bluuebunny/crossref_metadata_2025_split huggingface dataset:
P-elements strengthen reproductive isolation within theDrosophila simulansspecies complex
Authors: Serrato-Capuchina Antonio , D’Agostino Emmanuel R. R. , Peede David , Roy Baylee , Isbell Kristin , Wang Jeremy , Matute Daniel R. 
Published: August 2020

ABSTRACTDetermining mechanisms that underlie reproductive isolation is key to understanding how species boundaries are maintained in nature. Transposable elements (TEs) are ubiquitous across eukaryotic genomes. However, the role of TEs in modulating the strength of reproductive isolation between species is poorly understood. Several species ofDrosophilahave been found to harbor P-elements (PEs), yet onlyD. simulansis known to be polymorphic for their presence in wild populations. PEs can cause reproductive isolation between PE-containing (P) and PE-lacking (M) lineages of the same species. However, it is unclear whether they also contribute to the magnitude of reproductive isolation between species. Here, we use thesimulansspecies complex to assess whether differences in PE status betweenD. simulansand its sister species, which do not harbor PEs, contribute to multiple barriers to gene flow between species. We show that crosses involving a PD. simulansfather and an M mother from a sister species exhibit lower F1 female fecundity than crosses involving an MD. simulansfather and an M sister-species mother. Our results suggest that the presence of PEs in a species can strengthen isolation from its sister species, providing evidence that transposable elements can play a role in reproductive isolation and facilitate the process of speciation.IMPACT SUMMARYTransposable elements (TEs) are repetitive genetic units found across the tree of life. They play a fundamental role on the evolution of each species’ genome. TEs have been implicated in diversification, extinction, and the origin of novelty. However, their potential role in contributing to the maintenance of species boundaries remains largely understudied. Using whole genome sequences, we compared the relative content of TEs across the three species of theDrosophila simulanscomplex. We find that the presence of one TE,P-element, inD. simulans, and its absence in the sister taxa, differentiates the three species.P-elements (PEs) cause a suite of fitness defects inDrosophilapure-species individuals if their father has PEs but their mother does not, a phenomenon known as hybrid dysgenesis (HD). We thus studied the possibility that PEs enhance isolation between recently-diverged species. In particular, we studied whether the progeny from interspecific crosses were more prone to suffer from HD than pure species. We found that the presence of paternal PEs reduces hybrid female fecundity, mirroring observations of HD described within species. The effect of PEs is stronger in the interspecific hybrids than in pure species. Our results suggest that PEs can strengthen reproductive isolation in well-formed sister species that still hybridize in nature and pose the question of whether other TEs are involved in the formation of species or in their persistence over time.
Structure of the extracellular region of the bacterial type VIIb secretion system subunit EsaA
Authors: Klein Timothy A. , Grebenc Dirk W. , Gandhi Shil Y. , Shah Vraj S. , Kim Youngchang , Whitney John C. 
Published: August 2020

SummaryGram-positive bacteria use type VII secretion systems (T7SSs) to export effector proteins that manipulate the physiology of nearby prokaryotic and eukaryotic cells. Several mycobacterial T7SSs have established roles in virulence. By contrast, recent work has demonstrated that the genetically distinct T7SSb pathway found in Firmicutes bacteria more often functions to mediate interbacterial competition. A lack of structural information on the T7SSb has limited the understanding of effector export by this protein secretion apparatus. In this work, we present the 2.4Å crystal structure of the extracellular region of the elusive T7SSb subunit EsaA fromStreptococcus gallolyticus. Our structure reveals that homodimeric EsaA is an elongated, arrow-shaped protein with a surface-accessible ‘tip’, which serves as a receptor for lytic bacteriophages in some species of bacteria. Because it is the only T7SSb subunit large enough to traverse the thick peptidoglycan layer of Firmicutes bacteria, we propose that EsaA plays a critical role in transporting effectors across the entirety of the Gram-positive cell envelope.
Retracing the evolution of kinesin-2 deployment from mouse to worm
Authors: Cleetus Augustine , Merck Georg , Ökten Zeynep 
Published: August 2020

SummaryDuring the course of evolution, cells have repurposed homologous motor proteins for the transport of an astonishingly diverse set of intracellular cargo. One prominent example of such diversification is the deployment of the respective kinesin-2 homologs inC. elegans(CeOSM-3) and mouse (MmKIF-17). WhileCeOSM-3 is deployed exclusively inside the cilium as a transport motor, its mouse counterpart behaves as a ciliary cargo. Instead,MmKIF-17 powers many different transport processes in the cytoplasm. Here we turned to functional reconstitution assays to uncover the molecular underpinnings of kinesin-2 deployment. Based on our findings, we propose that cells specified adaptor proteins as strictly conserved ‘on- and off-switches’, and ‘tailored’ the motors to fit the respective switches. This is exemplified by the surprising ability of the mouse adaptor to function as a ciliary on-switch for the distantly relatedCeOSM-3, but not for its ownMmKIF-17 motor. Worms, in contrast, retained ciliary on- and off-switches, and can thus deployCeOSM-3 as a regulatable transport motor inside the cilium.MmKIF-17 escaped this regulatory control by losing its interaction with the ciliary on-switch and has evidently been tailored to fit many different cytoplasmic adaptors over the course of evolution. We could further trace the robustness of an adaptor to serve as a conserved on-switch back to a few strictly conserved residues, which are also present in unicellular organisms. It is therefore conceivable that eukaryotes started to engineer dedicated on- and off-switches early in the evolution and kept their function conserved up to mammals.
Parkinson’s Disease Genetic Risk Evaluation in Microglia Highlights Autophagy and Lysosomal Genes
Authors: Booms Alix , Pierce Steven E. , Coetzee Gerhard A. 
Published: August 2020

AbstractGenome-wide association studies (GWAS) have uncovered thousands of single nucleotide polymorphisms (SNPs) that are associated with Parkinson’s disease (PD) risk. The functions of most of these SNPs, including the cell type they influence, and how they affect PD etiology remain largely unknown. To identify functional SNPs, we aligned PD risk SNPs within active regulatory regions of DNA in microglia, a cell type implicated in PD development. Out of 6,749 ‘SNPs of interest’ from the most recent PD GWAS metanalysis, 73 were located in open regulatory chromatin as determined by both ATAC-seq and H3K27ac ChIP-seq. We highlight a subset of SNPs that are favorable candidates for further mechanistic studies. These SNPs are located in regulatory DNA at theSLC50A1, SNCA, BAG3, FBXL19, SETD1A, andNUCKS1loci. A network analysis of the genes with risk SNPs in their promoters, implicated substance transport, involving autophagy and lysosomal genes. Our study provides a more focused set of risk SNPs and their associated risk genes as candidates for further follow-up studies, which will help identify mechanisms in microglia that increase the risk for PD.
Vector and cell-culture passaging of dengue clinical samples for virus isolation and amplification does not significantly change genome consensus or frequencies of intra-host viral variants
Authors: Fung Christian K. , Li Tao , Pollett Simon , Alera Maria Theresa , Yoon In-Kyu , Hang Jun , Macareo Louis , Srikiatkhachorn Anon , Ellison Damon , Rothman Alan L. , Fernandez Stefan , Jarman Richard G. , Berry Irina Maljkovic 
Published: August 2020

ABSTRACTIntra-host single nucleotide variants (iSNVs) have been increasingly used in genomic epidemiology to increase phylogenetic resolution and reconstruct fine-scale outbreak dynamics. These analyses are preferably done on sequence data from direct clinical samples, but in many cases due to low viral loads, there might not be enough genetic material for deep sequencing and iSNV determination. Isolation of the virus from clinical samples with low passage number increases viral load, but to date, no studies have investigated how dengue virus (DENV) culture isolation from a clinical sample impacts the consensus sequence, and there is no information on the intra-host virus population changes that may result from viral isolation. In this study, we investigate consensus and iSNV frequency differences between DENV sequenced directly from clinical samples and their corresponding low-passage isolates. Twenty five DENV1 and DENV2 positive sera and their corresponding viral isolates (T.splendensinoculation and C6/36 passage) were obtained from a prospective cohort study in the Philippines. These were sequenced on MiSeq with minimum nucleotide depth of coverage of 1000x, and iSNVs were detected using LoFreq. For both DENV1 and DENV2, we found that the nucleotide call concordance (including called iSNVs with variant cutoff at 5%) between direct sera sample and its cultured virus was on average 99.99%. There were a maximum of one consensus nucleotide difference between clinical sample and isolate. Interestingly, we found that iSNV frequencies were also largely preserved between the samples, with an average difference in minor variant frequency of 6.8% (95CI: 3.6%-10%) and 9.6% (95CI: 7%-12.2%) for DENV1 and DENV2, respectively. Furthermore, we found no significant differences in either DENV1 or DENV2 between the sample pairs (clinical sample and isolate) in their number of iSNV positions per genome, or in the difference in variant frequencies (p=0.36 andp=0.13, respectively, F-test). Our results show that low-passage DENV isolates may be used for identification of the majority of their human-derived within-host variant populations, which are increasingly being used for precision tracking of DENV and other RNA viruses.
HDAC1 SUMOylation promotes Argonaute directed transcriptional silencing inC. elegans
Authors: Kim Heesun , Ding Yue-He , Zhang Gangming , Yan Yong-Hong , Conte Darryl , Dong Meng-Qiu , Mello Craig C. 
Published: August 2020

SUMMARYEukaryotic cells use guided search to coordinately control dispersed genetic elements. The transitive effectors of these mechanisms, Argonaute proteins and their small-RNA co-factors, engage nascent RNAs and chromatin-associated proteins to direct transcriptional silencing. The small ubiquitin-like modifier (SUMO) has been shown to promote the induction and maintenance of silent chromatin (called heterochromatin) in yeast, plants, and animals. Here we show that Argonaute-directed transcriptional silencing inC. elegansrequires SUMOylation of the type 1 histone deacetylase HDA-1. SUMOylation of HDA-1 promotes interactions with components of the nucleosome remodeling and deacetylase (NuRD) complex and with the nuclear Argonaute HRDE-1/WAGO-9. Our findings suggest how HDAC1 SUMOylation promotes the association of HDAC and other chromatin remodeling factors with a nuclear Argonaute in order to initiate de novo heterochromatin silencing.
NMR unveils an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibrils
Authors: Yang Xue , Wang Baifan , Hoop Cody L. , Williams Jonathan K. , Baum Jean 
Published: August 2020

AbstractAmyloid fibril formation of α-synuclein (αS) is associated with multiple neurodegenerative diseases, including Parkinson’s Disease (PD). Growing evidence suggests that progression of PD is linked to cell-to-cell propagation of αS fibrils, which leads to seeding of endogenous intrinsically disordered monomer via templated elongation and secondary nucleation. A molecular understanding of the seeding mechanism and driving interactions is crucial to inhibit progression of amyloid formation. Here, using relaxation-based solution NMR experiments designed to probe large complexes, we probe weak interactions of intrinsically disordered acetylated-αS (Ac-αS) monomers with seeding-competent Ac-αS fibrils and seeding-incompetent off-pathway oligomers to identify Ac-αS monomer residues at the binding interface. Under conditions that favor fibril elongation, we determine that the first 11 N-terminal residues on the monomer form a common binding site for both fibrils and off-pathway oligomers. Additionally, the presence of off-pathway oligomers within a fibril seeding environment suppresses seeded amyloid formation, as observed through thioflavin-T fluorescence experiments. This highlights that off-pathway αS oligomers can act as an auto-inhibitor against αS fibril elongation. Based on these data taken together with previous results, we propose a model in which Ac-αS monomer recruitment to the fibril is driven by interactions between the intrinsically disordered monomer N-terminus and the intrinsically disordered flanking regions (IDR) on the fibril surface. We suggest that this monomer recruitment may play a role in the elongation of amyloid fibrils and highlight the potential of the IDRs of the fibril as important therapeutic targets against seeded amyloid formation.SignificanceCell-to-cell spreading of αS fibrils leads to amyloid seeding of endogenous monomer. Detailed atomic-level mechanistic understanding of the fibril seeding process of αS is essential for design of therapeutic approaches against Parkinson’s disease. In light of its complexity, this process remains ill-defined at the molecular level. Using relaxation-based solution NMR experiments, we mapped a common N-terminal binding interface of the Ac-αS intrinsically disordered monomer with Ac-αS fibrils and off-pathway oligomers to elucidate critical monomer–aggregate interactions during seeded aggregation and in equilibrium with mature aggregates. From this work, we propose a new paradigm, in which Ac-αS monomer recruitment to the fibril is driven by interactions between the intrinsically disordered monomer N-terminus and the flanking IDRs on the fibril surface.
The Role of Temperature on the Development of Circadian Rhythms in Honey Bee Workers
Authors: Giannoni-Guzmán Manuel A. , Aleman-Rios Janpierre , Moreno Alexander M. Melendez , Hernandez Gabriel Diaz , Perez Melina , Loubriel Darimar , Giray Tugrul , Agosto-Rivera Jose L. 
Published: August 2020

AbstractCircadian rhythms in honey bees are involved in various processes that impact colony survival. For example, young nurses take care of the brood constantly throughout the day and lack circadian rhythms, while foragers use the circadian clock to remember and predict food availability in subsequent days. Previous studies suggested that development of circadian rhythms both in the field and the laboratory began around 7-9 days of age. However, not much is understood about the postembryonic development of circadian rhythms in honey bees. In the current study, we examine the effects of socially regulated colony temperature on the ontogeny of circadian rhythms of young workers under controlled laboratory conditions. We hypothesized that temperature plays a key role in the development of circadian rhythmicity in young workers. Our results show that young workers kept at 35°C develop circadian rhythmicity faster and in greater proportion than bees kept at 25°C. In addition, we examine if the effect of colony temperature during the first 48 hours after emergence is enough to observe effects on the rate and proportion of development of circadian rhythmicity. We observed that twice as many individuals that were exposed to 35°C during the first 48 hours develop circadian rhythms compared to individuals kept at 25°C. In addition, we observed differences in the average endogenous period length consistent with temperature compensation of the circadian rhythms between the 25°C and 35°C cohorts. We also observed differences in the degree of period length variation between the 25°C and 35°C cohorts, which combined with the proportion of arrhythmic individuals and survival data suggest that development of circadian rhythms is incomplete in individuals exposed to 25°C adult emergence. This study shows that temperature, which is socially regulated inside the hive, is a key factor that influences the ontogeny of circadian rhythmicity of workers.
Growth hormone receptor (GHR)-expressing neurons in the hypothalamic arcuate nucleus regulate glucose metabolism and energy homeostasis
Authors: de Lima Juliana Bezerra Medeiros , Debarba Lucas Kniess , Khan Manal , Ubah Chidera , Didyuk Olesya , Ayyar Iven , Koch Madelynn , Sadagurski Marianna 
Published: August 2020

AbstractGrowth hormone (GH) receptor (GHR), expressed in different brain regions, is known to participate in the regulation of whole-body energy homeostasis and glucose metabolism. However, GH activation of these GHR-expressing neurons is less studied. We have generated a novel GHR-driven Cre recombinase transgenic mouse line (GHRcre) in combination with the floxed tdTomato reporter mouse line we tracked and activated GHR-expressing neurons in different regions of the brain. We focused on neurons of the hypothalamic arcuate nucleus (ARC) where GHR was shown to elicit a negative feedback loop that regulates GH production. We found that ARCGHR+neurons are co-localized with AgRP, GHRH, and somatostatin neurons, which were activated by GH stimulation. Using designer receptors exclusively activated by designer drugs (DREADDs) to control GHRARCneuronal activity, we revealed that activation of GHRARCneurons was sufficient in regulating distinct aspects of energy balance and glucose metabolism. Overall, our study provides a novel mouse model to studyin vivoregulation and physiological function of GHR-expressing neurons in various brain regions. Furthermore, we identified for the first time specific neuronal population that responds to GH and directly linked it to metabolic responsesin vivo.
Harnessing population-specific protein truncating variants to improve the annotation of loss-of-function alleles
Authors: Skitchenko Rostislav K. , Kornienko Julia S. , Maksiutenko Evgeniia M. , Glotov Andrey S. , Predeus Alexander V. , Barbitoff Yury A. 
Published: August 2020

AbstractAccurate annotation of putative loss-of-function (pLoF) variants is an important problem in human genomics and disease, which recently drew substantial attention. Since such variants in disease-related genes are under strong negative selection, their frequency across major ancestral groups is expected to be highly similar. In this study, we tested this assumption by systematically assessing the presence of highly population-specific protein-truncating variants (PTVs) in human genes using latest population-scale data. We discovered an unexpectedly high incidence of population-specific PTVs in all major ancestral groups. This does not conform to a recently proposed model, indicating either systemic differences in disease penetrance in different human populations, or a failure of current annotation criteria to accurately predict the loss-of-function potential of PTVs. We show that low-confidence pLoF variants are enriched in genes with non-uniform PTV count distribution, and developed a computational tool called LoFfeR that can efficiently predict tolerated pLoF variants. To evaluate the performance of LoFfeR, we use a set of known pathogenic and benign PTVs from the ClinVar database, and show that LoFfeR allows for a more accurate annotation of low-confidence pLoF variants compared to existing methods. Notably, only 4.4% of protein-truncating gnomAD SNPs in canonical transcripts can be filtered out using a recommended threshold value of the recently proposedpextscore, while up to 10.9% of such variants are filtered using LoFfeR with the same false positive rate. Hence, we believe that LoFfeR can be used for additional filtering of low-confidence pLoF variants in population genomics and medical genetics studies.
Interspecies variation in hominid gut microbiota controls host gene regulation
Authors: Muehlbauer Amanda L. , Richards Allison L. , Alazizi Adnan , Burns Michael , Gomez Andres , Clayton Jonathan B. , Petrzelkova Klara , Cascardo Camilla , Resztak Justyna , Wen Xiaoquan , Pique-Regi Roger , Luca Francesca , Blekhman Ran 
Published: August 2020

AbstractThe gut microbiome exhibits extreme compositional variation between hominid hosts. However, it is unclear how this variation impacts host physiology, and whether this effect can be mediated through microbial regulation of host gene expression in interacting epithelial cells. Here, we characterized the transcriptional response of colonic epithelial cellsin vitroto live microbial communities extracted from humans, chimpanzees, gorillas, and orangutans. We found most host genes exhibit a conserved response, whereby they respond similarly to the four hominid microbiomes, while some genes respond only to microbiomes from specific host species. Genes that exhibit such a divergent response are associated with relevant intestinal diseases in humans, such as inflammatory bowel disease and Crohn’s disease. Lastly, we found that inflammation-associated microbial species regulate the expression of host genes previously associated with inflammatory bowel disease, suggesting health-related consequences for species-specific host-microbiome interactions across hominids.
Divergent features of the coenzyme Q:cytochromecoxidoreductase complex inToxoplasma gondiiparasites
Authors: Hayward Jenni A. , Rajendran Esther , Zwahlen Soraya M. , Faou Pierre , van Dooren Giel G. 
Published: August 2020

AbstractThe mitochondrion is critical for the survival of apicomplexan parasites. Several major anti-parasitic drugs, such as atovaquone and endochin-like quinolones, act through inhibition of the mitochondrial electron transport chain at the coenzyme Q:cytochromecoxidoreductase complex (Complex III). Despite being an important drug target, the protein composition of Complex III of apicomplexan parasites has not been elucidated. Here, we undertake a mass spectrometry-based proteomic analysis of Complex III in the apicomplexanToxoplasma gondii. Along with canonical subunits that are conserved across eukaryotic evolution, we identify several novel or highly divergent Complex III components that are conserved within the apicomplexan lineage. We demonstrate that one such subunit, which we termTgQCR11, is critical for parasite proliferation, mitochondrial oxygen consumption and Complex III activity, and establish that loss of this protein leads to defects in Complex III integrity. We conclude that the protein composition of Complex III in apicomplexans differs from that of the mammalian hosts that these parasites infect.Author summaryApicomplexan parasites cause numerous diseases in humans and animals, including malaria (Plasmodiumspecies) and toxoplasmosis (Toxoplasma gondii). The coenzyme Q:cytochromecoxidoreductase protein complex (Complex III) performs a central role in the mitochondrial electron transport chain of many eukaryotes. Despite being the target of several major anti-apicomplexan drugs, the protein composition of Complex III in apicomplexans was previously unknown. Our work identifies novel proteins in Complex III of apicomplexans, one of which is critical for complex function and integrity. Our study highlights divergent features of Complex III in apicomplexans, and provides a broader understanding of Complex III evolution in eukaryotes. Our study also provides important insights into what sets this major drug target apart from the equivalent complex in host species.