bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants
Authors: Ose Nicholas J. , Butler Brandon M. , Kumar Avishek , Sanderford Maxwell , Kumar Sudhir , Ozkan S. Banu 
Published: September 2021

AbstractMany pathogenic missense mutations are found in protein positions that are neither well-conserved nor belong to any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for such mutations. In this study, we present an analysis of 144 human enzymes containing 591 pathogenic missense variants, in which allosteric dynamic coupling of mutated positions with known active sites provides insights into a primary biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of β-Glucocerebrosidase (GCase), which contains 94 Gaucher disease-associated missense variants located some distance away from the active site. An analysis of the conformational dynamics of GCase suggests that mutations on these distal sites cause changes in the flexibility of active site residues despite their distance, indicating a dynamic communication network throughout the protein. The disruption of the long-distance dynamic coupling due to the presence of missense mutations may provide a plausible general mechanistic explanation for biological dysfunction and disease.Author SummaryGenetic diseases occur when mutations to a particular gene cause a gain/loss in function of the related protein. Although several methods based on conservation and protein biochemistry exist to predict which genetic mutations may impact function, many disease causing changes remain unexplained by these metrics. In this study, we propose an explanation for these genetic changes may cause disease. In order to function, important regions of a protein must be able to exhibit collective motion. Through computer simulations, we observed that changing even a single amino acid within a protein can change the protein motion. Notably, disease causing genetic changes tend to alter the motion of regions which are critically important to protein function, even the mutations are far from these critical regions. In addition, we examined the degree that two amino acids within a protein may “couple” to one another, meaning the degree to which motion in one amino acid will affect the other. We found that amino acids which are highly coupled to the active site of a protein are more likely to result in disease if mutated, thereby offering a new tool for predicting genetic disease which incorporates internal protein dynamics.
FSTruct: anFST-based tool for measuring ancestry variation in inference of population structure
Authors: Morrison Maike L. , Alcala Nicolas , Rosenberg Noah A. 
Published: September 2021

AbstractIn model-based inference of population structure from individual-level genetic data, individuals are assigned membership coefficients in a series of statistical clusters generated by clustering algorithms. Distinct patterns of variability in membership coefficients can be produced for different groups of individuals, for example, representing different predefined populations, sampling sites, or time periods. Such variability can be difficult to capture in a single numerical value; membership coefficient vectors are multivariate and potentially incommensurable across groups, as the number of clusters over which individuals are distributed can vary among groups of interest. Further, two groups might share few clusters in common, so that membership coefficient vectors are concentrated on different clusters. We introduce a method for measuring the variability of membership coefficients of individuals in a predefined group, making use of an analogy between variability across individuals in membership coefficient vectors and variation across populations in allele frequency vectors. We show that in a model in which membership coefficient vectors in a population follow a Dirichlet distribution, the measure increases linearly with a parameter describing the variance of a specified component of the membership vector. We apply the approach, which makes use of a normalizedFSTstatistic, to data on inferred population structure in three example scenarios. We also introduce a bootstrap test for equivalence of two or more groups in their level of membership coefficient variability. Our methods are implemented in the R package FSTruct.
Bakdrive: Identifying the Minimum Set of Bacterial Driver Species across Multiple Microbial Communities
Authors: Wang Qi , Nute Michael , Treangen Todd 
Published: September 2021

AbstractInteractions among microbes within microbial communities have been shown to play crucial roles in human health. In spite of recent progress, low-level knowledge of bacteria driving microbial interactions within microbiomes remains unknown, limiting our ability to fully understand and control microbial communities. In this study, we present a novel approach for identifying driver species within microbiomes. Bakdrive infers ecological networks of given metagenomic sequencing samples and identifies minimum sets of driver species using control theory. Bakdrive has three key innovations in this space: (i) it leverages inherent information from metagenomic sequencing samples to identify driver species, (ii) it explicitly takes host-specific variation into consideration, and (iii) it does not require a known ecological network. In extensive simulated data, we demonstrate identifying driver species identified from healthy donor samples and introducing them to the disease samples, we can restore the gut microbiome in recurrent Clostridioides difficile infection patients to a healthy state. We also applied Bakdrive to two real datasets, rCDI and Crohn’s disease patients, uncovering driver species consistent with previous work. In summary, Bakdrive provides a novel approach for teasing apart microbial interactions. Bakdrive is open-source and available at https://gitlab.com/treangenlab/bakdrive
BRCA2 BRC missense variants disrupt RAD51-dependent DNA repair
Authors: Jimenez-Sainz Judit , Mathew Joshua , Moore Gemma , Lahiri Sudipta , Garbarino Jennifer , Eder Joseph P. , Rothenberg Eli , Jensen Ryan B. 
Published: September 2021

ABSTRACTPathogenic mutations in the BRCA2 tumor suppressor gene predispose to breast, ovarian, pancreatic, prostate, and other cancers. BRCA2 maintains genome stability through homology-directed repair (HDR) of DNA double-strand breaks (DSBs) and replication fork protection. Nonsense or frameshift mutations leading to truncation of the BRCA2 protein are typically considered pathogenic, however, missense mutations resulting in single amino acid substitutions can be challenging to functionally interpret. The majority of missense mutations in BRCA2 have been classified as Variants of Uncertain Significance (VUS) with unknown functional consequences. In this study, we identified three BRCA2 VUS located within the BRC repeat region to determine their impact on canonical HDR and fork protection functions. We provide evidence that S1221P and T1980I, which map to conserved residues in the BRC2 and BRC7 repeats, compromise the cellular response to chemotherapeutics and ionizing radiation, and display deficits in fork protection. We further demonstrate biochemically that S1221P and T1980I disrupt RAD51 binding and diminish the ability of BRCA2 to stabilize RAD51-ssDNA complexes. The third variant, T1346I, located within the spacer region between BRC2 and BRC3 repeats, is fully functional. We conclude that T1346I is a benign allele whereas S1221P and T1980I are hypomorphic disrupting the ability of BRCA2 to fully engage and stabilize RAD51 nucleoprotein filaments. Our results underscore the importance of correctly classifying BRCA2 VUS as pathogenic variants can impact both future cancer risk and guide therapy selection during cancer treatment.Graphical Abstract
Social behavioral profiling by unsupervised deep learning reveals a stimulative effect of dopamine D3 agonists on zebrafish sociality
Authors: Geng Yijie , Peterson Randall T. 
Published: September 2021

ABSTRACTIt has been a major challenge to systematically evaluate and compare how pharmacological perturbations influence social behavioral outcomes. Although some pharmacological agents are known to alter social behavior, precise description and quantification of such effects have proven difficult. The complexity of brain functions regulating sociality makes it challenging to predict drug effects on social behavior without testing in live animals, and most existing behavioral assays are low-throughput and provide only unidimensional readouts of social function. To achieve richer characterization of drug effects on sociality, we developed a scalable social behavioral assay for zebrafish named ZeChat based on unsupervised deep learning. High-dimensional and dynamic social behavioral phenotypes are automatically classified using this method. By screening a neuroactive compound library, we found that different classes of chemicals evoke distinct patterns of social behavioral fingerprints. By examining these patterns, we discovered that dopamine D3 agonists possess a social stimulative effect on zebrafish. The D3 agonists pramipexole, piribedil, and 7-hydroxy-DPAT-HBr rescued social deficits in a valproic acid-induced zebrafish autism model. The ZeChat platform provides a promising approach for dissecting the pharmacology of social behavior and discovering novel social-modulatory compounds.
The germline-specific region of the sea lamprey genome plays a key role in spermatogenesis
Authors: Yasmin Tamanna , Grayson Phil , Docker Margaret F. , Good Sara V. 
Published: September 2021

AbstractThe sea lamprey genome undergoes programmed genome rearrangement (PGR) in which ∼20% is jettisoned from somatic cells soon after fertilization. Although the role of PGR in embryonic development has been studied, the role of the germline-specific region (GSR) in gonad development is unknown. We analysed RNA-sequence data from 28 sea lamprey gonads sampled across life-history stages, generated a genome-guided de novo superTransciptome with annotations, and identified genes in the GSR. We found that the 638 genes in the GSR are enriched for reproductive processes, exhibit 36x greater odds of being expressed in testes than ovaries, show little evidence of conserved synteny with other chordates, and most have putative paralogues in the GSR and/or somatic genomes. Further, several of these genes play known roles in sex determination and differentiation in other vertebrates. We conclude that the GSR of sea lamprey plays an important role in testicular differentiation and potentially sex determination.
Leafy and Weedy Seadragon Genomes Connect Genic and Repetitive DNA Features to the Extravagant Biology of Syngnathid Fishes
Authors: Small Clayton M. , Healey Hope M. , Currey Mark C. , Beck Emily A. , Catchen Julian , Lin Angela S. P. , Cresko William A. , Bassham Susan 
Published: September 2021

AbstractSeadragons are a remarkable lineage of teleost fishes, and they are members of the family Syngnathidae renowned for having evolved male pregnancy. Comprising three known species, seadragons are widely recognized and admired for their fantastical body forms and coloration, and their specific habitat requirements have made them flagship representatives for marine conservation and natural history interests. Until recently, a gap has been the lack of significant genomic resources for seadragons. We have produced gene-annotated, chromosome-scale genome models for the leafy and weedy seadragon to advance investigations into evolutionary innovation and elaboration of morphological traits in seadragons as well as their pipefish and seahorse relatives. We identified several interesting features specific to seadragon genomes, including divergent non-coding regions near a developmental gene important for integumentary outgrowth, a high genome-wide density of repetitive DNA, and recent expansions of transposable elements and a vesicular trafficking gene family. Surprisingly, comparative analyses leveraging the seadragon genomes and additional syngnathid and outgroup genomes revealed striking, syngnathid-specific losses in the family of fibroblast growth factors (FGFs), which likely involve re-organization of highly conserved gene regulatory networks in ways that have not previously been documented in natural populations. The resources presented here serve as important tools for future evolutionary studies of developmental processes in syngnathids and will be a key resource for conservation studies of the extravagant seadragons and their relatives.
‘Wanting’ versus ‘Needing’ related value: an fMRI meta-analysis
Authors: Bosulu J , Allaire M.-A. , Tremblay-Grénier L. , Luo Y. , Eickhoff S. , Hétu S. 
Published: September 2021

ABSTRACTConsumption and its excesses are sometimes explained by imbalance of need or lack of control over ‘wanting’. ‘Wanting’ assigns value to cues that predict rewards, whereas ‘needing’ assigns value to biologically significant stimuli that one is deprived of. Here we aimed at studying how the brain activation patterns related to value of ‘wanted’ stimuli differs from that of ‘needed’ stimuli using ALE neuroimaging meta-analysis approaches. We used the perception of a cue predicting a reward for ‘wanting’ related value and the perception of food stimuli in a hungry state as a model for ‘needing’ related value. We carried out separate, contrasts, and conjunction meta-analyses to identify differences and similarities between ‘wanting’ and ‘needing’ values. Our overall results for ‘wanting’ related value show consistent activation of the ventral tegmental area, striatum and pallidum, regions that both activate behaviour and direct choice; while for ‘needing’ related value we found an overall consistent activation of the middle insula and to some extent the caudal-ventral putamen, regions that only direct choice. Our study suggests that wanting has more control on consumption, and a needed stimuli must become wanted in order to be pursued.
Rapid in vivo development of resistance to daptomycin in vancomycin-resistant Enterococcus faecium due to genomic rearrangements
Authors: Mollerup Sarah , Elmeskov Christine , Gumpert Heidi , Pinholt Mette , Sejersen Tobias Steen , Pedersen Martin Schou , Worning Peder , Frees Dorte , Westh Henrik 
Published: September 2021

AbstractBackgroundDaptomycin is a cyclic lipopeptide used in the treatment of vancomycin-resistant Enterococcus faecium (VREfm). However, the development of daptomycin-resistant VREfm challenges the treatment of nosocomial VREfm infections. Resistance mechanisms of daptomycin are not fully understood. Here we analysed the genomic changes leading to a daptomycin-susceptible VREfm isolate becoming resistant after 40 days of daptomycin and linezolid combination therapy.MethodsThe two isogenic VREfm isolates (daptomycin-susceptible and daptomycin-resistant) were analysed using whole genome sequencing with Illumina and Nanopore.ResultsWhole genome comparative analysis identified the loss of a 46.5 kb fragment and duplication of a 29.7 kb fragment in the daptomycin-resistant isolate, with many implicated genes involved in cell wall synthesis. Two plasmids of the daptomycin-susceptible isolate were also found integrated in the chromosome of the resistant isolate. One nonsynonymous SNP in the rpoC gene was identified in the daptomycin-resistant isolate.ConclusionsDaptomycin resistance developed through chromosomal rearrangements leading to altered cell wall structure. Such novel types of resistance mechanisms can only be identified by comparing closed genomes of isogenic isolates.
Kin discrimination modifies fitness, spatial segregation and matrix sharing between strains with low relatedness inBacillus subtilisbiofilms
Authors: Bolješić Maja , Kraigher Barbara , Dogša Iztok , Kokelj Barbara Jerič , Mulec Ines Mandić 
Published: September 2021

ABSTRACTMicroorganisms in nature form multicellular groups called biofilms. In biofilms bacteria embedded in a matrix of extracellular polymeric substances (EPS) interact intensely, due to their proximity to each other. Most studies have investigated genetically homogeneous biofilms, leaving a gap in knowledge on genetically heterogeneous biofilms. Recent insights show that a Gram-positive model bacterium,Bacillus subtilis, discriminates between strains of high (kin) and low (non-kin) phylogenetic relatedness, reflected in merging (kin) and boundaries (non-kin) between swarms. However, it is not clear how kinship between interacting strains affects their fitness, the genotype distribution, and the EPS sharing in floating biofilms (pellicles). To address this gap in knowledge we cultivateB. subtilisstrains as mixtures of kin and non-kin strains in static cultures, allowing them to form pellicles. We show here that in non-kin pellicles only one strain’s fitness was reduced; at the same time, strains segregated into larger patches and exhibited decreased matrix sharing, as compared to kin and isogenic pellicles, in which both strains had comparable colony forming units (CFU) counts and more homogenous cell mixing. Overall, our results emphasize kin discrimination (KD) as a social behavior that shapes fitness, spatial segregation and sharing of the extracellular matrix in genetically heterogenous biofilms ofB. subtilis.IMPORTANCEBiofilm communities have both beneficial and harmful effects on human societies in natural, medical and industrial environments.Bacillus subtilis, a Gram-positive and biotechnologically important bacterium, serves as a model for studying biofilms. Recent studies have shown that this species engages in kin discriminatory behavior during swarming, which may have implications for community assembly, thus being of fundamental importance. Effects of KD on fitness, genotype segregation and matrix sharing in biofilms is not well understood. By using environmental strains with determined kin types and integrated fluorescent reporters we provide evidence that KD involves antagonism of the dominant strain against non-kin, which has important implications for genotype segregation and sharing of matrix polysaccharides between producers and non-producers. Our results reveal novel consequences of KD and are important for advancing our fundamental understanding of microbial sociality, and its role in the assembly of multicellular groups and in the shaping of microbial diversity.
Human metapneumovirus P protein independently drives phase separation and recruits N protein to liquid-like inclusion bodies
Authors: Boggs Kerri Beth , Cifuentes-Munoz Nicolas , Edmonds Kearstin , Najjar Farah El , Ossandón Conny , Roe McKenna , Moncman Carole L. , Creamer Trevor , Dutch Rebecca Ellis 
Published: September 2021

ABSTRACTHuman metapneumovirus (HMPV) inclusion bodies (IBs) are dynamic structures required for efficient viral replication and transcription. The minimum components needed to form IB-like structures in cells are the nucleoprotein (N) and the tetrameric phosphoprotein (P). HMPV P binds to two versions of N protein in infected cells: C-terminal P residues interact with oligomeric, RNA-bound N (N-RNA), and N-terminal P residues interact with monomeric N (N0) to maintain a pool of protein to encapsidate new RNA. Recent work on other negative-strand viruses has suggested that IBs are liquid-like organelles formed via liquid-liquid phase separation (LLPS). Here, HMPV IBs in infected or transfected cells were shown to possess liquid organelle properties, such as fusion and fission. Recombinant versions of HMPV N and P proteins were purified to analyze the interactions required to drive LLPS in vitro. Purified HMPV P was shown to form liquid droplets in the absence of other protein binding partners, a novel finding compared to other viral systems. Removal of nucleic acid from purified P altered phase separation dynamics, suggesting that nucleic acid interactions also play a role in IB formation. HMPV P also recruits monomeric N (N0-P) and N-RNA to IBs in vitro. These findings suggest that, in contrast to what has been reported for other viral systems, HMPV P acts as a scaffold protein to mediate multivalent interactions with monomeric and oligomeric HMPV N to promote phase separation of IBs.IMPORTANCEHuman metapneumovirus (HMPV) is a leading cause of respiratory disease among children, immunocompromised individuals, and the elderly. Currently, no vaccines or antivirals are available for treatment of HMPV infections. Cytoplasmic inclusion bodies (IBs), where HMPV replication and transcription occur, represent a promising target for the development of novel antivirals. The HMPV nucleoprotein (N) and phosphoprotein (P) are the minimal components needed for IB formation in eukaryotic cells. However, interactions that regulate the formation of these dynamic structures are poorly understood. Here, we showed that HMPV IBs possess the properties of liquid organelles and that purified HMPV P phase separates independently in vitro. Our work suggests that HMPV P phase separation dynamics are altered by nucleic acid. We provide strong evidence that, unlike results reported from other viral systems, HMPV P alone serves as a scaffold for multivalent interactions with monomeric (N0) and oligomeric (N-RNA) HMPV N for IB formation.
Means, motive, and opportunity for biological invasions: genetic introgression in a fungal pathogen
Authors: Rogério Flávia , Van Oosterhout Cock , Ciampi-Guillardi Maisa , Correr Fernando Henrique , Hosaka Guilherme Kenichi , Cros-Arteil Sandrine , Margarido Gabriel Rodrigues Alves , Massola Nelson S. , Gladieux Pierre 
Published: September 2021

ABSTRACTInvasions by fungal plant pathogens pose a significant threat to the health of agriculture ecosystems. Despite limited standing genetic variation, many invasive fungal species can adapt and spread rapidly, resulting in significant losses in crop yields. Here, we report on the population genomics of Colletotrichum truncatum, a polyphagous pathogen that can infect more than 460 plant species, and an invasive pathogen on soybean in Brazil. We study the whole-genome sequences of 18 isolates representing 10 fields from two major regions of soybean production. We show that Brazilian C. truncatum is subdivided into three phylogenetically distinct lineages that exchange genetic variation through hybridization. Introgression affects 2 to 30% of the nucleotides of genomes and varies widely between the lineages. We find that introgressed regions comprise secreted protein-encoding genes, suggesting possible co-evolutionary targets for selection in those regions. We highlight the inherent vulnerability of genetically uniform crops in the agro-ecological environment, particularly when faced with pathogens that can take full advantage of the opportunities offered by an increasingly globalized world. Finally, we discuss “The Means, Motive, and Opportunity” of fungal pathogens and how they can become invasive species of crops. We call for more population genomic studies because such analyses can help identify geographic areas and pathogens that pose a risk, thereby helping to inform control strategies to better protect crops in the future.