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The COVID-19 pandemic has prompted an unprecedented global effort to understand and mitigate the spread of the SARS-CoV-2 virus. In this study, we present a comprehensive analysis of COVID-19 in Western New York (WNY), integrating individual patient-level genomic sequencing data with a spatially informed agent-based disease Susceptible-Exposed-Infectious-Recovered (SEIR) computational model. The integration of genomic and spatial data enables a multi-faceted exploration of the factors influencing the transmission patterns of COVID-19, including genetic variations in the viral genomes, population density, and movement dynamics in New York State (NYS). Our genomic analyses provide insights into the genetic heterogeneity of SARS-CoV-2 within a single lineage, at region-specific resolutions, while our population analyses provide models for SARS-CoV-2 lineage transmission. Together, our findings shed light on localized dynamics of the pandemic, revealing potential cross-county transmission networks. This interdisciplinary approach, bridging genomics and spatial modeling, contributes to a more comprehensive understanding of COVID-19 dynamics. The results of this study have implications for future public health strategies, including guiding targeted interventions and resource allocations to control the spread of similar viruses. 

Abstract The Msh2–Msh3 mismatch repair (MMR) complex in Saccharomyces cerevisiae recognizes and directs repair of insertion/deletion loops (IDLs) up to ∼17 nucleotides. Msh2–Msh3 also recognizes and binds distinct looped and branched DNA structures with varying affinities, thereby contributing to genome stability outside post-replicative MMR through homologous recombination, double-strand break repair (DSBR) and the DNA damage response. In contrast, Msh2–Msh3 promotes genome instability through trinucleotide repeat (TNR) expansions, presumably by binding structures that form from single-stranded (ss) TNR sequences. We previously demonstrated that Msh2–Msh3 binding to 5′ ssDNA flap structures interfered with Rad27 (Fen1 in humans)-mediated Okazaki fragment maturation (OFM) in vitro. Here we demonstrate that elevated Msh2–Msh3 levels interfere with DNA replication and base excision repair in vivo. Elevated Msh2–Msh3 also induced a cell cycle arrest that was dependent on RAD9 and ELG1 and led to PCNA modification. These phenotypes also required Msh2–Msh3 ATPase activity and downstream MMR proteins, indicating an active mechanism that is not simply a result of Msh2–Msh3 DNA-binding activity. This study provides new mechanistic details regarding how excess Msh2–Msh3 can disrupt DNA replication and repair and highlights the role of Msh2–Msh3 protein abundance in Msh2–Msh3-mediated genomic instability. 

The sequencing of human virus genomes from wastewater samples is an efficient method for tracking viral transmission and evolution at the community level. However, this requires the recovery of viral nucleic acids of high quality. We developed a reusable tangential-flow filtration system to concentrate and purify viruses from wastewater for genome sequencing. A pilot study was conducted with 94 wastewater samples from four local sewersheds, from which viral nucleic acids were extracted, and the whole genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was sequenced using the ARTIC V4.0 primers. Our method yielded a high probability (0.9) of recovering complete or near-complete SARS-CoV-2 genomes (>90% coverage at 10× depth) from wastewater when the COVID-19 incidence rate exceeded 33 cases per 100 000 people. The relative abundances of sequenced SARS-CoV-2 variants followed the trends observed from patient-derived samples. We also identified SARS-CoV-2 lineages in wastewater that were underrepresented or not present in the clinical whole-genome sequencing data. The developed tangential-flow filtration system can be easily adopted for the sequencing of other viruses in wastewater, particularly those at low concentrations.