Molecular underpinnings and environmental drivers of loss of heterozygosity in Drosophila intestinal stem cells
Lara Al Zouabi,
Marine Stefanutti,
Spyridon Roumeliotis,
Gwenn Le Meur,
Benjamin Boumard,
Nick Riddiford,
Natalia Rubanova,
Mylène Bohec,
Louis Gervais,
Nicolas Servant,
Allison J. Bardin
Affiliations
Lara Al Zouabi
Genetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, France
Marine Stefanutti
Genetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, France
Spyridon Roumeliotis
Genetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, France
Gwenn Le Meur
Genetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, France
Benjamin Boumard
Genetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, France
Nick Riddiford
Genetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, France
Natalia Rubanova
Genetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, France; Bioinformatics, Biostatistics, Epidemiology and Computational Systems Unit, Institut Curie, PSL Research University, INSERM U900, 75005 Paris, France
Mylène Bohec
ICGex Next-Generation Sequencing Platform, Institut Curie, PSL Research University, 75005 Paris, France
Louis Gervais
Genetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, France
Nicolas Servant
Bioinformatics, Biostatistics, Epidemiology and Computational Systems Unit, Institut Curie, PSL Research University, INSERM U900, 75005 Paris, France
Allison J. Bardin
Genetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, France; Corresponding author
Summary: During development and aging, genome mutation leading to loss of heterozygosity (LOH) can uncover recessive phenotypes within tissue compartments. This phenomenon occurs in normal human tissues and is prevalent in pathological genetic conditions and cancers. While studies in yeast have defined DNA repair mechanisms that can promote LOH, the predominant pathways and environmental triggers in somatic tissues of multicellular organisms are not well understood. Here, we investigate mechanisms underlying LOH in intestinal stem cells in Drosophila. Infection with the pathogenic bacteria, Erwinia carotovora carotovora 15, but not Pseudomonas entomophila, increases LOH frequency. Using whole genome sequencing of somatic LOH events, we demonstrate that they arise primarily via mitotic recombination. Molecular features and genetic evidence argue against a break-induced replication mechanism and instead support cross-over via double Holliday junction-based repair. This study provides a mechanistic understanding of mitotic recombination, an important mediator of LOH, and its effects on stem cells in vivo.
