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  1. Artikel ; Online: Canadian COVID-19 host genetics cohort replicates known severity associations.

    Garg, Elika / Arguello-Pascualli, Paola / Vishnyakova, Olga / Halevy, Anat R / Yoo, Samantha / Brooks, Jennifer D / Bull, Shelley B / Gagnon, France / Greenwood, Celia M T / Hung, Rayjean J / Lawless, Jerald F / Lerner-Ellis, Jordan / Dennis, Jessica K / Abraham, Rohan J S / Garant, Jean-Michel / Thiruvahindrapuram, Bhooma / Jones, Steven J M / Strug, Lisa J / Paterson, Andrew D /
    Sun, Lei / Elliott, Lloyd T

    PLoS genetics

    2024  Band 20, Heft 3, Seite(n) e1011192

    Abstract: The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic ... ...

    Abstract The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic contributors to severe COVID-19 (considering 3,499 hospitalized cases and 4,975 non-hospitalized after quality control). We investigated the evidence for replication of loci reported by the International Host Genetics Initiative (HGI); analyzed the X chromosome; conducted rare variant gene-based analysis and polygenic risk score testing. Population stratification was adjusted for using meta-analysis across ancestry groups. We replicated two loci identified by the HGI for COVID-19 severity: the LZTFL1/SLC6A20 locus on chromosome 3 and the FOXP4 locus on chromosome 6 (the latter with a variant significant at P < 5E-8). We found novel significant associations with MRAS and WDR89 in gene-based analyses, and constructed a polygenic risk score that explained 1.01% of the variance in severe COVID-19. This study provides independent evidence confirming the robustness of previously identified COVID-19 severity loci by the HGI and identifies novel genes for further investigation.
    Mesh-Begriff(e) Humans ; COVID-19/genetics ; SARS-CoV-2/genetics ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Canada/epidemiology ; Genome-Wide Association Study ; Membrane Transport Proteins ; Forkhead Transcription Factors ; North American People
    Chemische Substanzen SLC6A20 protein, human ; Membrane Transport Proteins ; FOXP4 protein, human ; Forkhead Transcription Factors
    Sprache Englisch
    Erscheinungsdatum 2024-03-22
    Erscheinungsland United States
    Dokumenttyp Meta-Analysis ; Journal Article
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1011192
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: DNA replication fork speed underlies cell fate changes and promotes reprogramming.

    Nakatani, Tsunetoshi / Lin, Jiangwei / Ji, Fei / Ettinger, Andreas / Pontabry, Julien / Tokoro, Mikiko / Altamirano-Pacheco, Luis / Fiorentino, Jonathan / Mahammadov, Elmir / Hatano, Yu / Van Rechem, Capucine / Chakraborty, Damayanti / Ruiz-Morales, Elias R / Arguello Pascualli, Paola Y / Scialdone, Antonio / Yamagata, Kazuo / Whetstine, Johnathan R / Sadreyev, Ruslan I / Torres-Padilla, Maria-Elena

    Nature genetics

    2022  Band 54, Heft 3, Seite(n) 318–327

    Abstract: Totipotency emerges in early embryogenesis, but its molecular underpinnings remain poorly characterized. In the present study, we employed DNA fiber analysis to investigate how pluripotent stem cells are reprogrammed into totipotent-like 2-cell-like ... ...

    Abstract Totipotency emerges in early embryogenesis, but its molecular underpinnings remain poorly characterized. In the present study, we employed DNA fiber analysis to investigate how pluripotent stem cells are reprogrammed into totipotent-like 2-cell-like cells (2CLCs). We show that totipotent cells of the early mouse embryo have slow DNA replication fork speed and that 2CLCs recapitulate this feature, suggesting that fork speed underlies the transition to a totipotent-like state. 2CLCs emerge concomitant with DNA replication and display changes in replication timing (RT), particularly during the early S-phase. RT changes occur prior to 2CLC emergence, suggesting that RT may predispose to gene expression changes and consequent reprogramming of cell fate. Slowing down replication fork speed experimentally induces 2CLCs. In vivo, slowing fork speed improves the reprogramming efficiency of somatic cell nuclear transfer. Our data suggest that fork speed regulates cellular plasticity and that remodeling of replication features leads to changes in cell fate and reprogramming.
    Mesh-Begriff(e) Animals ; Cell Differentiation/genetics ; Cellular Reprogramming/genetics ; DNA Replication/genetics ; Embryo, Mammalian ; Embryonic Development/genetics ; Mice ; Pluripotent Stem Cells
    Sprache Englisch
    Erscheinungsdatum 2022-03-07
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/s41588-022-01023-0
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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