G3: Genes|Genomes|Genetics最新文献

CX-5461 (CX) is under investigation for the treatment of late-stage cancers. While CX was first described as an RNA polymerase I inhibitor, it has recently been shown to primarily inhibit the beta isoform of topoisomerase II. This isoform is also inhibited by anthracycline drugs including Doxorubicin (DOX) and mediates the toxic effects of these drugs on the heart. It is unclear whether CX will similarly cause cardiotoxicity. We therefore tested the effects of CX on iPSC-derived cardiomyocytes from six individuals. CX induces cell death in cardiomyocytes at micromolar concentrations. Transcriptome profiling following treatment over time reveals gene expression programs that correspond to the DNA damage response, which are pathways shared with DOX response genes. Micromolar CX concentrations affect heart-specific genes and 14 functionally-validated genes in loci associated with DOX cardiotoxicity. Our data demonstrate the impact of CX on the transcriptome of cardiomyocytes, a potential off-target cell type of the drug.

Selection intensity is expected to influence the magnitude and genetic architecture of adaptive responses, yet it is rarely evaluated as a standalone variable in experimental evolution studies. Here, we evolved outcrossing populations of Saccharomyces cerevisiae for ∼200 generations across a spectrum of environmental stress from zero to moderate to high ethanol exposure, to examine how genomic responses vary with stress intensity. Across treatments, adaptation proceeded through many subtle allele and haplotype frequency shifts rather than large changes at single loci, consistent with a highly polygenic response. At loci associated with ethanol adaptation, the high stress treatment led to larger allele frequency changes compared to the moderate or no ethanol stress treatments, with the genomic architecture of adaptation becoming increasingly polygenic as selection intensity decreased. Moderate and high stress conditions engaged partially distinct biological pathways, indicating that selection intensity shapes both the magnitude and targets of adaptive change. Within this stress continuum, we also observed substantial, ongoing adaptation in control populations despite extensive prior domestication. Many alleles associated with this adaptation showed reduced or absent responses under ethanol stress, consistent with antagonistic pleiotropy. Consequently, laboratory adaptation can represent a major component of evolutionary change and may confound treatment-specific inferences when not explicitly accounted for. Broadly, our results demonstrate that selection intensity structures adaptive responses in experimental evolution and that continued laboratory adaptation remains an important force in these studies. Our findings underscore the importance of clearly-defined controls and careful consideration of selection intensity when interpreting or comparing across experimental evolution studies.

Hedgehog signaling is a conserved developmental pathway that patterns diverse tissues during vertebrate embryogenesis. In zebrafish, disruptions to the hedgehog pathway cause well-characterized defects in specific cell types including neurons and glia derived from the ventral neural tube. We inhibited hedgehog signaling by overexpressing the Gli3 repressor ubiquitously and performed bulk RNA-seq of 30 hours post-fertilization zebrafish embryos. Consistent with known roles of hedgehog signaling, we observed reduced expression of genes marking lateral floor plate, motor neurons, Kolmer-Agduhr cells, dopaminergic neurons, slow muscle cells, and anterior pituitary. Gene set enrichment analysis using marker genes derived from the Daniocell atlas also revealed downregulation of genes marking H+-ATPase-rich ionocytes, which are located in the embryonic skin and are responsible for osmotic homeostasis. Reduced expression of ionocyte-specific transporter genes and the transcription factor foxi3a suggests that Gli activity may play a previously unrecognized role in the specification of this cell type.

Disruption of ribosome biogenesis triggers nucleolar stress, a conserved cellular response that activates p53. We previously demonstrated that depletion of Nucleolar Complex Protein 1 (Noc1) in Drosophila wing imaginal discs impairs rRNA maturation and ribosome assembly, resulting in elevated p53 levels and apoptosis, hallmarks of nucleolar stress. The Drosophila p53 gene produces four mRNA isoforms, yet their individual contributions to nucleolar stress responses remain poorly understood. Using newly designed isoform-specific qPCR primers, we found that although all p53 isoforms exhibit moderate transcriptional changes following Noc1 reduction, the truncated isoform p53E is robustly and preferentially upregulated. Notably, p53E lacks the N-terminal transactivation domain and has been reported to negatively regulate p53-induced apoptosis in specific tissues. Furthermore, our analyses indicate that γ-H2AV accumulation arises from caspase-dependent apoptosis rather than primary genomic lesions, suggesting the activation of a p53-dependent stress pathway distinct from canonical genotoxic pathways. Together, these findings suggest that p53E may be part of a novel mechanism activated during nucleolar stress, providing insight into how cells adapt to defects in ribosome biogenesis.

The Coffee Leaf Miner (Lepidoptera: Lyonetiidae: Leucoptera coffeella) is a specialist herbivore and major global pest of coffee plants. Current pest control strategies primarily rely on chemical pesticides which in turn negatively impact both human health and ecological stability. Additionally, the emergence of insecticide-resistant populations underscores the urgent need for more specific and efficient pest management strategies. The development of novel techniques for controlling this insect pest requires rigorous interrogation of its physiology and interactions with host plants at a molecular/genetic level. To enable future research in this vein, we sequenced and assembled a draft L. coffeella genome using PacBio highly accurate long-reads (HiFi). Our assembly is comprised of 1615 contigs showing fragmentation, yet the majority of gene content is represented (BUSCO complete = 91.7%). We annotated 17467 protein-coding genes within our assembly, seven of which are core components of the small interfering RNA machinery. The expression of these genes was further confirmed via qPCR. This analysis - and the underlying genomic data - highlights potential targets for RNAi-based biopesticide development and will serve as the foundation for important future research aimed at protecting global coffee production from one of its most destructive pests.

Reduced insulin/IGF signaling (IIS) in Caenorhabditis elegans increases starvation resistance in a daf-16/FoxO-dependent fashion, but it is unclear whether the effects of reduced IIS are entirely dependent on daf-16/FoxO. We used RNA sequencing and phenotypic analysis of L1 starvation resistance to assess epistasis between daf-2/InsR and daf-16/FoxO. We identified 4,653 putative DAF-16/FoxO targets, many of which had not been previously identified, providing a valuable reference data set. Differential gene expression and increased survival caused by disruption of daf-2/InsR during starvation are daf-16-dependent. The effect of daf-2/InsR on growth following starvation is largely but not entirely daf-16-dependent. Notably, daf-16 is dispensable for reproduction following extended starvation, and daf-2 loss preserves reproductive success independent of daf-16. These results show that the effects of reduced IIS during L1 starvation are daf-16/FoxO-dependent but that IIS engages 1 or more additional effectors to buffer larval growth and especially reproduction from persistent effects of early life starvation.

The genus Silene is an important model system for fields as diverse as sex chromosome evolution, speciation and disease ecology. However, genomic resources remain scarce in the genus. Here, we present a near chromosome-scale genome assembly and high-density linkage map for S. uniflora, a hermaphroditic/gynodioecious species which is an important model for rapid adaptation to anthropogenic disturbance and the role of phenotypic plasticity in adaptive evolution. Using a combination of long-read and Hi-C sequencing technologies, we generated a 1,268 Mb genome assembly with a scaffold N50 of 40.72 Mb and 682 Mb assembled into 12 chromosomes. We annotated the genome using evidence from transcriptome and protein mapping in combination with ab initio gene prediction, resulting in 41,603 protein-coding genes and a BUSCO completeness score of 91%. We also present a linkage map which we used to validate the genome assembly and estimate local recombination rate across the genome. Comparison to the only two other Silene species with chromosome-scale genome assemblies reveals widespread genome rearrangements in the genus, suggesting Silene may be a promising study system for the role of genome rearrangement in evolution, particularly in the evolution of sex chromosomes and adaptation.

The Micrapis subgenus, which includes the black dwarf honey bee (Apis andreniformis) and the red dwarf honey bee (Apis florea), remains underrepresented in genomic studies despite its ecological significance. Here, we present high-quality de novo genome assemblies for both species, generated using a hybrid sequencing approach combining Oxford Nanopore Technologies long reads with Illumina short reads. The final assemblies are highly contiguous, with contig N50 values of 5.0 Mb (A. andreniformis) and 4.3 Mb (A. florea), representing a major improvement over the previously published A. florea genome. Genome completeness assessments indicate high quality, with BUSCO scores exceeding 98.5% using the Hymenoptera database and k-mer analyses supporting base-level accuracy. Repeat annotation revealed a relatively low repetitive sequence content (∼6%), consistent with other Apis species. Using RNA sequencing data, we annotated 12,189 genes for A. andreniformis and 12,207 genes for A. florea, with ∼98% completeness in predicted proteomes. These genome assemblies provide a valuable resource for comparative and functional genomic studies, with the potential to offer new insights into the genetic basis of dwarf honey bee adaptations.

This study explored the genetics of cortisol (CL), cortisone (CN), DHEA (DH), and DHEA-S (DS) in hair of 610 pigs that was grown while they were exposed to infectious stressors (IS) from a natural polymicrobial disease challenge. Results were then contrasted with previous results on hair from these same pigs grown while experiencing non-infectious stressors (NIS), such as weaning, castration, transportation, and mixing. All pigs were genotyped for 50K SNPs and imputed to 650K SNPs. Heritability estimates for hormone levels in hair grown under IS ranged from 0.01 for DS to 0.27 for CL. Estimates of genetic correlations between levels of a hormone in hair grown in response to IS versus NIS were not significantly different from zero and was highest, at 0.52, for CL. Genome-wide association studies identified the same major QTL for CL in response to IS that was previously found for response to NIS, near the glucocorticoid receptor gene. The minor allele at the lead SNPs (frequency = 9%) significantly (p < 0.001) reduced CL under IS by 30±4% and CN by 23±6%, had no significant effect on DH or DS, and drove the genetic correlation between CL in hair grown under NIS versus IS. A comparative GSEA approach revealed that genomic windows that were associated with active forms of the stress hormones (CL and DH) tended to explain more variance during response to IS than to NIS, while the opposite was true for their inactive forms (CN and DS). These results may facilitate the selection of pigs that cope better with IS and NIS using hormone levels in hair as a non-invasive sample.

We present G2P Datasets, a novel, open-access repository of publicly available genomic datasets for plants and animals. G2P Datasets currently hosts more than 100 public genomic datasets, meticulously compiled from diverse publications. The repository hosts meta-data (including digital object identifier for the hosted datasets) and scripts that can be used to download and read each dataset hosted into an R-environment. Scientists can submit new datasets by completing an online form. Additionally, many of the curated datasets are accessible through Kaggle and through links that allow rapid download of formatted R-objects. A searchable database of meta-data allows users to search through datasets for more than 60 species of plants and animals in a variety of traits and sample sizes. The repository is accessible via a web app interface with a catalog and clear instructions to contribute by adding new datasets and through GitHub. By unifying genomic and phenotypic meta-data into a navigable platform, we aim to facilitate genome-to-phenotype research in plant and animal genetics. This article provides an overview of the repository's content, organization, and utility.