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George Church

Xiaoge Guo, Alejandro Chavez, Angela Tung, Yingleong Chan, Christian Kaas, Yi Yin, Ryan Cecchi, Santiago Lopez Garnier, Eric D Kelsic, Max Schubert, James E DiCarlo, James J Collins, George M Church
Construction and characterization of large genetic variant libraries is essential for understanding genome function, but remains challenging. Here, we introduce a Cas9-based approach for generating pools of mutants with defined genetic alterations (deletions, substitutions, and insertions) with an efficiency of 80-100% in yeast, along with methods for tracking their fitness en masse. We demonstrate the utility of our approach by characterizing the DNA helicase SGS1 with small tiling deletion mutants that span the length of the protein and a series of point mutations against highly conserved residues in the protein...
May 21, 2018: Nature Biotechnology
Idan Frumkin, Marc J Lajoie, Christopher J Gregg, Gil Hornung, George M Church, Yitzhak Pilpel
Although the genetic code is redundant, synonymous codons for the same amino acid are not used with equal frequencies in genomes, a phenomenon termed "codon usage bias." Previous studies have demonstrated that synonymous changes in a coding sequence can exert significant cis effects on the gene's expression level. However, whether the codon composition of a gene can also affect the translation efficiency of other genes has not been thoroughly explored. To study how codon usage bias influences the cellular economy of translation, we massively converted abundant codons to their rare synonymous counterpart in several highly expressed genes in Escherichia coli This perturbation reduces both the cellular fitness and the translation efficiency of genes that have high initiation rates and are naturally enriched with the manipulated codon, in agreement with theoretical predictions...
May 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
George McHardy
John Hunter died in 1793 and was buried in the vaults of the church of St Martin-in-the-Fields, London. In 1859, the vaults were required to be cleared and Hunter's coffin was found and his remains were reinterred in Westminster Abbey beneath a memorial brass. In the course of research on several such memorials in a Worcestershire village church, a letter was found that a clerk, having misread the writer's signature, consequently misfiled. Following this lead, it is now possible to tell something not only of the genesis of Weekes's statue of Hunter but also of the making and cost of the brass over his grave...
January 1, 2018: Journal of Medical Biography
Alexandra M de Paz, Thaddeus R Cybulski, Adam H Marblestone, Bradley M Zamft, George M Church, Edward S Boyden, Konrad P Kording, Keith E J Tyo
DNA polymerase fidelity is affected by both intrinsic properties and environmental conditions. Current strategies for measuring DNA polymerase error rate in vitro are constrained by low error subtype sensitivity, poor scalability, and lack of flexibility in types of sequence contexts that can be tested. We have developed the Magnification via Nucleotide Imbalance Fidelity (MagNIFi) assay, a scalable next-generation sequencing assay that uses a biased deoxynucleotide pool to quantitatively shift error rates into a range where errors are frequent and hence measurement is robust, while still allowing for accurate mapping to error rates under typical conditions...
April 30, 2018: Nucleic Acids Research
Steven Henikoff, George M Church
No abstract text is available yet for this article.
May 2018: Genetics
Nita A Farahany, Henry T Greely, Steven Hyman, Christof Koch, Christine Grady, Sergiu P Pașca, Nenad Sestan, Paola Arlotta, James L Bernat, Jonathan Ting, Jeantine E Lunshof, Eswar P R Iyer, Insoo Hyun, Beatrice H Capestany, George M Church, Hao Huang, Hongjun Song
No abstract text is available yet for this article.
April 2018: Nature
Assaf C Bester, Jonathan D Lee, Alejandro Chavez, Yu-Ru Lee, Daphna Nachmani, Suhani Vora, Joshua Victor, Martin Sauvageau, Emanuele Monteleone, John L Rinn, Paolo Provero, George M Church, John G Clohessy, Pier Paolo Pandolfi
Resistance to chemotherapy plays a significant role in cancer mortality. To identify genetic units affecting sensitivity to cytarabine, the mainstay of treatment for acute myeloid leukemia (AML), we developed a comprehensive and integrated genome-wide platform based on a dual protein-coding and non-coding integrated CRISPRa screening (DICaS). Putative resistance genes were initially identified using pharmacogenetic data from 760 human pan-cancer cell lines. Subsequently, genome scale functional characterization of both coding and long non-coding RNA (lncRNA) genes by CRISPR activation was performed...
April 19, 2018: Cell
Yingleong Chan, Ying Kai Chan, Daniel B Goodman, Xiaoge Guo, Alejandro Chavez, Elaine T Lim, George M Church
We describe a method that enables the multiplex screening of a pool of many different donor cell lines. Our method accurately predicts each donor proportion from the pool without requiring the use of unique DNA barcodes as markers of donor identity. Instead, we take advantage of common single nucleotide polymorphisms, whole-genome sequencing, and an algorithm to calculate the proportions from the sequencing data. By testing using simulated and real data, we showed that our method robustly predicts the individual proportions from a mixed-pool of numerous donors, thus enabling the multiplexed testing of diverse donor cells en masse...
April 19, 2018: Genome Medicine
Joseph T Church, Nicole L Werner, Meghan A Coughlin, Julia Menzel-Smith, Mary Najjar, Benjamin D Carr, Hemant Parmar, Jeff Neil, Dimitrios Alexopoulos, Carlos Perez-Torres, Xia Ge, Scott C Beeman, Joel R Garbow, George B Mychaliska
PURPOSE: We evaluated whether brain development continues and brain injury is prevented during Artificial Placenta (AP) support utilizing extracorporeal life support (ECLS). METHODS: Lambs at EGA 118days (term=145; n=4) were placed on AP support (venovenous ECLS with jugular drainage and umbilical vein reinfusion) for 7days and sacrificed. Early (EGA 118; n=4) and late (EGA 127; n=4) mechanical ventilation (MV) lambs underwent conventional MV for up to 48h and were sacrificed, and early (n=5) and late (n=5) tissue control (TC) lambs were sacrificed at delivery...
March 8, 2018: Journal of Pediatric Surgery
Jennifer S McLeod, Joseph T Church, Prathusha Yerramilli, Megan A Coughlin, Elena M Perkins, Raja Rabah, Robert H Bartlett, Alvaro Rojas-Pena, Joel K Greenson, Erin E Perrone, George B Mychaliska
BACKGROUND: An Artificial Placenta (AP) utilizing extracorporeal life support (ECLS) could revolutionize care of extremely premature newborns, but its effects on gastrointestinal morphology and injury need investigation. METHODS: Lambs (116-121days GA, term=145; n=5) were delivered by C-section, cannulated for ECLS, had total parenteral nutrition (TPN) provided, and were supported for 7days before euthanasia. Early and Late Tissue Controls (ETC, n=5 and LTC, n=5) delivered at 115-121days and 125-131days, respectively, were immediately sacrificed...
March 8, 2018: Journal of Pediatric Surgery
Christopher J Wilson, Tim Fennell, Anne Bothmer, Morgan L Maeder, Deepak Reyon, Cecilia Cotta-Ramusino, Cecilia A Fernandez, Eugenio Marco, Luis A Barrera, Hariharan Jayaram, Charles F Albright, Gerald F Cox, George M Church, Vic E Myer
No abstract text is available yet for this article.
March 30, 2018: Nature Methods
Joseph T Church, Rodrigo Mon, Tiffany Wright, Megan A Coughlin, Maria Ladino-Torres, Christopher Tapley, Heather Bowen, Niki Matusko, George B Mychaliska
PURPOSE: Survivors of congenital diaphragmatic hernia (CDH) face high morbidity. We studied the neurodevelopmental outcomes of CDH survivors at a single institution. METHODS: CDH survivors born July 2006-March 2016 at a free-standing children's hospital were reviewed. Neurodevelopment was assessed using the Peabody Developmental Motor Scales (PDMS-2) broken into gross, fine, and total motor quotients. Data collected included prenatal variables (liver herniation, defect laterality, observed:expected total fetal lung volume (o:eTFLV) on MRI), birth demographics (sex, race, estimated gestational age (EGA), birth weight (BtWt), 5 min APGAR, associated anomalies), and therapies/hospital course (HFOV/HFJV, ECMO, timing of repair, pulmonary hypertension (PHTN) severity, length of stay, ventilator days)...
March 5, 2018: Journal of Pediatric Surgery
Alejandro Chavez, Benjamin W Pruitt, Marcelle Tuttle, Rebecca S Shapiro, Ryan J Cecchi, Jordan Winston, Brian M Turczyk, Michael Tung, James J Collins, George M Church
Here, we present a generalized method of guide RNA "tuning" that enables Cas9 to discriminate between two target sites that differ by a single-nucleotide polymorphism. We employ our methodology to generate an in vivo mutation prevention system in which Cas9 actively restricts the occurrence of undesired gain-of-function mutations within a population of engineered organisms. We further demonstrate that the system is scalable to a multitude of targets and that the general tuning and prevention concepts are portable across engineered Cas9 variants and Cas9 orthologs...
April 3, 2018: Proceedings of the National Academy of Sciences of the United States of America
Jonathan T Macy, Elizabeth A S Moser, Adam T Hirsh, Patrick O Monahan, George J Eckert, Gerardo Maupomé
BACKGROUND: Mexican immigrants in the United States suffer from poor oral health. The objective of the current study was to explore the utility of applying theory-based factors associated with seeking preventive dental care in a sample of Mexican American adults. METHODS: Data were collected from a cross-sectional survey of a sample of 157 people of Mexican origin (64% female; age 34 ± 11 years) recruited primarily from church congregations and lay community organizations in Central Indiana...
March 12, 2018: BMC Oral Health
Joseph T Church, Elena M Perkins, Megan A Coughlin, Jennifer S McLeod, Katherine Boss, J Kelley Bentley, Marc B Hershenson, Raja Rabah, Robert H Bartlett, George B Mychaliska
BACKGROUND: Extremely premature neonates suffer high morbidity and mortality. An artificial placenta (AP) using extracorporeal life support (ECLS) is a promising therapy. OBJECTIVES: We hypothesized that intratracheal perfluorocarbon (PFC) instillation during AP support would reduce lung injury and promote lung development relative to intratracheal amniotic fluid or crystalloid. METHODS: Lambs at an estimated gestational age (EGA) 116-121 days (term 145 days) were placed on venovenous ECLS with jugular drainage and umbilical vein reinfusion and intubated...
February 23, 2018: Neonatology
Timothy M Wannier, Aditya M Kunjapur, Daniel P Rice, Michael J McDonald, Michael M Desai, George M Church
Efforts are underway to construct several recoded genomes anticipated to exhibit multivirus resistance, enhanced nonstandard amino acid (nsAA) incorporation, and capability for synthetic biocontainment. Although our laboratory pioneered the first genomically recoded organism ( Escherichia coli strain C321.∆A), its fitness is far lower than that of its nonrecoded ancestor, particularly in defined media. This fitness deficit severely limits its utility for nsAA-linked applications requiring defined media, such as live cell imaging, metabolic engineering, and industrial-scale protein production...
March 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Michael J McGeachie, George L Clemmer, Boris Hayete, Heming Xing, Karl Runge, Ann Chen Wu, Xiaofeng Jiang, Quan Lu, Bruce Church, Iya Khalil, Kelan Tantisira, Scott Weiss
BACKGROUND: Variation in response to the most commonly used class of asthma controller medication, inhaled corticosteroids, presents a serious challenge in asthma management, particularly for steroid-resistant patients with little or no response to treatment. OBJECTIVE: We applied a systems biology approach to primary clinical and genomic data to identify and validate genes that modulate steroid response in asthmatic children. METHODS: We selected 104 inhaled corticosteroid-treated asthmatic non-Hispanic white children and determined a steroid responsiveness endophenotype (SRE) using observations of 6 clinical measures over 4 years...
February 27, 2018: Journal of Allergy and Clinical Immunology
Jeff Nivala, Seth L Shipman, George M Church
The adaptation phase of CRISPR-Cas immunity depends on the precise integration of short segments of foreign DNA (spacers) into a specific genomic location within the CRISPR locus by the Cas1-Cas2 integration complex. Although off-target spacer integration outside of canonical CRISPR arrays has been described in vitro, no evidence of non-specific integration activity has been found in vivo. Here, we show that non-canonical off-target integrations can occur within bacterial chromosomes at locations that resemble the native CRISPR locus by characterizing hundreds of off-target integration locations within Escherichia coli...
March 2018: Nature Microbiology
Richie E Kohman, Aditya M Kunjapur, Eriona Hysolli, Yu Wang, George M Church
Since the elucidation of its structure, DNA has been at the forefront of biological research. In the past half century, an explosion of DNA-based technology development has occurred with the most rapid advances being made for DNA sequencing. In parallel, dramatic improvements have also been made in the synthesis and editing of DNA from the oligonucleotide to the genome scale. In this Review, we will summarize four different subfields relating to DNA technologies following this trajectory of smaller to larger scale...
April 9, 2018: Angewandte Chemie
Aditya M Kunjapur, Devon A Stork, Erkin Kuru, Oscar Vargas-Rodriguez, Matthieu Landon, Dieter Söll, George M Church
Incorporation of nonstandard amino acids (nsAAs) leads to chemical diversification of proteins, which is an important tool for the investigation and engineering of biological processes. However, the aminoacyl-tRNA synthetases crucial for this process are polyspecific in regard to nsAAs and standard amino acids. Here, we develop a quality control system called "posttranslational proofreading" to more accurately and rapidly evaluate nsAA incorporation. We achieve this proofreading by hijacking a natural pathway of protein degradation known as the N-end rule, which regulates the lifespan of a protein based on its amino-terminal residue...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
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