Frequent Somatic Mutation in Adult Intestinal Stem Cells Drives Neoplasia and Genetic Mosaicism during Aging

Adult stem cells may acquire mutations that modify cellular behavior, leading to functional declines in homeostasis or providing a competitive advantage resulting in premalignancy. However, the frequency, phenotypic impact, and mechanisms underlying spontaneous mutagenesis during aging are unclear....

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Bibliographic Details
Published in:Cell stem cell 2015-12, Vol.17 (6), p.663-674
Main Authors: Siudeja, Katarzyna, Nassari, Sonya, Gervais, Louis, Skorski, Patricia, Lameiras, Sonia, Stolfa, Donato, Zande, Maria, Bernard, Virginie, Frio, Thomas Rio, Bardin, Allison J.
Format: Article
Language:English
Subjects:
Adult Stem Cells - cytology
Aging
Animals
Drosophila melanogaster
Female
Gene Deletion
Genomic Instability
Intestines - cytology
Life Sciences
Male
Mitosis
Mosaicism
Mutation
Receptors, Notch - metabolism
Recombination, Genetic
Transgenes
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Summary:Adult stem cells may acquire mutations that modify cellular behavior, leading to functional declines in homeostasis or providing a competitive advantage resulting in premalignancy. However, the frequency, phenotypic impact, and mechanisms underlying spontaneous mutagenesis during aging are unclear. Here, we report two mechanisms of genome instability in adult Drosophila intestinal stem cells (ISCs) that cause phenotypic alterations in the aging intestine. First, we found frequent loss of heterozygosity arising from mitotic homologous recombination in ISCs that results in genetic mosaicism. Second, somatic deletion of DNA sequences and large structural rearrangements, resembling those described in cancers and congenital diseases, frequently result in gene inactivation. Such modifications induced somatic inactivation of the X-linked tumor suppressor Notch in ISCs, leading to spontaneous neoplasias in wild-type males. Together, our findings reveal frequent genomic modification in adult stem cells and show that somatic genetic mosaicism has important functional consequences on aging tissues. [Display omitted] •The aging Drosophila intestine is genetically mosaic•Somatic recombination, genomic deletions, and rearrangements occur in aging ISCs•Somatic inactivation of the tumor-suppressor Notch causes male-specific neoplasia Bardin and colleagues show that aging Drosophila intestinal stem cells (ISCs) acquire frequent spontaneous mutations, including frequent loss of heterozygosity arising from homologous mitotic recombination that results in clonal mosaicism. They also show spontaneous gene deletions and chromosomal rearrangements in aging ISCs, which can promote neoplasia formation through inactivating Notch.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2015.09.016