Natural populations exhibit a great deal of interindividual genetic variation in the response to toxins, exemplified by the variable clinical efficacy of pharmaceutical drugs in humans, and the evolution of pesticide resistant insects. Such variation can result from several phenomena, including variable metabolic detoxification of the xenobiotic, and differential sensitivity of the molecular target of the toxin. Our goal is to genetically dissect variation in the response to xenobiotics, and characterize naturally-segregating polymorphisms that modulate toxicity. Here, we use the Drosophila Synthetic Population Resource (DSPR), a multiparent advanced intercross panel of recombinant inbred lines, to identify QTL (Quantitative Trait Loci) underlying xenobiotic resistance, and employ caffeine as a model toxic compound. Phenotyping over 1,700 genotypes led to the identification of ten QTL, each explaining 4.5–14.4% of the broad-sense heritability for caffeine resistance. Four QTL harbor members of the cytochrome P450 family of detoxification enzymes, which represent strong a priori candidate genes. The case is especially strong for Cyp12d1, with multiple lines of evidence indicating the gene causally impacts caffeine resistance. Cyp12d1 is implicated by QTL mapped in both panels of DSPR RILs, is significantly upregulated in the presence of caffeine, and RNAi knockdown robustly decreases caffeine tolerance. Furthermore, copy number variation at Cyp12d1 is strongly associated with phenotype in the DSPR, with a trend in the same direction observed in the DGRP (Drosophila Genetic Reference Panel). No additional plausible causative polymorphisms were observed in a full genomewide association study in the DGRP, or in analyses restricted to QTL regions mapped in the DSPR. Just as in human populations, replicating modest-effect, naturally-segregating causative variants in an association study framework in flies will likely require very large sample sizes.

Background: Transposable elements (TEs) are endogenous mutagens and their harmful effects are especially evident in syndromes of hybrid dysgenesis. In Drosophila virilis, hybrid dysgenesis is a syndrome of incomplete gonadal atrophy that occurs when males with multiple active TE families fertilize females that lack active copies of the same families. This has been demonstrated to cause the transposition of paternally inherited TE families, with gonadal atrophy driven by the death of germline stem cells. Because there are abundant, active TEs in the male inducer genome, that are not present in the female reactive genome, the D. virilis syndrome serves as an excellent model for understanding the effects of hybridization between individuals with asymmetric TE profiles. Results: Using the D. virilis syndrome of hybrid dysgenesis as a model, we sought to determine how the landscape of germline recombination is affected by parental TE asymmetry. Using a genotyping-by-sequencing approach, we generated a high-resolution genetic map of D. virilis and show that recombination rate and TE density are negatively correlated in this species. We then contrast recombination events in the germline of dysgenic versus non-dysgenic F1 females to show that the landscape of meiotic recombination is hardly perturbed during hybrid dysgenesis. In contrast, hybrid dysgenesis in the female germline increases transmission of chromosomes with mitotic recombination. Using a de novo PacBio assembly of the D. virilis inducer genome we show that clusters of mitotic recombination events in dysgenic females are associated with genomic regions with transposons implicated in hybrid dysgenesis. Conclusions: Overall, we conclude that increased mitotic recombination is likely the result of early TE activation in dysgenic progeny, but a stable landscape of meiotic recombination indicates that either transposition is ameliorated in the adult female germline or that regulation of meiotic recombination is robust to ongoing transposition. These results indicate that the effects of parental TE asymmetry on recombination are likely sensitive to the timing of transposition.

21Germline DNA damage is a double-edged sword. Programmed double-strand breaks establish 22 the foundation for meiotic recombination and chromosome segregation. However, double-strand 23 breaks also pose a significant challenge for genome stability. Because of this, meiotic double-24 strand break formation is tightly regulated. However, natural selection can favor selfish behavior 25 in the germline and transposable elements can cause double-strand breaks independent of the 26 carefully regulated meiotic process. To understand how the regulatory mechanisms of meiotic 27 recombination accommodate unregulated transposition, we have characterized the female 28 recombination landscape in a syndrome of hybrid dysgenesis in Drosophila virilis. In this 29 system, a cross between two strains of D. virilis with divergent transposable element and piRNA 30 profiles results in germline transposition of diverse transposable elements, reduced fertility, and 31 male recombination. We sought to determine how increased transposition during hybrid 32 dysgenesis might perturb the meiotic recombination landscape. Our results show that the overall 33 frequency and distribution of meiotic recombination is extremely robust to germline transposable 34 element activation. However, we also find that hybrid dysgenesis can result in mitotic 35 recombination within the female germline. Overall, these results show that landscape of meiotic 36 recombination may be insensitive to the DNA damage caused by transposition during early 37 development. 38 2011). Moreover, TEs can activate the DNA damage response within developing germline stem 51 cells and alter stem cell fate (Chen et al. 2007;Wylie et al. 2014; Tasnim and Kelleher 2018). 52 53The harmful effects of TEs are especially evident in syndromes of hybrid dysgenesis, where 54 sterility can arise in intraspecific crosses between males carrying TEs and females that lack them 55 (Bingham et al. 1982; Bucheton et al. 1984;Yannopoulos et al. 1987; Lozovskaya et al. 1990). 56 Hybrid dysgenesis is the result of TE activation in the absence of maternal repression by interacting RNAs (piRNAs) (Aravin et al. 2007; Brennecke et al. 2008). The piRNA system of 58 genome defense requires maternal deposition of piRNA to successfully silence TEs across 59 generations. The combination of unrecognized TEs introduced to a naive genome via sperm and 60 the absence of corresponding piRNAs in the egg results in TE activation and hybrid dysgenesis 61 5 (Brennecke et al. 2008). A unique syndrome of hybrid dysgenesis in D. virilis is observed in 62 intraspecific crosses between males of an inducing strain (designated strain 160) and reactive 63 strain females (designated strain 9) (Lozovskaya et al. 1990). The primary TE family responsible 64 for inducing dysgenesis remains unknown and sterility appears to be due to the mass activation 65 of several TE families abundant in strain 160 but not strain 9. At least four elements are proposed 66 to contribute significantly to dysgenesis: Penelope, Helena, Paris, an...

Drosophila melanogaster is a model for the study of innate immunity, yet we have limited knowledge of its natural pathogens. In this study, we sequenced the genome of Lysinibacillus fusiformis strain Juneja, isolated from laboratory fly stocks. As a Gram-positive bacterium with unique peptidoglycans, this strain may provide a new model for pathogen recognition.

There is considerable variation in sleep duration, timing and quality in human populations, and sleep dysregulation has been implicated as a risk factor for a range of health problems. Human sleep traits are known to be regulated by genetic factors, but also by an array of environmental and social factors. These uncontrolled, non-genetic effects complicate powerful identification of the loci contributing to sleep directly in humans. The model system, Drosophila melanogaster, exhibits a behavior that shows the hallmarks of mammalian sleep, and here we use a multitiered approach, encompassing high-resolution QTL mapping, expression QTL data, and functional validation with RNAi to investigate the genetic basis of sleep under highly controlled environmental conditions. We measured a battery of sleep phenotypes in >750 genotypes derived from a multiparental mapping panel and identified several, modest-effect QTL contributing to natural variation for sleep. Merging sleep QTL data with a large head transcriptome eQTL mapping dataset from the same population allowed us to refine the list of plausible candidate causative sleep loci. This set includes genes with previously characterized effects on sleep and circadian rhythms, in addition to novel candidates. Finally, we employed adult, nervous system-specific RNAi on the Dopa decarboxylase, dyschronic, and timeless genes, finding significant effects on sleep phenotypes for all three. The genes we resolve are strong candidates to harbor causative, regulatory variation contributing to sleep.