Molecular Underpinnings and Environmental Drivers of Spontaneous Loss of Heterozygosity in Drosophila Intestinal Stem Cells

Abstract

The genome stability of adult stem cells is of particular importance as these cells maintain long-term self-renewal capacity and can contribute extensively to adult tissues. During development and aging, genome mutation leading to loss of heterozygosity (LOH) can uncover recessive phenotypes and be propagated within tissue compartments. This phenomenon occurs in normal human tissues, and is prevalent in pathological genetic conditions and cancers. While previous studies in yeast have defined distinct DNA repair mechanisms that can promote LOH, the predominant pathways underlying LOH in complex somatic tissues of multicellular organisms are not well understood. In addition, how environmental triggers such as pathogenic bacterial infection may impact LOH is unclear. Here, we investigate the mechanisms giving rise to LOH in adult intestinal stem cells in Drosophila. Our data indicate that infection with the enteric 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 of recombination sites and genetic evidence argue against formation via break-induced replication and instead support cross-over events arising from double Holliday junction-based repair. This study provides a mechanistic understanding of mitotic recombination in stem cells in vivo, an important mediator of LOH.

E2F1 promotes, JNK and DIAP1 inhibit, and chromosomal position has little effect on radiation-induced Loss of Heterozygosity inDrosophila

“…This study noted, however, that the frequency of spontaneous LOH at 19E was higher than predicted from meiotic maps and higher than observed for a centromere-proximal locus on chromosome 3R, suggesting additional factors at play. Third, whole genome sequencing confirmed that spontaneous LOH of chromosome 2 loci in the adult intestine occur through mitotic recombination [15].…”