Biology subjects

Nguyen, A. D.

Publications and source records attributed to Nguyen, A. D..

15 recordsLinked to original sources

bioRxiv2026

Progranulin deficiency promotes neuroinflammation through cathepsin B-mediated activation of the NLRP3 inflammasome

Haploinsufficiency of progranulin (resulting from mutations in the GRN gene) is a major genetic cause of frontotemporal dementia (FTD), which is characterized by profound changes in personality and behavior, progressive impairments in executive function, speech, language and/or movement, TDP-43 pathology, lysosomal dysfunction, and neuroinflammation. Studies in progranulin-deficient mouse models have demonstrated the critical role of neuroinflammation in disease pathogenesis, as deletion of NF-kB or complement factors prevents FTD-associated behavioral deficits. While progranulin is known to be anti-inflammatory, the precise molecular mechanism by which its deficiency triggers inflammatory cascades remain unclear. Here, we investigate the involvement of the NLRP3 inflammasome in progranulin-deficient models, including mice, human microglial cells, and patient fibroblasts. In Grn mice, we found increased levels of several inflammasome-related proteins, including procaspase-1 and cleaved IL-1{beta}. Similarly, GRN knockout (KO) microglia cells showed significant increases in levels of procaspase-1, NLRP3, and cleaved IL-1{beta}. Moreover, KO cells had increased NLRP3 oligomerization, suggesting that progranulin negatively regulates inflammasome assembly. We also investigated the potential link between lysosomal dysfunction and NLRP3 inflammasome activation in progranulin deficiency. We found that pharmacological inhibition of cathepsin B reduced NLRP3 inflammasome oligomerization as well as inflammatory cytokine expression in GRN KO cells. Additionally, siRNA knockdown of cathepsin B reduced levels of procaspase-1 and cleaved IL-1{beta} in GRN KO cells. Finally, we found that heterozygous GRN fibroblasts exhibited similar increases in procaspase-1 and cleaved IL-1{beta} levels, and these increases were corrected by treatment with an antisense oligonucleotide (ASO) that increase progranulin protein levels. Overall, our results demonstrate that progranulin deficiency promotes NLRP3 inflammasome assembly and activity through cathepsin B-mediated signaling, thereby establishing a mechanistic link between lysosomal dysfunction and increased inflammation. The ability of the GRN-targeting ASO to correct NLRP3-mediated inflammation highlights a promising therapeutic strategy for FTD-GRN and inflammation in other neurodegenerative disorders linked to progranulin deficiency.

neuroscience↗

bioRxiv2026

Chronic Social Isolation Reshapes the Metabolome in Drosophila

Sleep, feeding, and metabolism are tightly coordinated outputs of the circadian system. Previous studies showed that chronic social isolation reduces sleep and increases feeding in Drosophila. Here, untargeted metabolomic profiling revealed that chronic social isolation induces a distinct metabolomic signature spanning amino acids, carbohydrates, and lipids, establishing a foundation for understanding the physiological consequences of social isolation.

neuroscience↗

bioRxiv2025

Somatostatin Receptors Shape Insulin and Glucagon Output within the Pancreatic Islet through Direct and Paracrine Effects

Aims/HypothesisPancreatic delta cells secrete somatostatin (SST), which can inhibit both alpha and beta cells of the pancreatic islet. By controlling insulin and glucagon release, delta cells play an important role in maintaining nutrient homeostasis. However, the mechanism by which a single inhibitory hormone inhibits both alpha and beta cells, which are often considered as functional antagonists in the counterregulatory control of blood glucose, has been a physiological riddle. Here, we solve this riddle through assessment of the contributions of alpha and beta cell specific somatostatin receptors to cell intrinsic behaviors and hormone release. MethodsIslets from mice constitutively expressing fluorescent sensors reporting on cyclic AMP and Ca2+ in both alpha and beta cells were imaged using stimuli to mimic the post-prandial state of a meal consisting of glucose and amino acids. This approach was coupled with cell specific somatostatin receptor antagonists to identify how somatostatin inhibits alpha and beta cell hormone output through modulation of cAMP and Ca2+ secondary messengers and paracrine interactions. ResultsOur results support and extend prior observation that somatostatin receptor 2 (SSTR2) is the only somatostatin receptor expressed by alpha cells, while somatostatin receptor 3 (SSTR3) is the only receptor expressed by mouse beta cells. Interestingly, SSTR2 and SSTR3 regulate downstream cAMP and Ca2+ signaling cascades differently within alpha and beta cells of intact islets. Stimulation of somatostatin receptors robustly inhibits cyclic AMP in alpha or beta cells. In contrast, stimulation of SSTR2 inhibits alpha cell Ca2+ with significantly greater potency compared to inhibition of beta cell Ca2+ via SSTR3. Despite the absence of SSTR2 on beta cells, blocking alpha cell SSTR2 during nutrient stimulation resulted in a significant increase in insulin release downstream of local release of glucagon. Conclusions/InterpretationOur observations address the physiological riddle of the delta cells role during the post-prandial phase where we demonstrate that somatostatin primarily inhibits alpha cell cAMP and Ca2+ via SSTR2, preventing glucagon release. Blocking SSTR2 resulted in an increase in locally released glucagon, which coupled with muted ability for SSTR3 to inhibit beta cell calcium under strong nutrient stimulation, results in potentiation of glucose stimulated insulin secretion from the beta cell. We conclude that the role of delta cells under nutrient stimulation is to modulate the volume of insulin release by tuning the strength of intra-islet paracrine potentiation of insulin secretion by glucagon, mediated via beta cell GLP1R. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LISomatostatin released by delta cells can attenuate glucagon release from the alpha cells and insulin release from the beta cells of the islet through inhibitory somatostatin receptors. C_LIO_LISomatostatin receptor 2 is a major receptor expressed on the mouse alpha cell surface, while mouse beta cells express SSTR3 on their primary cilia. C_LIO_LIParacrine signaling by alpha cell glucagon potentiates insulin release through the engagement of stimulatory glucagon-like peptide 1 receptors on beta cells. C_LI What are the key questions?O_LIHow do the cell specific somatostatin receptors of the alpha cell (SSTR2) and beta cell (SSTR3) differentially regulate cell-intrinsic Ca2+ and cAMP signaling and the indirect paracrine pathways that shape insulin secretion in the post-prandial state? C_LI What are the new findings?O_LIAlpha cells of the mouse islet express exclusively SSTR2 and not SSTR3. C_LIO_LISomatostatin is a more potent inhibitor of cytosolic calcium activity via alpha cell SSTR2 compared to beta cell SSTR3. C_LIO_LIPreventing somatostatin inhibition of the alpha cell in the presence of elevated glucose and amino acids potentiates insulin release through the engagement of glucagon-like peptide 1 receptors on the beta cell by glucagon. C_LI How might this impact on clinical practice in the foreseeable future?O_LIOur findings indicate that local feedback inhibition of beta cells is accomplished by tuning the strength of the paracrine potentiation of locally released glucagon. This is relevant in the context of developing treatments for hypoglycemia with alpha cell specific SSTR2-specific antagonists that could potentiate insulin release and potentially exacerbate hypoglycemic episodes. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/688371v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@1138ddaorg.highwire.dtl.DTLVardef@c613f9org.highwire.dtl.DTLVardef@49806eorg.highwire.dtl.DTLVardef@18ece86_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

UDP-6-glucose dehydrogenase in hormonally responsive breast cancers

Survival for metastatic breast cancer is low and thus, continued efforts to treat and prevent metastatic progression are critical. Estrogen is shown to promote aggressive phenotypes in multiple cancer models irrespective of estrogen receptor (ER) status. Similarly, UDP-Glucose 6-dehydrogenase (UGDH) a ubiquitously expressed enzyme involved in extracellular matrix precursors, as well as hormone processing increases migratory and invasive properties in cancer models. While the role of UGDH in cellular migration is defined, how it intersects with and impacts hormone signaling pathways associated with tumor progression in metastatic breast cancer has not been explored. Here we demonstrate that UGDH knockdown blunts estrogen-induced tumorigenic phenotypes (migration and colony formation) in ER+ and ER- breast cancer in vitro. Knockdown of UGDH also inhibits extravasation of ER- breast cancer ex vivo, primary tumor growth and animal survival in vivo in both ER+ and ER- breast cancer. We also use single cell RNA-sequencing to demonstrate that our findings translate to a human breast cancer clinical specimen. Our findings support the role of estrogen and UGDH in breast cancer progression provide a foundation for future studies to evaluate the role of UGDH in therapeutic resistance to improve outcomes and survival for breast cancer patients.

cancer biology↗

bioRxiv2024

Long G4-rich enhancer physically interacts with EXOC3 promoter via a G4:G4 DNA-based mechanism

Enhancers are genomic sequences that function as regulatory elements capable of increasing the transcription of a given gene often located at a considerable distance. The broadly accepted model of enhancer activation involves bringing an enhancer-bound activator protein complex into close spatial proximity to its target promoter through chromatin looping. Equally relevant to the work described herein, roles for guanine (G) rich sequences in transcriptional regulation are now widely accepted. Non-coding G-rich sequences are commonly found in gene promoters and enhancers, and various studies have described specific instances where G-rich sequences regulate gene expression via their capacity to form G-quadruplex (G4) structures under physiological conditions. In light of this, our group previously performed a search for long human genomic stretches significantly enriched for minimal G4 motifs (referred to as LG4s herein) leading to the identification of 301 LG4 loci with a density of at least 80 GGG repeats / 1,000 basepairs (bp) and averaging 1,843 bp in length. Further, in agreement with previous reports indicating that minimal G4s are highly enriched in promoters and enhancers, we found 217/301 LG4 sequences overlap a GeneHancer annotated enhancer, and the gene promoters regulated by these LG4 enhancers were found to be similarly, markedly enriched with G4-capable sequences. Importantly, while the generally accepted model for enhancer:promoter specificity maintains that interactions are dictated by enhancer- and promoter-bound transcriptional activator proteins, the current study was designed to test an alternative hypothesis: that LG4 enhancers physically interact with their cognate promoters via a direct G4:G4 DNA-based mechanism. As such, this work employs a combination of informatic mining and locus-specific immunoprecipitation strategies to establish the spatial proximity of enhancer:promoter pairs within the nucleus then biochemically confirms the ability of individual LG4 ssDNAs to directly and specifically interact with DNA sequences found in their target promoters. In addition, we also identify four single nucleotide polymorphisms (SNPs), occurring within a LG4 enhancer on human chromosome 5, significantly associated with Cystic Fibrosis (CF) lung disease severity (avg. p value = 2.83E-9), presumably due to their effects on the expressions of CF-relevant genes directly regulated by this LG4 enhancer (e.g., EXOC3 and CEP72). Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/577212v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1fee785org.highwire.dtl.DTLVardef@11f0a9org.highwire.dtl.DTLVardef@1cf198corg.highwire.dtl.DTLVardef@1963a55_HPS_FORMAT_FIGEXP M_FIG C_FIG In brief: LG4 enhancers physically interact with gene promoters by forming composite G4 structures where both the LG4 and cognate promoter contribute half of the necessary sequence for G4 formation.

genetics↗

bioRxiv2023

Biochemical, biomarker, and behavioral characterization of the GrnR493X mouse model of frontotemporal dementia

Heterozygous loss-of-function mutations in the progranulin gene (GRN) are a major cause of frontotemporal dementia due to progranulin haploinsufficiency; complete deficiency of progranulin causes neuronal ceroid lipofuscinosis. Several progranulin-deficient mouse models have been generated, including both knockout mice and knockin mice harboring a common patient mutation (R493X). However, the GrnR493X mouse model has not been characterized completely. Additionally, while homozygous GrnR493X and Grn knockout mice have been extensively studied, data from heterozygous mice is still limited. Here, we performed more in-depth characterization of heterozygous and homozygous GrnR493X knockin mice, which includes biochemical assessments, behavioral studies, and analysis of fluid biomarkers. In the brains of homozygous GrnR493X mice, we found increased phosphorylated TDP-43 along with increased expression of lysosomal genes, markers of microgliosis and astrogliosis, pro-inflammatory cytokines, and complement factors. Heterozygous GrnR493X mice did not have increased TDP-43 phosphorylation but did exhibit limited increases in lysosomal and inflammatory gene expression. Behavioral studies found social and emotional deficits in GrnR493X mice that mirror those observed in Grn knockout mouse models, as well as impairment in memory and executive function. Overall, the GrnR493X knockin mouse model closely phenocopies Grn knockout models. Lastly, in contrast to homozygous knockin mice, heterozygous GrnR493X mice do not have elevated levels of fluid biomarkers previously identified in humans, including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in both plasma and CSF. These results may help to inform pre-clinical studies that use this Grn knockin mouse model and other Grn knockout models.

neuroscience↗

bioRxiv2022

Antisense oligonucleotide-based therapeutic strategy for progranulin-deficient frontotemporal dementia

Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3 UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed miR-29b from binding to the GRN 3 UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by ribosomal profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.

neuroscience↗

bioRxiv2021

Progranulin deficiency results in reduced bis(monoacylglycero)phosphate (BMP) levels and gangliosidosis

Homozygous mutations of granulin precursor (GRN) lead to neuronal ceroid lipofuscinosis1, a severe neurodevelopmental disease, in humans and neuroinflammation in mice2. Haploinsufficiency of GRN almost invariably causes frontotemporal dementia (FTD)3,4. The GRN locus produces progranulin (PGRN), a lysosomal precursor protein that is cleaved to granulin peptides5,6. Despite intensive investigation, the function of granulins and the reason why their absence causes neurodegeneration remain unclear. Here, we investigated PGRN function in lipid degradation, a major function of lysosomes. We show that PGRN-knockout human cells, PGRN-deficient murine brain, and frontal lobes of human brains from patients with GRN mutation-related FTD have increased levels of gangliosides, highly abundant sialic acid-containing glycosphingolipids (GSL) that are degraded in lysosomes. Probing how PGRN deficiency causes these changes, we found normal levels and activities of enzymes that catabolize gangliosides. However, levels of bis(monoacylglycero)phosphate (BMP), a lysosomal lipid required for ganglioside catabolism7, were markedly reduced in PGRN-deficient cells and patient brain tissues. These data indicate that granulins are required to maintain BMP levels, which regulate ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. This aberrant accumulation of gangliosides may contribute to neuroinflammation and neurodegeneration susceptibility.

cell biology↗

bioRxiv2020

Molecular signatures of sexual communication in the phlebotomine sand flies

Phlebotomine sand flies employ an elaborate system of pheromone communication wherein males produce pheromones that attracts other males to leks (thus acting as aggregation pheromone) and females to the lekking males (sex pheromone). In addition, the type of pheromone produced varies among populations. Despite the numerous studies on sand fly chemical communication, little is known of their chemosensory genome. Chemoreceptors interact with chemicals in an organisms environment to elicit essential behaviors such as the identification of suitable mates and food sources, thus, they play important roles during adaptation and speciation. Major chemoreceptor gene families, odorant receptors (ORs), gustatory receptors (GRs) and ionotropic receptors (IRs) together detect and discriminate the chemical landscape. Here, we annotated the chemoreceptor repertoire in the genomes of Lutzomyia longipalpis and Phlebotomus papatasi, major phlebotomine vectors in the New World and Old World, respectively. Comparison with other sequenced Diptera revealed a large and unique expansion where over 80% of the ~140 ORs belong to a single, taxonomically restricted clade. We next conducted comprehensive analysis of the chemoreceptors in 63 Lu. longipalpis individuals from four different locations in Brazil representing allopatric and sympatric populations and three aggregation-sex pheromone types (chemotypes). Population structure based on single nucleotide polymorphisms (SNPs) and gene copy number in the chemoreceptors corresponded with their putative chemotypes, and corroborate previous studies that identified multiple populations. Our work provides genomic insights into the underlying behavioral evolution of sexual communication in the L. longipalpis species complex in Brazil, and highlights the importance of accounting for the ongoing speciation in central and South American Lutzomyia that could have important implications for vectorial capacity.

evolutionary biology↗

bioRxiv2020

A rapidly evolved shift in life history timing during ecological speciation is driven by the transition between developmental phases

For insect species in temperate environments, seasonal timing is often governed by the regulation of diapause, a complex developmental program that allows insects to weather unfavorable conditions and synchronize their lifecycles with available resources. Diapause consists of a series of phases that govern initiation, maintenance, and termination of this developmental pathway. The evolution of insect seasonal timing depends in part on how these phases of diapause development and post-diapause development interact to affect variation in phenology. Here, we dissect the physiological basis of a recently evolved phenological shift in Rhagoletis pomonella (Diptera: Tephritidae), a model system for ecological divergence. A recently derived population of R. pomonella shifted from specializing on native hawthorn fruit to earlier fruiting introduced apples, resulting in a 3-4 week shift in adult emergence timing. We tracked metabolic rates of individual flies across post-winter development to test which phases of development may act either independently or in combination to contribute to this recently evolved divergence in timing. Apple and hawthorn flies differed in a number of facets of their post-winter developmental trajectories. However, divergent adaptation in adult emergence phenology in these flies was due almost entirely to the end of the pupal diapause maintenance phase, with post-diapause development having a very small effect. The relatively simple underpinnings of variation in adult emergence phenology suggest that further adaptation to seasonal change in these flies for this trait might be largely due to the timing of diapause termination unhindered by strong covariance among different components of post-diapause development. Data accessibilityAll data (in the form of tables of all metabolic rate measurements for all individual flies in the study) will be available on DRYAD when the manuscript is published.

evolutionary biology↗

bioRxiv2019

Analysis of model organism viability through an interspecies pathway comparison pipeline using the dynamic impact approach

BackgroundComputational biologists investigate gene expression time-series data using estimation, clustering, alignment, and enrichment methods to make biological sense of the data and provide compelling visualization. While there is an abundance of microarray and RNA-seq data available, interpreting the data while capturing the dynamism of a time-course experiment remains a difficult challenge. Advancements in RNA-seq technologies have allowed us to collect extensive profiles of diverse developmental processes but also requires additional methods for analysis and data integration to capture the increased dynamism. An approach that can both capture the dynamism and direction of change in a time-course experiment in a holistic manner and simultaneously identify which biological pathways are significantly altered is necessary for the interpretation of systems biology data. In addition, there is a need for a method to evaluate the viability of model organisms across different treatments and conditions. By comparing effects of a specific treatment (e.g., a drug) on the target pathway between multiple species and determining pathways with a similar response to biological cues between organisms, we can determine the best animal model for that treatment for future studies. MethodsHere, we present Dynamic Impact Approach with Normalization (DIA-norm), a dynamic pathway analysis tool for the analysis of time-course data without unsupervised dimensionality reduction. We analyzed five datasets of mesenchymal stem cells retrieved from the Gene Expression Omnibus data repository (3 human, 1 mouse cell line, 1 pig) which were differentiated in vitro towards adipogenesis. In the first step, DIA-norm calculated an impact and flux score for each biological term using p-value and fold change. In the second step, these scores were normalized and interpolated using cubic spline. Cross-correlation was then performed between all the data sets with r[≥]0.6 as a benchmark for high correlation as r = 0.7 is the limit of experimental reproducibility. ResultsDIA-norm predicted that the pig was a better model for humans than a mouse for the study of adipogenesis. The pig model had a higher number of correlating pathways with humans (64.5 to 30.5) and higher average correlation (r = 0.51 vs r = 0.46) as compared to mouse model vs human. While not a definitive conclusion, the results are in accordance with prior phylogenetic and disease studies in which pigs are a good model for studying humans, specifically regarding obesity. In addition, DIA-norm identified a larger number of biologically important pathways (approximately 2x number of pathways) versus a comparable enrichment analysis tool, DAVID. DIA-norm also identified some possible pathways of interests for adipogenesis, namely, nitrogen metabolism (r = 0.86), where there is little to no existing literature. ConclusionDIA-norm captured 80+% of biological important pathways and achieved high pathway correlation between species for the vast majority of important adipogenesis pathways. DIA-norm can be used for both time-series pathway analysis and the determination of a model organism. Our findings indicate that DIA-norm can be used to study the effect of any treatment, including drugs, on specific pathways between multiple species to determine the best animal model for that treatment for future studies. The reliability of DIA-norm to provide biological insights compared to enrichment approach tools has been demonstrated in the selected transcriptomic studies by identifying a higher number of total and biologically relevant pathways. DIA-norms final advantage was its easily interpretable graphical outputs that aid in visualizing dynamic changes in expression.

bioinformatics↗

bioRxiv2019

Shaky Scaffolding: Age Differences In Cerebellar Activation Revealed Through Activation Likelihood Estimation Meta-Analysis

Cognitive neuroscience research has provided foundational insights into aging, but has focused primarily on the cerebral cortex. However, the cerebellum is subject to the effects of aging. Given the importance of this structure in the performance of motor and cognitive tasks, cerebellar differences stand to provide critical insights into age differences in behavior. But, our understanding of cerebellar functional activation in aging is limited. Thus, we completed a meta-analysis of neuroimaging studies across task domains. Unlike in the cortex where an increase in bilateral activation is seen during cognitive task performance with advanced age, there is less overlap in cerebellar activation across tasks in older adults relative to young. Conversely, we see an increase in activation overlap in older adults during motor tasks. We propose that this is due to inputs for comparator processing in the context of control theory (cortical and spinal) that may be differentially impacted in aging. These findings advance our understanding of the aging mind and brain.

neuroscience↗

bioRxiv2019

Genomic signature of shifts in selection in a sub-alpine ant and its physiological adaptations

Understanding how organisms adapt to extreme environments is fundamental and can provide insightful case studies for both evolutionary biology and climate-change biology. Here, we take advantage of the vast diversity of lifestyles in ants to identify genomic signatures of adaptation to extreme habitats such as high altitude. We hypothesised two parallel patterns would occur in a genome adapting to an extreme habitat: i) strong positive selection on genes related to adaptation and, ii) a relaxation of previous purifying selection. We tested this hypothesis by sequencing the high-elevation specialist Tetramorium alpestre and four other phylogenetic related species. In support of our hypothesis, we recorded a strong shift of selective forces in T. alpestre, in particular a stronger magnitude of diversifying and relaxed selection when compared to all other ants. We further disentangled candidate molecular adaptations in both gene expression and protein-coding sequence that were identified by our genome-wide analyses. In particular, we demonstrate that T. alpestre has i) a derived level of expression for stv and other heat-shock proteins in chill shock tests, and ii) enzymatic enhancement of Hex-T1, a rate-limiting regulatory enzyme that controls the entry of glucose into the glycolytic pathway. Together, our analyses highlight the adaptive molecular changes that support colonisation of high-altitude environments.

evolutionary biology↗

bioRxiv2018

The telomere bouquet is a hub where meiotic double-strand breaks, synapsis, and stable homolog juxtaposition are coordinated in the zebrafish, Danio rerio

Meiosis is a cellular program that generates haploid gametes for sexual reproduction. While chromosome events that contribute to reducing ploidy (homologous chromosome pairing, synapsis, and recombination) are well conserved, their execution varies across species and even between sexes of the same species. The telomere bouquet is a conserved feature of meiosis that was first described nearly a century ago, yet its role is still debated. Here we took advantage of the prominent telomere bouquet in zebrafish, Danio rerio, and super-resolution microscopy to show that axis morphogenesis, synapsis, and the formation of double-strand breaks (DSBs) all take place within the immediate vicinity of telomeres. We established a coherent timeline of events and tested the dependence of each event on the formation of Spo11-induced DSBs. First, we found that the axis protein Sycp3 loads adjacent to telomeres and extends inward, suggesting a specific feature common to all telomeres seeds the development of the axis. Second, we found that newly formed axes near telomeres engage in presynaptic co-alignment by a mechanism that depends on DSBs, even when stable juxtaposition of homologous chromosomes at interstitial regions is not yet evident. Third, we were surprised to discover that ~30% of telomeres in early prophase I engage in associations between two or more chromosome ends and these interactions decrease in later stages. Finally, while pairing and synapsis were disrupted in both spo11 males and females, their reproductive phenotypes were starkly different; spo11 mutant males failed to produce sperm while females produced offspring with severe developmental defects. Our results support zebrafish as an important vertebrate model for meiosis with implications for differences in fertility and genetically derived birth defects in males and females.\n\nAuthor SummaryInherent to reproduction is the transmission of genetic information from one generation to the next. In sexually reproducing organisms, each parent contributes an equal amount of genetic information, packaged in chromosomes, to the offspring. Diploid organisms, like humans, have two copies of every chromosome, while their haploid gametes (e.g. eggs and sperm) have only one. This reduction in ploidy depends on the segregation of chromosomes during meiosis, resulting in gametes with one copy of each chromosome. Missegregation of the chromosomes in the parents leads to abnormal chromosome numbers in the offspring, which is usually lethal or has detrimental developmental effects. While it has been known for over a century that homologous chromosomes pair and recombine to facilitate proper segregation, how homologs find their partners has remained elusive. A structure that has been central to the discussion of homolog pairing is the bouquet, or the dynamic clustering of telomeres during early stages of meiosis. Here we use zebrafish to show that the telomere bouquet is the site where key events leading to homologous chromosome pairing are coordinated. Furthermore, we show that deletion of spo11, a gene required for proper recombination in most studied organisms, resulted in very different effects in males and females where males were sterile while females produced deformed progeny.

genetics↗

bioRxiv2018

Expanded view of the ecological genomics of ant responses to climate change

Given the abundance, broad distribution, and diversity of roles that ants play in many ecosystems, they are an ideal group to serve as ecosystem indicators of climatic change. At present, only a few whole-genome sequences of ants are available (19 of > 16,000 species), mostly from tropical and sub-tropical species. To address this limited sampling, we sequenced genomes of temperate-latitude species from the genus Aphaenogaster, a genus with important seed dispersers. In total, we sampled seven colonies of six species: A. ashmeadi, A. floridana, A. fulva, A. miamiana, A. picea, and A. rudis. The geographic ranges of these species collectively span eastern North America from southern Florida to southern Canada, which encompasses a latitudinal gradient in which many climatic variables are changing rapidly. For the six genomes, we assembled an average of 271,039 contigs into 47,337 scaffolds. The mean genome size was 370.5 Mb, ranging from 310.3 to 429.7, which is comparable to that of other sequenced ant genomes (212.8 to 396.0 Mb) and flow cytometry estimates (210.7 to 690.4 Mb). In an analysis of currently sequenced ant genomes and the new Aphaenogaster sequences, we found that after controlling for both spatial autocorrelation and phylogenetics ant genome size was marginally correlated with sample site climate similarity. Of all examined climate variables, minimum temperature showed the strongest correlation with genome size, with ants from locations with colder minimum temperatures having larger genomes. These results suggest that temperature extremes could be a selective force acting on ant genomes and point to the need for more extensive sequencing of ant genomes.

genomics↗