Genetics最新文献

Understanding the molecular basis of adaptation and the genetic architecture of complex traits are longstanding goals in biology. One problem impeding this understanding is the complexity of continental populations, with their complicated demographic histories, gene flow and secondary contact. In contrast, island populations represent simpler systems where uncovering the genetic basis of complex traits and tracing how traits built up is much more tractable. In Arabidopsis thaliana, the Cape Verde Islands populations represent a case of long-range colonization and adaptation to a divergent selective regime. Here, we describe the development and testing of a new multiparent intercross doubled haploid population of A. thaliana from the Cape Verde Islands. This population balances the representation of natural diversity and overcomes the shortcomings of existing resources, such as biparental recombinant inbred lines and genome-wide association populations. Specifically, it captures variation that segregates within the archipelago but is fixed on individual islands. We mapped the genetic basis of flowering time, rosette size, and photosystem II efficiency (ΦPSII) in this inter-island intercross population, representing traits that we hypothesized may be evolving under strong selection during the colonization of the archipelago. We identified functional loci underlying these traits, including FRI K232X and FLC R3X for flowering time, and IRT1 G130X for ΦPSII and rosette size. Our multiparent intercross population complements existing mapping resources and provides a robust framework for investigating the genetic basis of complex traits in A. thaliana. This work emphasizes the value of island systems and complementary approaches for advancing our understanding of genetic adaptation.

The circadian clock in Drosophila generates the 24 hour (h) rhythmicity in its behaviour. MicroRNAs are essential post-transcriptional regulators that can influence circadian rhythms by modulating clock mRNA expression or by aiding in the rhythmic oscillation of gene transcripts and their protein products. Previous studies identified around 27 miRNAs robustly expressed in Drosophila clock neurons. We conducted a genetic screen of 21 of these relatively underexplored miRNAs to investigate their effects on circadian clock properties. Each miRNA was downregulated in circadian clock neurons using specific sponge lines, and the impact on free running period and rhythm robustness was analyzed through locomotor activity-rest assessments. We observed that downregulation of two miRNAs shortened the free running period, while two miRNAs reduced rhythm robustness. Our findings reveal that miR-275 modulates locomotor activity-rest rhythm, circadian rhythmicity, and the transcript levels of the circadian neuropeptide PIGMENT DISPERSING FACTOR (PDF). Overexpression of Pdf in miR-275 overexpressed flies partially rescued the altered circadian rhythm parameters under 12h light: 12h dark cycles and constant darkness. Overall, this study identifies miR-275 as a critical regulator of circadian locomotor activity-rest rhythm.

The Genome Database for Vaccinium (GDV, https://www.vaccinium.org/) is a knowledgebase serving the global Vaccinium research community. GDV centralizes genetics, genomics, and breeding data for blueberry, cranberry, bilberry, and lingonberry. Launched in 2011, GDV transforms research data into an integrated resource through data curation, standardization, and value-added analyses that enable cross-study comparisons and knowledge synthesis. GDV houses diverse data types including germplasm records, genetic markers, linkage maps, QTL/GWAS results, traits, genome assemblies, gene annotations, and expression profiles. The database team perform comprehensive analyses including homology searches against protein databases, InterPro domain identification, and synteny analyses between Vaccinium genomes to identify orthologous relationships. These analyses facilitate knowledge transfer within and between species, enabling researchers to leverage findings across the Vaccinium genus. Users access data through intuitive search interfaces and specialized tools for genetic map visualization, genome browsing, metabolic pathway exploration, and sequence similarity searches. The integrated Breeding Information Management System (BIMS) enables breeders to manage private breeding programs as well as accessing public breeding data. Currently containing 46 genome assemblies, over 287,000 genetic markers, 4,328 QTL, and 3.3 million gene models, GDV continues expanding through collaborations with the VacCAP project and international research groups. The database evolves based on community needs and emerging data types, ensuring its continued relevance for advancing Vaccinium research and crop improvement efforts worldwide.

Ruggedness - the prevalence of fitness peaks - and navigability - the existence of fitness-increasing paths to a target - are key factors affecting evolution on fitness landscapes. Here, we analyse these properties in landscapes that inherit biophysically grounded genotype-phenotype (GP) maps. By assuming a random phenotype-fitness assignment as a baseline, the structure of the GP maps is included without imposing further fitness correlations. We show analytically that the expected ruggedness can be predicted from two quantities: the sizes of neutral components (NCs)-mutationally connected genotype sets with the same phenotype-and their evolvabilities, defined as the number of distinct phenotypes among the NC's mutational neighbours. Other features -such as robustness- influence ruggedness only indirectly via correlations with evolvability. Numerical results across diverse GP maps confirm that NC size and evolvability alone suffice to predict both the mean prevalence and heights of peaks. These calculations also provide new insights: Under random phenotype-fitness assignment, peaks arising from high-evolvability NCs have higher expected fitness than those from low-evolvability NCs. Thus, when evolvability correlates positively with NC size, the formation of large low-fitness peaks is impeded. We further derive an approximate scaling law for the minimal average evolvability required for navigability. Our framework applies broadly across GP maps, providing general insight into when and why fitness landscapes are expected to be rugged or navigable.

Drosophila and parasitic wasps in the genus Leptopilina have long been a model for understanding host-parasite interactions. Indeed, parasitic wasps are important drivers of ecological and evolutionary processes broadly, but we are generally lacking information about the diversity, natural history, and evolution of these relationships. We collected insects from the Caribbean Island of Saint Lucia, home to the eastern Caribbean dunni subgroup of Drosophila: a clade long appreciated for its recent patterns of speciation and adaptation. Here we present an integrative approach that incorporates natural history, taxonomy, physiology, and genomics to describe Leptopilina malgretoutensis Buffington, Lue, Davis & Tracey sp. nov. (Hymenoptera: Figitidae), a virulent parasitoid of dunni group flies, specifically Drosophila antillea. Leptopilina malgretoutensis is nested within an early-branching clade of Leptopilina, offering insights into the evolution of this important genus of Drosophila parasitoids. We present a high-quality assembly for this wasp's 1Gbp genome, and for its bacterial endosymbiont: Wolbachia strain "wLmal". Furthermore, we show that wLmal induces parthenogenesis in the wasp, and that these wasps are reliant upon their Wolbachia infections to produce female offspring. Finally, comparisons to historical museum specimens indicated that Leptopilina malgretoutensis had been collected approximately 40 years prior from the nearby island of Guadeloupe, and these wasps were also asexually reproducing. This work represents one of only a handful of studies in which field biology, taxonomy, systematics, genomics, and experimental biology are integrated into a species description: showcasing the possibilities for biodiversity research in the genomic era.

Genetic variation and lived experiences shape how our hearts respond to chronic stress and development of heart failure, manifested as compromised pumping function and abnormal hemodynamics. The hallmark of heart failure etiology is excessive stress signals followed by maladaptive structural, electrical, and functional changes to the heart muscle, also known as cardiac remodeling. The specific genetic mechanisms which underly such phenomenon, however, are still unclear, due in part to difficulties in accounting for environmental effects in human population studies. To overcome this challenge, we used the Collaborative Cross (CC) mouse population to investigate heritable susceptibility to cardiovascular stress by chronic β-adrenergic receptor stimulation with the β-agonist isoproterenol, which targets the common signaling gateway to heart failure, regardless of the particular upstream stressor. Across 8 founder and 63 CC lines, we measured non-failing and failing heart characteristics represented by cardiac structure and function, organ weights, and cell morphology. Genome-wide QTL mapping detected 49 genome-wide significant loci, collapsing to 20 unique intervals (nine significant for multiple traits and eleven trait-specific), averaging 12.83 Mb in size. To identify high-confidence candidate genes from these loci, we augmented our trait mapping with coding variants drawn from sequencing data, tractability in our in vitro rat cardiomyocyte model, and previously reported protein functions and mouse or human phenotypes. This approach recovered both known regulators, such as Hey2, and new candidates. Functional tests in in vitro models highlight three candidate genes that modulate hypertrophic growth: Abcb10, Mrps5 and Lmod3. Abcb10 knockdown increased cell size at baseline and further with isoproterenol, consistent with loss of a mitochondrial stress-buffering role. Mrps5 knockdown blunted stress-induced hypertrophy, possibly related to its previously known involvement in oxidative stress regulation. Lmod3 knockdown also attenuated hypertrophy, potentially via actin-assembly control under adrenergic stress. Together, these results reveal heritable pathways of β-adrenergic remodeling in mice and provide an interpretable, translational, and stepwise framework to prioritize candidate genes within broad loci for mechanistic studies of heart failure.

Meiotic chromosome segregation requires reciprocal exchanges between the parental chromosomes (homologs). Exchanges form via tightly-regulated repair of double-strand DNA breaks (DSBs). However, since repair intermediates have been mostly quantified in fixed images, our understanding of the mechanisms that control repair progression remains limited. Here, we study meiotic repair kinetics in Caenorhabditis elegans by extinguishing new DSBs and following the disappearance of a crucial intermediate - strand invasion mediated by the conserved RecA-family recombinase RAD-51. Assuming exponential decay, RAD-51 foci have a half-life of 1-2 hours, with >75% of foci disappearing within 4 hours. Previous work suggested that sister-directed repair is specifically blocked throughout most of pachytene. In contrast, we find that RAD-51 foci half-lives are 1-2 hours even in conditions where homolog engagement is prevented and only the sister is available as a template. This suggests that both sister- and homolog-engaged RAD-51 foci are continuously turned over during pachytene. We also use our kinetic information to revisit the total number of DSBs - the 'substrate' for the formation of exchanges - and find an average of 20-38 DSBs per nucleus. Our work opens the door for analysis of the interplay between meiotic repair kinetics and the fidelity of genome inheritance.

Post-transcriptional processing of pre-mRNAs by alternative polyadenylation (APA) generates a diversity of transcript isoforms at the 3' untranslated region (3'UTR) that can affect their function and stability. The differential enrichment of transcript isoforms has been implicated in diseases ranging from cancer to neurodevelopmental disorders. However, the post-embryonic developmental roles of the core ensemble of cleavage and polyadenylation (CPA) factors that mediate these post-transcriptional changes remain poorly characterized. Here, we report a stress-dependent role for the core CPA factor CFIM-1 in Caenorhabditis elegans germline integrity. Total loss-of-function of cfim-1 elicits a temperature-sensitive sterility phenotype in hermaphrodites but CFIM-1 protein levels do not change with temperature. Sterility is accompanied by sperm, oocyte and germline morphology defects. Surveying the transcriptome of cfim-1(lf) worms revealed changes in transcript isoform abundance for dozens of genes with functions related to the development and maintenance of these structures. Collectively, our findings define a post-embryonic role for a core CPA factor in tissue-specific development.

The coenzyme NAD+ (nicotinamide adenine dinucleotide) is a critical electron carrier in central metabolism and is required for cellular health. Cells are proposed to monitor and respond to fluctuating intracellular NAD+ levels using sirtuin deacetylases as sensors because these enzymes require NAD+ for activity. We tested this hypothesis by examining how intracellular NAD+ levels affect Sir2-mediated repression of transcription in the yeast Kluyveromyces lactis. Because K. lactis cannot synthesize NAD+, we could create a gradient of intracellular NAD+ levels by growing cells in varying concentrations of the precursor nicotinic acid. We found that as NAD+ levels decreased, acetylation of histones at target promoters increased, as did expression of these genes. RNA-Seq analysis revealed that genes induced in low nicotinic acid include some that would restore NAD+ levels, such as the high-affinity nicotinic acid transporter TNA1, and some that would enable long term survival by promoting sporulation. Most genes induced in low nicotinic acid (99/112 or 88%) were also induced by the deletion of SIR2. Moreover, in sir2Δ cells, few transcriptional changes occurred in response to low nicotinic acid. Thus, Sir2 is the primary sensor driving the transcriptional response to low NAD+ in K. lactis. Finally, the degree of transcriptional induction varied with NAD+ levels, suggesting that Sir2 behaves as a rheostat that tunes gene expression to NAD+ availability.

Despite long-lasting interest and research efforts, the genetic bases of developmental stability-the robustness to developmental noise-and its commonly used estimator, fluctuating asymmetry (FA), remain poorly understood. The Drosophila melanogaster Cyclin G gene (CycG) encodes a transcriptional cyclin that regulates growth and the cell cycle. Over-expression of a potentially more stable isoform of the protein (deletion of a PEST-rich domain, hereafter called CycGΔP) induces extreme wing size and shape FA (i.e. high developmental noise), indicating a major disruption of developmental stability. Previous attempts to identify the genetic bases of FA have been impeded by the constitutively low level of developmental noise, limiting the power to detect any effect. Here, we leverage the extreme developmental instability induced by overexpression of CycGΔP to explore the genetic bases of FA: we perform a genome-wide screen for deficiencies that enhance or reduce CycGΔP-induced wing FA. 495 deficiencies uncovering 90% of the euchromatic genome were combined with a recombinant chromosome expressing CycGΔP. We identified 13 and 16 deficiencies that respectively enhance and decrease FA. Analysis of mutants for some genes located in these deficiencies shows that Cyclin G ensures homogeneous growth of organs in synergy with the major morphogens of the wing, Dpp and Wg, as well as the Hippo and InR/TOR pathways. They also reveal that CycGΔP-induced FA involves Larp, a potential direct interactor of Cyclin G that regulates translation at the mitochondrial membrane. This opens up new research perspectives for understanding developmental stability, suggesting a significant role for mitochondrial activity.