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Bishop, T. C.

Publications and source records attributed to Bishop, T. C..

4 recordsLinked to original sources

Nucleosome-mediated conformational switches in micro-eccDNAs

Extrachromosomal-circular DNA (eccDNA) are circular-DNA elements that are implicated in cellular processes such as genomic diversification and instability, along with other genomic mechanisms. However, their structure and chromatinization state is poorly understood. Here we identified a 358-bp circular micro-eccDNA molecule derived from the human Titin gene, which was selected for this study based on its size and sequence characteristics, and used atomistic molecular dynamics simulations to study its interaction with nucleosomes and corresponding topological state. We show the presence or absence of bound nucleosomes provides a topological switch between intact and denatured DNA.

biophysics↗

A collaborative approach to improving representation in viral genomic surveillance

The lack of routine viral genomic surveillance delayed the initial detection of SARS-CoV-2, allowing the virus to spread unfettered at the outset of the U.S. epidemic. Over subsequent months, poor surveillance enabled variants to emerge unnoticed. Against this backdrop, long-standing social and racial inequities have contributed to a greater burden of cases and deaths among minority groups. To begin to address these problems, we developed a new variant surveillance model geared toward building microbial genome sequencing capacity at universities in or near rural areas and engaging the participation of their local communities. The resulting genomic surveillance network has generated more than 1,000 SARS-CoV-2 genomes to date, including the first confirmed case in northeast Louisiana of Omicron, and the first and sixth confirmed cases in Georgia of the emergent BA.2.75 and BQ.1.1 variants, respectively. In agreement with other studies, significantly higher viral gene copy numbers were observed in Delta variant samples compared to those from Omicron BA.1 variant infections, and lower copy numbers were seen in asymptomatic infections relative to symptomatic ones. Collectively, the results and outcomes from our collaborative work demonstrate that establishing genomic surveillance capacity at smaller academic institutions in rural areas and fostering relationships between academic teams and local health clinics represent a robust pathway to improve pandemic readiness. Author summaryGenomic surveillance involves decoding a pathogens genetic code to track its spread and evolution. During the pandemic, genomic surveillance programs around the world provided valuable data to scientists, doctors, and public health officials. Knowing the complete SARS-CoV-2 genome has helped detect the emergence of new variants, including ones that are more transmissible or cause more severe disease, and has supported the development of diagnostics, vaccines, and therapeutics. The impact of genomic surveillance on public health depends on representative sampling that accurately reflects the diversity and distribution of populations, as well as rapid turnaround time from sampling to data sharing. After a slow start, SARS-CoV-2 genomic surveillance in the United States grew exponentially. Despite this, many rural regions and ethnic minorities remain poorly represented, leaving significant gaps in the data that informs public health responses. To address this problem, we formed a network of universities and clinics in Louisiana, Georgia, and Mississippi with the goal of increasing SARS-CoV-2 sequencing volume, representation, and equity. Our results demonstrate the advantages of rapidly sequencing pathogens in the same communities where the cases occur and present a model that leverages existing academic and clinical infrastructure for a powerful decentralized genomic surveillance system.

microbiology↗

Genome dashboards: Framework and Examples

Genomics is a sequence-based informatics science and a 3D structure-based material science. Here we describe a framework for developing genome dashboards specifically designed to unify informatics with studies of chromatin structure and dynamics. The framework is based on the mathematical representation of geometrically exact rod models and the generalization of DNA base pair step parameters. A Model-View-Controller software design approach is proposed to implement genome dashboards as finite state machines either as desktop or web based applications. Two examples are demonstrated using our minimal genome dashboard called G-Dash-min. The data unification achieved with a genome dashboard supports the bi-directional exchange of data between informatics and structure. Thus any experimentally or theoretically determined sequence based informatics track can inform DNA, nucleosome or chromatin modeling (e.g. nucleosome positions) and structure features can be analyzed as informatics tracks in a genome browser (e.g. DNA base pair step parameters: Roll, Tilt, Twist). Here the framework is applied to chromatin, but genome dashboards are more broadly applicable. Genome dashboards are a novel means of investigating structure-function relationships for regions of the genome ranging from base pairs to entire chromosomes and for generating, validating, and testing mechanistic hypotheses.

genomics↗

G-Dash: A Genome Dashboard Integrating Modeling and Informatics

Genomics is a sequence based informatics science and a structure based molecular material science. There are few tools available that unite these approaches in a scientifically robust manner. Here we describe G-Dash, a web based prototype of a genomics dashboard, specifically designed to integrate informatics and 3D material studies of chromatin. G-Dash unites our Interactive Chromatin Modeling(ICM) tools with the Biodalliance genome browser and the JSMol molecular viewer to rapidly fold any DNA sequence into atomic or coarse-grained models of DNA, nucleosomes or chromatin. As a chromatin modeling tool, G-Dash enables users to specify nucleosome positions from various experimental or theoretical sources, interactively manipulate nucleosomes, and assign different conformational states to each nucleosome. As an informatics tool, data associated with 3D structures are displayed as tracks in a genome browser. The exchange of data between informatics and structure is bi-directional so any informatics track can inform a molecular structure (e.g. color by function) and structure features can be displayed as informatics tracks in a genome browser(e.g. Roll, Slide, or Twist). As a sample application, models of the CHA1 promoter based on experimentally determined nucleosome positions are explored with G-Dash. Steric clashes and DNA knotting are observed but can be resolved with G-Dashs minimal coarse-grained model without significant variation in structure. Results raise questions about the interpretation of nucleosome positioning data and promoter structures. In this regard, G-Dash is a novel tool for investigating structure-function relationships for regions of the genome ranging from base pairs to chromosomes and for generating, validating and testing mechanistic hypotheses. http://dna.engr.latech.edu/[~]gdash/GDash-landing-page

genomics↗