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

Katarzyna Siudeja,Sonya Nassari,Louis Gervais,Patricia Skorski,Sonia Lameiras,Donato Stolfa,Maria Zande,Virginie Bernard,Thomas Rio Frio,Allison J Bardin

doi:10.1016/j.stem.2015.09.016

Katarzyna Siudeja, Sonya Nassari + Show 8 more

Open Access

https://doi.org/10.1016/j.stem.2015.09.016

Copy DOI

Abstract

SummaryAdult 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.

Highlights

During aging, defects in stem cell function contribute to a decline in renewal and repair of adult tissues (Behrens et al, 2014)
It remains unaddressed whether such signs of genomic instability result in somatic mutations sufficient to contribute to age-related functional decline
Somatic Recombination Drives Frequent Loss of Heterozygosity in Aging Stem Cells To study somatic genome instability in adult intestinal stem cells, we first assessed the frequency of spontaneous inactivation of a single copy transgene inserted on the X chromosome at position 1E

Summary

Introduction

Defects in stem cell function contribute to a decline in renewal and repair of adult tissues (Behrens et al, 2014). This, remains controversial as recent work indicates that g-H2AX accumulation is due not to DNA damage per se but to an age-dependent increase in replication stress, which in turn, leads to stem cell functional decline (Flach et al, 2014). It remains unaddressed whether such signs of genomic instability result in somatic mutations sufficient to contribute to age-related functional decline

Results

Discussion

Conclusion