bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transmission distortion and genetic incompatibilities between alleles in a multigenerational mouse advanced intercross line
Authors: Arends Danny , Kärst Stefan , Heise Sebastian , Korkuc Paula , Hesse Deike , Brockmann Gudrun A. 
Published: June 2021

AbstractBackground/ObjectivesWhile direct additive and dominance effects on complex traits have been mapped repeatedly, additional genetic factors contributing to the heterogeneity of complex traits have been scarcely investigated. To assess genetic background effects, we investigated transmission ratio distortions (TRDs) of alleles from parent to offspring using an advanced intercross line (AIL) of an initial cross between the mouse inbred strains C57BL/6NCrl (B6N) and BFMI860-12 (BFMI).Subjects/Methods341 males of generation 28 and their respective 61 parents and 66 grandparents were genotyped using Mega Mouse Universal Genotyping Arrays (MegaMUGA). TRDs were investigated using allele transmission asymmetry tests, and pathway overrepresentation analysis was performed. Sequencing data was used to test for overrepresentation of non-synonymous SNPs in TRD regions. Genetic incompatibilities were tested using the Bateson-Dobzhansky-Muller two-locus model.Results62 TRD regions were detected, many in close proximity to the telocentric centromere. TRD regions contained 44.5% more non-synonymous SNPs than randomly selected regions (182 vs. 125.9 ± 17.0, P < 1×10−4). Testing for genetic incompatibilities between TRD regions identified 29 genome-wide significant incompatibilities between TRD regions (P(BF) < 0.05). Pathway overrepresentation analysis of genes in TRD regions showed that DNA methylation, epigenetic regulation of RNA, and meiotic/meiosis regulation pathways were affected independent of the parental origin of the TRD. Paternal BFMI TRD regions showed overrepresentation in the small interfering RNA (siRNA) biogenesis and in the metabolism of lipids and lipoproteins. Maternal B6N TRD regions harbored genes involved in meiotic recombination, cell death, and apoptosis pathways. The analysis of genes in TRD regions suggests the potential distortion of protein-protein interactions influencing obesity and diabetic retinopathy as a result of disadvantageous combinations of allelic variants in Aass, Pgx6 and Nme8.ConclusionsUsing an AIL significantly improves the resolution at which we can investigate TRD. Our analysis implicates distortion of protein-protein interactions as well as meiotic drive as the underlying mechanisms leading to the observed TRD in our AIL. Furthermore, genes with large amounts of non-synonymous SNPs located in TRD regions are more likely to be involved in pathways that are related to the phenotypic differences between the parental strains. Genes in these TRD regions provide new targets for investigating genetic adaptation, protein-protein interactions, and determinants of complex traits such as obesity.
Recurrent erosion ofCOA1/MITRAC15demonstrates gene dispensability in oxidative phosphorylation
Authors: Shinde Sagar Sharad , Sharma Sandhya , Teekas Lokdeep , Sharma Ashutosh , Vijay Nagarjun 
Published: June 2021

AbstractSkeletal muscle fibers rely upon either oxidative phosphorylation or glycolytic pathway to achieve muscular contractions that power mechanical movements. Species with energy-intensive adaptive traits that require sudden bursts of energy have a greater dependency on fibers that use the glycolytic pathway. Glycolytic fibers have decreased reliance on OXPHOS and lower mitochondrial content compared to oxidative fibers. Hence, we hypothesized that adaptive gene loss might have occurred within the OXPHOS pathway in lineages that largely depend on glycolytic fibers. The protein encoded by theCOA1/MITRAC15gene with conserved orthologs found in budding yeast to humans promotes mitochondrial translation. We show that gene disrupting mutations have accumulated within theCOA1/MITRAC15gene in the cheetah, several species of galliforms, and rodents. The genomic region containingCOA1/MITRAC15is a well-established evolutionary breakpoint region in mammals. Careful inspection of genome assemblies of closely related species of rodents and marsupials suggests two independentCOA1/MITRAC15gene loss events co-occurring with chromosomal rearrangements. Besides recurrent gene loss events, we document changes inCOA1/MITRAC15exon structure in primates and felids. The detailed evolutionary history presented in this study reveals the intricate link between skeletal muscle fiber composition and dispensability of the chaperone-like role of theCOA1/MITRAC15gene.
Time-resolved secretome analysis of threeColletotrichumspecies identifies copper radical alcohol oxidases for the production of fatty aldehydes
Authors: Ribeaucourt David , Saker Safwan , Navarro David , Bissaro Bastien , Drula Elodie , Correia Lydie Oliveira , Haon Mireille , Grisel Sacha , Lapalu Nicolas , Henrissat Bernard , O’Connell Richard J. , Lambert Fanny , Lafond Mickaël , Berrin Jean-Guy 
Published: June 2021

ABSTRACTCopper Radical Alcohol Oxidases (CRO-AlcOx), which have been recently discovered among fungal phytopathogens are attractive for the production of fragrant fatty aldehydes. To investigate the secretion of CRO-AlcOx by natural fungal strains, we undertook time-course analyses of the secretomes of threeColletotrichumspecies (C. graminicola, C. tabacumandC. destructivum) using proteomics. The addition of a copper-manganese-ethanol mixture toColletotrichumcultures unexpectedly induced the secretion of up to 400 proteins, 29-52% of which were carbohydrate-active enzymes (CAZymes), including a wide diversity of copper-containing oxidoreductases from the auxiliary activities (AA) class (AA1, AA3, AA5, AA7, AA9, AA11-AA13, AA16). Under these specific conditions, while a CRO-glyoxal oxidase from the AA5_1 subfamily was among the most abundantly secreted proteins, the targeted AA5_2 CRO-AlcOx were secreted at lower levels, suggesting heterologous expression as a more promising strategy for CRO-AlcOx production and utilization.C. tabacumandC. destructivumCRO-AlcOx were expressed inPichia pastorisand their preference toward both aromatic and aliphatic primary alcohols was assessed. The CRO-AlcOx fromC. destructivumwas further investigated in applied settings, revealing a full conversion of C6 and C8 alcohols into their corresponding fragrant aldehydes.IMPORTANCEIn the context of the industrial shift toward greener processes, the biocatalytic production of aldehydes is of utmost interest owing to their importance as intermediates in preparative chemistry and for their use as flavors and fragrances ingredients. In the search for new biocatalysts, CRO-AlcOx have the potential to become platform enzymes for the oxidation of alcohols to aldehydes. The use of crude fungal secretomes is often seen has an appealing approach by industries since alleviating various costs pertaining to biocatalysts production. However, the secretion of CRO-AlcOx by natural fungal strains has never been explored. This study showed thatColletotrichumspecies can secrete a broad diversity of copper-containing enzymes, but only little amount of CRO-AlcOx. Thus, recombinant expression remains the most promising approach. The potential of CRO-AlcOx as biocatalyst for flavor and fragrance applications was confirmed through the production of two new enzymes with activity on fatty alcohols.
A deep learning approach to capture the essence ofCandida albicansmorphologies
Authors: Bettauer V , Costa ACBP , Omran RP , Massahi S , Kirbizakis E , Simpson S , Dumeaux V , Law C , Whiteway M , Hallett MT 
Published: June 2021

AbstractWe present deep learning-based approaches for exploring the complex array of morphologies exhibited by the opportunistic human pathogenC. albicans. Our system entitled Candescence automatically detectsC. albicanscells from Differential Image Contrast microscopy, and labels each detected cell with one of nine vegetative, mating-competent or filamentous morphologies. The software is based upon a fully convolutional one-stage object detector and exploits a novel cumulative curriculum-based learning strategy that stratifies our images by difficulty from simple vegetative forms to more complex filamentous architectures. Candescence achieves very good performance on this difficult learning set which has substantial intermixing between the predicted classes. To capture the essence of eachC. albicansmorphology, we develop models using generative adversarial networks and identify subcomponents of the latent space which control technical variables, developmental trajectories or morphological switches. We envision Candescence as a community meeting point for quantitative explorations ofC. albicansmorphology.
Autonomic and respiratory components of orienting behaviors are mediated by descending pathways originating from the superior colliculus
Authors: Lynch Erin , Dempsey Bowen , Saleeba Christine , Monteiro Eloise , Turner Anita , Burke Peter GR , Allen Andrew M , Dampney Roger AL , Hildreth Cara M , Cornish Jennifer L , Goodchild Ann K , McMullan Simon 
Published: June 2021

SummaryThe ability to discriminate competing, external stimuli, and initiate contextually appropriate behaviors, is a key brain function. Neurons in the deep superior colliculus (dSC) integrate multisensory inputs and activate descending projections to premotor pathways responsible for orienting and attention, behaviors which involve adjustments to respiratory and cardiovascular parameters. However, the neural pathways that subserve the physiological components of orienting are poorly understood. We report that orienting responses to optogenetic dSC stimulation are accompanied by short-latency autonomic, respiratory and electroencephalographic effects in awake rats, closely mimicking those evoked by naturalistic alerting stimuli. Physiological responses were not accompanied by detectable aversion or fear and persisted under urethane anesthesia, indicating independence from emotional stress. Moreover, autonomic responses were replicated by selective stimulation of dSC inputs to a subregion in the ventromedial medulla containing spinally-projecting premotor neurons. This putative disynaptic pathway from the dSC represents a likely substrate for autonomic components of orienting.
The Candida albicans Cdk8-dependent phosphoproteome reveals repression of hyphal growth through a Flo8-dependent pathway
Authors: Hollomon Jeffrey M. , Liu Zhongle , Rusin Scott F. , Jenkins Nicole P. , Smith Allia K. , Koeppen Katja , Kettenbach Arminja N. , Myers Lawrence C. , Hogan Deborah A. 
Published: June 2021

AbstractSsn3, also known as Cdk8, is a member of the four protein Cdk8 submodule within the multi-subunit Mediator complex involved in the co-regulation of transcription. In Candida albicans, the loss of Ssn3 kinase activity affects multiple phenotypes including cellular morphology, metabolism, nutrient acquisition, immune cell interactions, and drug resistance. In these studies, we generated a strain in which Ssn3 was replaced with a functional variant of Ssn3 that can be rapidly and selectively inhibited by the ATP analog 3-MB-PP1. Consistent with ssn3 null mutant and kinase dead phenotypes, inhibition of Ssn3 kinase activity promoted hypha formation. Furthermore, the increased expression of hypha-specific genes was the strongest transcriptional signal upon inhibition of Ssn3 in transcriptomics analyses. Rapid inactivation of Ssn3 was used for phosphoproteomic studies performed to identify Ssn3 kinase substrates associated with filamentation potential. Both previously validated and novel Ssn3 targets were identified. Protein phosphorylation sites that were reduced specifically upon Ssn3 inhibition included two sites in Flo8 which is a transcription factor known to positively regulate C. albicans morphology. Mutation of the two Flo8 phosphosites (threonine 589 and serine 620) was sufficient to increase Flo8-HA levels and Flo8 dependent activity, suggesting that Ssn3 kinase activity negatively regulates Flo8. Previous work has also shown that loss of Ssn3 activity leads to increased alkalinization of medium with amino acids. Here, we show that FLO8 and STP2, a transcription factor involved in amino acid utilization, are required for ssn3Δ/Δ phenotype, but that loss of the Ssn3 phosphosites identified in Flo8 was not sufficient to phenocopy the ssn3Δ/Δ mutant. These data highlight the spectrum of processes affected by the modulation of Ssn3 activity and underscore the importance of considering Ssn3 function in the control of transcription factor activities.
A DNA Replication-Independent Function of the pre-Replication Complex during Cell Invasion in C. elegans
Authors: Lattmann Evelyn , Deng Ting , Walser Michael , Widmer Patrizia , Rexha-Lambert Charlotte , Prasad Vibhu , Eichhoff Ossia , Daube Michael , Dummer Reinhard , Levesque Mitchell P. , Hajnal Alex 
Published: June 2021

AbstractCell invasion is an initiating event during tumor cell metastasis and an essential process during development. A screen of C. elegans orthologs of genes over-expressed in invasive human melanoma cells has identified several components of the conserved DNA pre-replication complex (pre-RC) as positive regulators of anchor cell (AC) invasion. The pre-RC functions cell-autonomously in the G1-arrested AC to promote invasion, independently of its role in licensing DNA replication origins in proliferating cells. While the helicase activity of the pre-RC is necessary for AC invasion, the downstream acting DNA replication initiation factors are not required. The pre-RC promotes the invasive fate by regulating the expression of extracellular matrix genes and components of the PI3K signaling pathway. Increasing PI3K pathway activity partially suppressed the AC invasion defects caused by pre-RC depletion, suggesting that the PI3K pathway is one critical pre-RC target. We propose that the pre-RC acts in the non-proliferating AC as a transcriptional regulator that facilitates the switch to an invasive phenotype.
MGEnrichment: a web application for microglia gene list enrichment analysis
Authors: Jao Justin , Ciernia Annie Vogel 
Published: June 2021

AbstractGene expression analysis is becoming increasingly utilized in neuro-immunology research, and there is a growing need for non-programming scientists to be able to analyze their own genomic data. MGEnrichment is a web application developed both to disseminate to the community our curated database of microglia-relevant gene lists, and to allow non-programming scientists to easily conduct statistical enrichment analysis on their gene expression data. Users can upload their own gene IDs to assess the relevance of their expression data against gene lists from other studies. We include example datasets of differentially expressed genes (DEGs) from human postmortem brain samples from Autism Spectrum Disorder (ASD) and matched controls. We demonstrate how MGEnrichment can be used to expand the interpretations of these DEG lists in terms of regulation of microglial gene expression and provide novel insights into how ASD DEGs may be implicated specifically in microglial development, microbiome responses and relationships to other neuropsychiatric disorders. This tool will be particularly useful for those working in microglia, autism spectrum disorders, and neuro-immune activation research. MGEnrichment is available at https://ciernialab.shinyapps.io/MGEnrichmentApp/ and further online documentation and datasets can be found at https://github.com/ciernialab/MGEnrichmentApp. The app is released under the GNU GPLv3 open source license.
Unified classification of mouse retinal ganglion cells using function, morphology, and gene expression
Authors: Goetz Jillian , Jessen Zachary F. , Jacobi Anne , Mani Adam , Cooler Sam , Greer Devon , Kadri Sabah , Segal Jeremy , Shekhar Karthik , Sanes Joshua , Schwartz Gregory W. 
Published: June 2021

AbstractClassification and characterization of neuronal types are critical for understanding their function and dysfunction. Neuronal classification schemes typically rely on measurements of electrophysiological, morphological, and molecular features, but aligning such datasets has been challenging. Here, we present a unified classification of mouse retinal ganglion cells (RGCs), the sole retinal output neurons. We used visually-evoked responses to classify 1859 mouse RGCs into 42 types. We also obtained morphological or transcriptomic data from subsets and used these measurements to align the functional classification to publicly available morphological and transcriptomic data sets. We created an online database that allows users to browse or download the data and to classify RGCs from their light responses using a machine learning algorithm. This work provides a resource for studies of RGCs, their upstream circuits in the retina, and their projections in the brain, and establishes a framework for future efforts in neuronal classification and open data distribution.
Development of the Wheat Practical Haplotype Graph Database as a Resource for Genotyping Data Storage and Genotype Imputation
Authors: Jordan Katherine W. , Bradbury Peter J. , Miller Zachary R. , Nyine Moses , He Fei , Fraser Max , Anderson Jim , Mason Esten , Katz Andrew , Pearce Stephen , Carter Arron H. , Prather Samuel , Pumphrey Michael , Chen Jianli , Cook Jason , Liu Shuyu , Rudd Jackie C. , Wang Zhen , Chu Chenggen , Ibrahim Amir M. H. , Turkus Jonathan , Olson Eric , Nagarajan Ragupathi , Carver Brett , Yan Liuling , Taagen Ellie , Sorrells Mark , Ward Brian , Ren Jie , Akhunova Alina , Bai Guihua , Bowden Robert , Fiedler Jason , Faris Justin , Dubcovsky Jorge , Guttieri Mary , Brown-Guedira Gina , Buckler Ed , Jannink Jean-Luc , Akhunov Eduard D. 
Published: June 2021

AbstractTo improve the efficiency of high-density genotype data storage and imputation in bread wheat (Triticum aestivum L.), we applied the Practical Haplotype Graph (PHG) tool. The wheat PHG database was built using whole-exome capture sequencing data from a diverse set of 65 wheat accessions. Population haplotypes were inferred for the reference genome intervals defined by the boundaries of the high-quality gene models. Missing genotypes in the inference panels, composed of wheat cultivars or recombinant inbred lines genotyped by exome capture, genotyping-by-sequencing (GBS), or whole-genome skim-seq sequencing approaches, were imputed using the wheat PHG database. Though imputation accuracy varied depending on the method of sequencing and coverage depth, we found 93% imputation accuracy with 0.01x sequence coverage, which was only slightly lower than the accuracy obtained using the 0.5x sequence coverage (96.9%). Compared to Beagle, on average, PHG imputation was ~4% (p-value = 0.00027) more accurate, and showed 27% higher accuracy at imputing a rare haplotype introgressed from a wild relative into wheat. The reduced accuracy of imputation with GBS data (90.4%) is likely associated with the small overlap between GBS markers and the exome capture dataset, which was used for constructing PHG. The highest imputation accuracy was obtained with exome capture for the wheat D genome, which also showed the highest levels of linkage disequlibrium and proportion of identity-by-descent regions among accessions in our reference panel. We demonstrate that genetic mapping based on genotypes imputed using PHG identifies SNPs with a broader range of effect sizes that together explain a higher proportion of genetic variance for heading date and meiotic crossover rate compared to previous studies.
A reference-quality, fully annotated genome from a Puerto Rican individual
Authors: Zimin Aleksey , Shumate Alaina , Shinder Ida , Heinz Jakob , Puiu Daniela , Pertea Mihaela , Salzberg Steven L. 
Published: June 2021

AbstractUntil 2019, the human genome was available in only one fully-annotated version, GRCh38, which was the result of 18 years of continuous improvement and revision. Despite dramatic improvements in sequencing technology, no other genome was available as an annotated reference until 2019, when the genome of an Ashkenazi individual, Ash1, was released. In this study, we describe the assembly and annotation of a second individual genome, from a Puerto Rican individual whose DNA was collected as part of the Human Pangenome project. The new genome, called PR1, is the first true reference genome created from an individual of African descent. Due to recent improvements in both sequencing and assembly technology, and particularly to the use of the recently completed CHM13 human genome as a guide to assembly, PR1 is more complete and more contiguous than either GRCh38 or Ash1. Annotation revealed 37,755 genes (of which 19,999 are protein-coding), including 12 additional gene copies that are present in PR1 and missing from CHM13. 57 genes have fewer copies in PR1 than in CHM13, 9 map only partially, and 3 genes (all non-coding) from CHM13 are entirely missing from PR1.
Using networks to analyze and visualize the distribution of overlapping reading frames in virus genomes
Authors: Muñoz-Baena Laura , Poon Art F. Y. 
Published: June 2021

ABSTRACTGene overlap occurs when two or more genes are encoded by the same nucleotides. This phenomenon is found in all taxonomic domains, but is particularly common in viruses, where it may increase the information content of compact genomes or influence the creation of new genes. Here we report a global comparative study of overlapping reading frames (OvRFs) of 12,609 virus reference genomes in the NCBI database. We retrieved metadata associated with all annotated reading frames in each genome record to calculate the number, length, and frameshift of OvRFs. Our results show that while the number of OvRFs increases with genome length, they tend to be shorter in longer genomes. The majority of overlaps involve +2 frameshifts, predominantly found in ds-DNA viruses. However, the longest overlaps involve no shift in reading frame (+0), increasing the selective burden of the same nucleotide positions within codons, instead of exposing additional sites to purifying selection. Next, we develop a new graph-based representation of the distribution of OvRFs among the reading frames of genomes in a given virus family. In the absence of an unambiguous partition of reading frames by homology at this taxonomic level, we used an alignment-free k-mer based approach to cluster protein coding sequences by similarity. We connect these clusters with two types of directed edges to indicate (1) that constituent reading frames are adjacent in one or more genomes, and (2) that the reading frames overlap. These adjacency graphs not only provide a natural visualization scheme, but also a novel statistical framework for analyzing the effects of gene- and genome-level attributes on the frequencies of overlaps.