for by a deficit of 41 honoree slots from China, France, and Italy. Furthermore, within the U.S., we identify racial disparities with an excess of white honorees and a depletion of Asian honorees. This pattern replicated globally, where we find names of East Asian origin have been persistently underrepresented among ISCB honorees. Early indications suggest the ICSB has taken note of our findings by selecting more diverse honorees.

Published
2020

26. RBMX enables productive RNA processing of ultra-long exons important for genome stability

Author

Luzzi, Sara, primary, Hysenaj, Gerald, additional, Siachisumo, Chileleko, additional, Cheung, Kathleen, additional, Gazzara, Matthew, additional, James, Katherine, additional, Dalgliesh, Caroline, additional, Chadegani, Mahsa Kheirollahi, additional, Ehrmann, Ingrid, additional, Smith, Graham R, additional, Cockell, Simon J, additional, Munkley, Jennifer, additional, Barash, Yoseph, additional, and Elliott, David J, additional

Published
2020
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29. A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior

Author

Ehrmann, Ingrid, Gazzara, Matthew R., Pagliarini, Vittoria, Dalgliesh, Caroline, Kheirollahi-Chadegani, Mahsa, Yaobo Xu, Cesari, Eleonora, Danilenko, Marina, Maclennan, Marie, Lowdon, Kate, Vogel, Tanja, Keskivali-Bond, Piia, Wells, Sara, Cater, Heather, Fort, Philippe, Santibanez-Koref, Mauro, Middei, Silvia, Sette, Claudio, Clowry, Gavin J., Barash, Yoseph, Cunningham, Mark O., Elliott, David J., Institute of Human Genetics (NEWCASTLE UNIVERSITY), Newcastel University, Department of Biomedicine and Prevention, Università degli Studi di Roma Tor Vergata [Roma], Institute of Anatomy and Cell Biology, Albert-Ludwigs-Universität Freiburg, Mary Lyon Centre, MRC Harwell Institute, Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Medical Research Counc, Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Dulbecco Telethon Institute/Department of Biology, University of Pennsylvania [Philadelphia], United States Nuclear Regulatory Commission (U.S.NRC), Institute of Genetic Medicine [Newcastle, U.K.], and Newcastle University [Newcastle]

Subjects
Genetics and Molecular Biology (all), hippocampus, Knockout, brain, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Biochemistry, Article, Mice, alternative splicing, RNA Precursors, Animals, Homeostasis, Neural Cell Adhesion Molecules, lcsh:QH301-705.5, Adaptor Proteins, Signal Transducing, Settore BIO/16 - ANATOMIA UMANA, Mice, Knockout, Behavior, Behavior, Animal, Animal, Pyramidal Cells, Calcium-Binding Proteins, Signal Transducing, Adaptor Proteins, RNA-Binding Proteins, Neurexin splicing, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, neuron, gene expression, RNA binding proteins, RNA-seq, transcriptome, Alternative Splicing, Synapses, Nerve Net, Biochemistry, Genetics and Molecular Biology (all), [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, lcsh:Biology (General)
Abstract

Summary The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function. Cortical neural network activity dependent on synaptic connections between SLM2-expressing-pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeostatic auto-regulation controlling brain network activity and behavior., Graphical Abstract, Highlights • SLM2 splicing targets are spatially controlled within the hippocampus • RNA-seq reveals SLM2 feedback control and synaptic protein splicing targets • Loss of SLM2 dampens patterns of hippocampal γ oscillations • Loss of SLM2 changes mouse behavior that depends on these neural networks, SLM2 is an RNA binding protein conserved for ∼550 million years. Ehrmann et al. identify a homeostatic feedback pathway that controls SLM2 expression across the brain. Loss of SLM2 protein causes defects in neural network activity and changes mouse behavior.

Published
2016

30. An ancient germ cell-specific RNA-binding protein protects the germline from cryptic splice site poisoning

Author

Ehrmann, Ingrid, Crichton, James H, Gazzara, Matthew R, James, Katherine, Liu, Yilei, Grellscheid, Sushma Nagaraja, Curk, Tomaž, de Rooij, Dirk, Steyn, Jannetta S, Cockell, Simon, Adams, Ian R, Barash, Yoseph, Elliott, David J, Sub Developmental Biology, and Developmental Biology

Abstract

Male germ cells of all placental mammals express an ancient nuclear RNA binding protein of unknown function called RBMXL2. Here we find that deletion of the retrogene encoding RBMXL2 blocks spermatogenesis. Transcriptome analyses of age-matched deletion mice show that RBMXL2 controls splicing patterns during meiosis. In particular, RBMXL2 represses the selection of aberrant splice sites and the insertion of cryptic and premature terminal exons. Our data suggest a Rbmxl2 retrogene has been conserved across mammals as part of a splicing control mechanism that is fundamentally important to germ cell biology. We propose that this mechanism is essential to meiosis because it buffers the high ambient concentrations of splicing activators, thereby preventing poisoning of key transcripts and disruption to gene expression by aberrant splice site selection.

Published
2019

31. An ancient germ cell-specific RNA-binding protein protects the germline from cryptic splice site poisoning

Author

Sub Developmental Biology, Developmental Biology, Ehrmann, Ingrid, Crichton, James H, Gazzara, Matthew R, James, Katherine, Liu, Yilei, Grellscheid, Sushma Nagaraja, Curk, Tomaž, de Rooij, Dirk, Steyn, Jannetta S, Cockell, Simon, Adams, Ian R, Barash, Yoseph, Elliott, David J, Sub Developmental Biology, Developmental Biology, Ehrmann, Ingrid, Crichton, James H, Gazzara, Matthew R, James, Katherine, Liu, Yilei, Grellscheid, Sushma Nagaraja, Curk, Tomaž, de Rooij, Dirk, Steyn, Jannetta S, Cockell, Simon, Adams, Ian R, Barash, Yoseph, and Elliott, David J

Published
2019

33. Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19

Author

Asnani, Mukta, primary, Hayer, Katharina E., additional, Naqvi, Ammar S., additional, Zheng, Sisi, additional, Yang, Scarlett Y., additional, Oldridge, Derek, additional, Ibrahim, Fadia, additional, Maragkakis, Manolis, additional, Gazzara, Matthew R., additional, Black, Kathryn L., additional, Bagashev, Asen, additional, Taylor, Deanne, additional, Mourelatos, Zissimos, additional, Grupp, Stephan A., additional, Barrett, David, additional, Maris, John M., additional, Sotillo, Elena, additional, Barash, Yoseph, additional, and Thomas-Tikhonenko, Andrei, additional

Published
2019
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34. Mutator dynamics in sexual and asexual experimental populations of yeast

Author

Gazzara Matthew R, Raynes Yevgeniy, and Sniegowski Paul D

Subjects
Evolution, QH359-425
Abstract

Abstract Background In asexual populations, mutators may be expected to hitchhike with associated beneficial mutations. In sexual populations, recombination is predicted to erode such associations, inhibiting mutator hitchhiking. To investigate the effect of recombination on mutators experimentally, we compared the frequency dynamics of a mutator allele (msh2Δ) in sexual and asexual populations of Saccharomyces cerevisiae. Results Mutator strains increased in frequency at the expense of wild-type strains in all asexual diploid populations, with some approaching fixation in 150 generations of propagation. Over the same period of time, mutators declined toward loss in all corresponding sexual diploid populations as well as in haploid populations propagated asexually. Conclusions We report the first experimental investigation of mutator dynamics in sexual populations. We show that a strong mutator quickly declines in sexual populations while hitchhiking to high frequency in asexual diploid populations, as predicted by theory. We also show that the msh2Δ mutator has a high and immediate realized cost that is alone sufficient to explain its decline in sexual populations. We postulate that this cost is indirect; namely, that it is due to a very high rate of recessive lethal or strongly deleterious mutation. However, we cannot rule out the possibility that msh2Δ also has unknown directly deleterious effects on fitness, and that these effects may differ between haploid asexual and sexual populations. Despite these reservations, our results prompt us to speculate that the short-term cost of highly deleterious recessive mutations can be as important as recombination in preventing mutator hitchhiking in sexual populations.

Published
2011
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35. Author response: An ancient germ cell-specific RNA-binding protein protects the germline from cryptic splice site poisoning

Author

Ehrmann, Ingrid, primary, Crichton, James H, additional, Gazzara, Matthew R, additional, James, Katherine, additional, Liu, Yilei, additional, Grellscheid, Sushma Nagaraja, additional, Curk, Tomaž, additional, de Rooij, Dirk, additional, Steyn, Jannetta S, additional, Cockell, Simon, additional, Adams, Ian R, additional, Barash, Yoseph, additional, and Elliott, David J, additional

Published
2018
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36. Aberrant splicing in B-cell acute lymphoblastic leukemia

Author

Black, Kathryn L, primary, Naqvi, Ammar S, additional, Asnani, Mukta, additional, Hayer, Katharina E, additional, Yang, Scarlett Y, additional, Gillespie, Elisabeth, additional, Bagashev, Asen, additional, Pillai, Vinodh, additional, Tasian, Sarah K, additional, Gazzara, Matthew R, additional, Carroll, Martin, additional, Taylor, Deanne, additional, Lynch, Kristen W, additional, Barash, Yoseph, additional, and Thomas-Tikhonenko, Andrei, additional

Published
2018
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39. Aberrant splicing in B-cell acute lymphoblastic leukemia

Author

Black, Kathryn L., primary, Naqvi, Ammar S., additional, Hayer, Katharina E., additional, Yang, Scarlett Y., additional, Gillespie, Elisabeth, additional, Bagashev, Asen, additional, Pillai, Vinodh, additional, Tasian, Sarah K., additional, Gazzara, Matthew R., additional, Carroll, Martin, additional, Taylor, Deanne, additional, Lynch, Kristen W., additional, Barash, Yoseph, additional, and Thomas-Tikhonenko, Andrei, additional

Published
2017
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49. Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy

Author

Sotillo, Elena, primary, Barrett, David M., additional, Black, Kathryn L., additional, Bagashev, Asen, additional, Oldridge, Derek, additional, Wu, Glendon, additional, Sussman, Robyn, additional, Lanauze, Claudia, additional, Ruella, Marco, additional, Gazzara, Matthew R., additional, Martinez, Nicole M., additional, Harrington, Colleen T., additional, Chung, Elaine Y., additional, Perazzelli, Jessica, additional, Hofmann, Ted J., additional, Maude, Shannon L., additional, Raman, Pichai, additional, Barrera, Alejandro, additional, Gill, Saar, additional, Lacey, Simon F., additional, Melenhorst, Jan J., additional, Allman, David, additional, Jacoby, Elad, additional, Fry, Terry, additional, Mackall, Crystal, additional, Barash, Yoseph, additional, Lynch, Kristen W., additional, Maris, John M., additional, Grupp, Stephan A., additional, and Thomas-Tikhonenko, Andrei, additional

Published
2015
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