The development of gene mapping techniques has a long and storied history in the Drosophila melanogaster model system (reviewed in ), beginning with Alfred Sturtevant’s fundamental publication of the first genetic map in 1913 . In this work, Sturtevant showed that genes are arranged in a linear order along chromosomes and that the recombination frequency between two genes could be used as a measure of the distance between them. This discovery created the foundation for other key advances in Drosophila gene mapping, including the generation of detailed polytene chromosome cytogenetic maps [3,4], the development of deletion kits covering the genome [5–7], and the sequencing of the D. melanogaster genome . However, despite these advances, the current D. melanogaster genome annotation includes 14,184 genes that have not yet been mapped to the molecular genome (FlyBase R6.43; ), including many genes that were discovered in forward genetic screens. In these cases, alleles have been discovered that produce a phenotype of interest, but the molecular locus responsible for this phenotype remains unknown. For example, several forward genetic screens have been conducted to identify D. melanogaster mutants with defects in DNA repair (e.g., [10–15]). In these screens, flies that showed reduced survival in the presence of a mutagen—usually the alkylating agent methyl methanesulfonate (MMS)— were identified as probable DNA repair mutants. To date, 58 of these mutagen-sensitive (mus) stocks have been generated, yet the gene responsible for the mus phenotype is known for only 15 of these stocks [16,17]. Importantly, each mapped mus gene has encoded an ortholog of a human DNA repair protein , including proteins implicated in disorders such as Bloom syndrome , Fanconi anemia , and xeroderma pigmentosum . The knowledge derived from studies of these 15 mapped mus genes demonstrates the utility of mapping mus genes to facilitate DNA repair research in Drosophila. With this in mind, we sought to map mus109, an X-linked essential gene with three extant alleles: mus109D1  and mus109D2  are homozygous viable hypomorphic alleles, whereas mus109lS is a homozygous lethal null allele . mus109 mutants are characterized by chromosomal instability in the absence of mutagen treatment [20–23], with the majority of chromosome breaks occurring in heterochromatin . Further, mus109 mutants are sensitive to MMS, 4-nitroquinoline-1-oxide (4NQO), and γ irradiation [13,14,24,25], which are mutagens that create DNA adducts (MMS and 4NQO; [26,27]) and oxidative damage (γ irradiation; ). In this manuscript, we present detailed mapping data obtained through complementation analysis, deletion crosses, and DNA sequence alignment showing that mus109 is the uncharacterized Drosophila gene CG2990 (human DNA2). We further discuss the potential functionality of the mus109 mutant alleles by comparing the mutations to conserved catalytic regions in DNA2.
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Mitchell, Chandani; Becker, Vada; DeLoach, Jordan; Nestore, Erica; Bolterstein, Elyse; and Kohl, Kathryn P., "The Drosophila Mutagen-Sensitivity Gene mus109 Encodes DmDNA2" (2022). Biology Faculty Publications. 45.