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π Artificial Intelligence in Bulk RNA-Seq: Challenges and Potential Solutions. Computational and Structural Biotechnology Journal (CSBJ). DOI: https://doi.org/10.34133/csbj.0039
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Genetic evidence for fluctuating selection has begun to accumulate for different species over the past few decades, especially for the Drosophila genus where studies have reported hundreds of loci undergoing putatively adaptive oscillations across successive seasons. However, most theoretical and simulation studies of fluctuating selection have relied on abstract or weakly parameterized models, making it difficult to assess their relevance for natural populations. In this study, we simulate multilocus seasonally fluctuating selection under a recently developed model and examine its effect on the variance effective population size (Ne) at a genome-wide scale. By recapitulating genomic, demographic, and evolutionary parameters from natural Drosophila populations in our simulations, we were able to reproduce allele frequency oscillations reported in recent studies and show that these lead to ~50% genome-wide reductions in Ne. We also demonstrate that Ne reductions are well predicted by the maximum frequency amplitude among all adaptively fluctuating loci, and that the frequency amplitudes are largely determined by the number of adaptively fluctuating loci and the strength of their epistatic interactions. Our results demonstrate that fluctuating selection can substantially reduce effective population size and underscore the importance of temporally variable selection in shaping genome-wide patterns of variation beyond classical models.
Background: Although strict maternal transmission of mitochondria is a general feature of animals and humans for ensuring homogeneity in mitochondrial DNA (mtDNA) across generations, exceptions were reported in the recent past. For example, some extremely rare but spectacular cases of heteroplasmy and paternal transmission in humans have questioned the universal evolutionary principle. Hence, as an alternative, the Mega-NUMT concept was coined to explain this discovery and was thereafter partly proven to exist. This concept expands on the quite common transfer of mtDNA fragments to the nucleus (NUMTs) by considering the existence of multicopy mitochondrial nuclear insertions. Mega-NUMT reports are currently restricted to a few cases in animals, including humans. However, even in humans, their detailed genomic organization, natural prevalence, and potential biological functions remain unclear. Methodology/Principal Findings: Here, we discovered that up to 60 full-sized mitochondrial genomes are integrated into the nuclear genome of the neotropical fruit fly Drosophila paulistorum using long-read sequencing and confirmed their presence by in situ hybridization. The copies are organized in one cluster on chromosome 3, which we, due to its similarity with the Mega-NUMT concept, designated the Dpau Mega-NUMT. Contrary to the rarity in humans, this Mega-NUMT is found at high prevalence (40%) in both long-term laboratory lines and natural D. paulistorum populations of different semispecies. Additionally, the mitochondrial copies in the Mega-NUMT cluster are phylogenetically separated from the current mitotypes of D. paulistorum. Together, these observations suggest long-term maintenance of the Mega-NUMT in nature. Hence, we propose that the Dpau Mega-NUMT may have been transferred to the nuclear genome before D. paulistorum semispecies radiation and maintained at relatively high prevalence in nature by balancing selection due to yet undetermined functions. Conclusions/Significance: To our knowledge, this is the first verified existence and detailed dissection of a Mega-NUMT outside cats and humans. We show that Mega-NUMTs can be persistent in nature, even at high prevalence, potentially due to balancing selection. Our findings strengthen the importance of high-quality long-read sequencing technologies for deciphering complex repeat-rich genomic regions to deepen our understanding of the dynamics of genome evolution within genomic dark matter. ### Competing Interest Statement The authors have declared no competing interest. FWF Austrian Science Fund, P28255B22, FW613A0501, FW613A0502 Swedish Research Council, 2014Β4353
Sexual signals are thought to reflect metabolic capacity, allowing females to assess male genetic quality. In insects, cuticular hydrocarbons (CHCs) are central to mate recognition and sexual signalling, and their biosynthesis is directly tied to mitochondrial metabolism. Because mitochondrial performance requires coordination between the mitochondrial and nuclear genomes, non-compatible genomes may disrupt CHC production and reduce male attractiveness. We tested this prediction using a global Drosophila melanogaster mitonuclear panel comprising 80 cybrid genotypes. Multivariate analyses of male CHC profiles revealed strong nuclear effects, smaller but significant mitochondrial effects, and substantial non-additive mitonuclear interactions that accounted for ~10% of the variance after controlling for body mass. These interactions reorganised CHC blends in genotype-specific ways, with certain hydrocarbons contributing disproportionately to differentiation. In behavioural assays, females preferentially mated with males whose mitonuclear genomes were coadapted. Conversely, coadapted males had higher copulation success than males presenting disrupted combinations to the female. Our results demonstrate that mitonuclear compatibility influences the production of sexual signals and shapes reproductive outcomes, linking genomic interactions to mate choice. ### Competing Interest Statement The authors have declared no competing interest. Leverhulme Trust, RPG-2023-198 UK Research and Innovation, NE/V014307/1
Endosymbiotic bacteria such as Wolbachia pose significant challenges to genetic and molecular investigation due to their obligate intracellular lifestyle and complex growth requirements. Current understanding of their protein biology relies heavily on functional assignments inferred by homology, which may not reflect the specific roles endosymbiont proteins play within the host. This work addresses the need for robust genetic perturbation by demonstrating the successful application and detection of chemical mutagenesis in the genome of the wMel strain of Wolbachia grown within a stably infected Drosophila melanogaster JW18 cell line. To accurately detect EMS-induced mutations in a large, unsorted cell culture population, in which mutations remain at very low allele frequency, we implemented an ultra-low error rate sequencing strategy, circle sequencing. This technique enables confident detection of EMS-induced single nucleotide polymorphisms (SNPs) that would be swamped by the inherent error rates of standard next-generation sequencing. Circle sequencing library preparations successfully revealed a clear EMS mutation signal in treated cells, characterized by a significant enrichment of canonical C/G>T/A transitions. Furthermore we present a model explaining observed EMS mutation rates across the genome for different sequence contexts. These findings show that EMS-treatment can successfully leave detectable mutation signals in intracellular genomes, and offer promise for the future development of protocols to make targeted edits in Wolbachia genomes. ### Competing Interest Statement The authors have declared no competing interest. NIH Common Fund, https://ror.org/001d55x84, R00GM135583, R35GM157189, T32HG012344
Silencing complexes formed by PIWI-clade Argonaute (Ago) proteins and PIWI-interacting RNAs (piRNAs) are essential guardians of genome integrity, controlling the deleterious activities of transposable elements (TEs) in animal germline. However, our understanding of PIWI-piRNA-directed TE silencing remains incomplete. Here, we systemically characterize the proximity proteome of PIWI members, Piwi, Aubergine (Aub), and Ago3 in the germline of Drosophila ovaries. Functional screening identifies previously uncharacterized factors involved in TE silencing, including H3K4me3 writer and transcriptional coactivator Set1. Transcriptome analysis reveals that Set1 acts as an indispensable repressor for TEs, particularly those forming telomeres. The involvement of Set1 in Piwi pathway is further supported by its critical role in the production of antisense, TE-targeting piRNAs. Notably, catalytic activity of Set1 is dispensable for TE silencing. Genome-wide chromatin binding analysis using CUT&Tag demonstrates that Set1 preferentially associates with TE sequences and localizes to subtelomeric piRNA cluster loci, suggesting a role in promoting piRNA precursor transcription through direct binding. Collectively, these findings uncover a noncanonical function of Set1 in Piwi-mediated TE silencing and telomere control in germline nuclei.-
Tauopathies, including Alzheimers disease, are age-related neurodegenerative disorders characterized by abnormal phosphorylation and buildup of microtubule-associated protein tau. Gene expression dysregulation is a key molecular feature of tauopathies, but how aging and disease interact to disrupt crucial transcriptional regulators and pathways remains largely unknown. Here, we examined how pathological tau affects gene expression programs in age-related neurodegenerative disease using a well-established Drosophila melanogaster tauopathy model with neuronal expression of the toxic human tauR406W. Transcriptomic analysis of tau-expressing fly heads showed a preferential downregulation of long neuronal genes with long introns. Notably, we found that these downregulated genes in the tauopathy model are marked by increased accumulation of initiating RNA polymerase II (RNAP II) near the transcription start site and reduced elongating RNAP II within gene bodies, indicating a problem with the transition from initiation to elongation. By calculating an RNAP II Pause Index (PI) for each gene, we identified a strong link between promoter-proximal RNAP II stalling, gene expression deficits, and gene length in the tauopathy model. Overall, we have uncovered the genomic and transcriptomic features of tau-dependent downregulated genes and identified increased RNAP II promoter-proximal stalling as a significant mechanism of transcription stress in tauopathy. ### Competing Interest Statement The authors have declared no competing interest. NIH Common Fund, https://ror.org/001d55x84, 1R21AG077058-01, 5R01NS135611-03
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