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Xu, George

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Xu, George
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    Comprehensive Approaches to Identifying the Targets of Natural and Synthetic Antibodies Using Microarray DNA Synthesis and High-Throughput Sequencing
    (2015-09-24) Xu, George; Church, George M.; Sharpe, Arlene H.; Wong, Wesley P.; Hogle, James M.
    The incredible flexibility and specificity of the humoral immune response is dependent on the highly diverse repertoire of naïve and affinity-matured antibodies. Utilizing and understanding the power of this response requires high-throughput approaches. This thesis describes three projects that use recent advances in DNA sequencing and synthesis to develop and apply methods to probe the diversity of these responses at unprecedented depth. Chapter 2 describes a synthetic antibody library designed for high-throughput sequencing assisted selection which enables rapid in vitro selection of antibodies that bind specifically to a target of interest by bypassing the need for laborious single-clone screening for specific binding. Chapter 3 describes a high-throughput assay for detection of antibodies against all known human viruses using immunoprecipitation and high-throughput sequencing of bacteriophage displaying a library of peptides tiling through the proteome of all known human viruses. And last, chapter 4 describes the use of immunoprecipitation and high-throughput sequencing of both bacteriophage displayed peptides from the human peptidome and ribosome displayed proteins from the human proteome to identify a novel subclass of patients with scleroderma with autoantibodies against the minor spliceosome complex. The work described in this thesis will enhance our ability to study and exploit the properties of antibodies and the humoral immune response.
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    Enhanced multiplex genome engineering through co-operative oligonucleotide co-selection
    (Oxford University Press, 2012) Carr, Peter A.; Wang, Harris He; Sterling, Bram; Isaacs, Farren J.; Lajoie, Marc; Xu, George; Church, George; Jacobson, Joseph M.
    Genome-scale engineering of living organisms requires precise and economical methods to efficiently modify many loci within chromosomes. One such example is the directed integration of chemically synthesized single-stranded deoxyribonucleic acid (oligonucleotides) into the chromosome of Escherichia coli during replication. Herein, we present a general co-selection strategy in multiplex genome engineering that yields highly modified cells. We demonstrate that disparate sites throughout the genome can be easily modified simultaneously by leveraging selectable markers within 500 kb of the target sites. We apply this technique to the modification of 80 sites in the E. coli genome.
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    PhIP-Seq Characterization of Autoantibodies From Patients With Multiple Sclerosis, Type 1 Diabetes and Rheumatoid Arthritis
    (Elsevier BV, 2013-06) Larman, H. Benjamin; Laserson, Uri; Querol, Luis; Verhaeghen, Katrijn; Solimini, Nicole L.; Xu, George; Klarenbeek, Paul L.; Church, George; Hafler, David A.; Plenge, Robert M.; Nigrovic, Peter; De Jager, Philip; Weets, Ilse; Martens, Geert A.; O'Connor, Kevin C.; Elledge, Stephen
    Autoimmune disease results from a loss of tolerance to self-antigens in genetically susceptible individuals. Completely understanding this process requires that targeted antigens be identified, and so a number of techniques have been developed to determine immune receptor specificities. We previously reported the construction of a phage-displayed synthetic human peptidome and a proof-of-principle analysis of antibodies from three patients with neurological autoimmunity. Here we present data from a large-scale screen of 298 independent antibody repertoires, including those from 73 healthy sera, using phage immunoprecipitation sequencing. The resulting database of peptide-antibody interactions characterizes each individual’s unique autoantibody fingerprint, and includes specificities found to occur frequently in the general population as well as those associated with disease. Screening type 1 diabetes (T1D) patients revealed a prematurely polyautoreactive phenotype compared with their matched controls. A collection of cerebrospinal fluids and sera from 63 multiple sclerosis patients uncovered novel, as well as previously reported antibody-peptide interactions. Finally, a screen of synovial fluids and sera from 64 rheumatoid arthritis patients revealed novel disease-associated antibody specificities that were independent of seropositivity status. This work demonstrates the utility of performing PhIP-Seq screens on large numbers of individuals and is another step toward defining the full complement of autoimmunoreactivities in health and disease.