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Negative Selection Allows DNA Mismatch Repair-Deficient Mouse Fibroblasts In Vitro to Tolerate High Levels of Somatic Mutations.
Zhang, Lei; Lee, Moonsook; Hao, Xiaoxiao; Ehlert, Joseph; Chi, Zhongxuan; Jin, Bo; Maslov, Alexander Y; Barabási, Albert-László; Hoeijmakers, Jan H J; Edelmann, Winfried; Vijg, Jan; Dong, Xiao.
Afiliación
  • Zhang L; Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN 55455, USA.
  • Lee M; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
  • Hao X; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • Ehlert J; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • Chi Z; Current affiliation: the Big Data Center of Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510123, China.
  • Jin B; Network Science Institute, Northeastern University, Boston, MA, USA.
  • Maslov AY; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • Barabási AL; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • Hoeijmakers JHJ; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • Edelmann W; Network Science Institute, Northeastern University, Boston, MA, USA.
  • Vijg J; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Dong X; Department of Network and Data Science, Central European University, Budapest, Hungary.
bioRxiv ; 2024 May 07.
Article en En | MEDLINE | ID: mdl-38766154
ABSTRACT
Substantial numbers of somatic mutations have been found to accumulate with age in different human tissues. Clonal cellular amplification of some of these mutations can cause cancer and other diseases. However, it is as yet unclear if and to what extent an increased burden of random mutations can affect cellular function without clonal amplification. We tested this in cell culture, which avoids the limitation that an increased mutation burden in vivo typically leads to cancer. We performed single-cell whole-genome sequencing of primary fibroblasts from DNA mismatch repair (MMR) deficient Msh2-/- mice and littermate control animals after long-term passaging. Apart from analyzing somatic mutation burden we analyzed clonality, mutational signatures, and hotspots in the genome, characterizing the complete landscape of somatic mutagenesis in normal and MMR-deficient mouse primary fibroblasts during passaging. While growth rate of Msh2-/- fibroblasts was not significantly different from the controls, the number of de novo single-nucleotide variants (SNVs) increased linearly up until at least 30,000 SNVs per cell, with the frequency of small insertions and deletions (INDELs) plateauing in the Msh2-/- fibroblasts to about 10,000 INDELS per cell. We provide evidence for negative selection and large-scale mutation-driven population changes, including significant clonal expansion of preexisting mutations and widespread cell-strain-specific hotspots. Overall, our results provide evidence that increased somatic mutation burden drives significant cell evolutionary changes in a dynamic cell culture system without significant effects on growth. Since similar selection processes against mutations preventing organ and tissue dysfunction during aging are difficult to envision, these results suggest that increased somatic mutation burden can play a causal role in aging and diseases other than cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos