bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variation in genetic relatedness is determined by the aggregate recombination process
Authors: Veller Carl , Edelman Nathaniel B. , Muralidhar Pavitra , Nowak Martin A. 
Published: May 2020

AbstractThe genomic proportion that two relatives share identically by descent—their genetic relatedness— can vary depending on the history of recombination and segregation in their pedigree. This variation is important in many applications of genetics, including pedigree-based estimation of the genetic variance and heritability of traits, and estimation of pedigree relationships from sequence data. Here, we calculate the variance of genetic relatedness for general pedigree relationships, making no assumptions about the recombination process. For the specific relationships of grandparent-grandoffspring and siblings, the variance of genetic relatedness is a simple decreasing function of, the average proportion of locus pairs that recombine in meiosis. For general pedigree relationships, the variance of genetic relatedness is likewise the average of some function of pairwise recombination rates. Therefore, features of the aggregate recombination process that affectand analogs also affect variance in genetic relatedness. Such features include the number of chromosomes and heterogeneity in their size, and the number of crossovers and their location along chromosomes. Our calculations help to explain several recent observations about variance in genetic relatedness, including that it is reduced by crossover interference (which is known to increase). Our methods further allow us to calculate the neutral variance of ancestry among F2s in a hybrid cross, enabling precise statistical inference in F2-based tests for various kinds of selection.
Network bipartitioning in the anti-communicability euclidean space
Authors: Gómez-Gardeñes Jesús , Estrada Ernesto 
Published: May 2020

AbstractWe define the anti-communicability function for the nodes of a simple graph as the nondiagonal entries of exp (−A). We prove that it induces an embedding of the nodes into a Euclidean space. The anti-communicability angle is then defined as the angle spanned by the position vectors of the corresponding nodes in the anti-communicability Euclidean space. We prove analytically that in a givenk-partite graph, the anti-communicability angle is larger than 90° for every pair of nodes in different partitions and smaller than 90° for those in the same partition. This angle is then used as a similarity metric to detect the “best”k-partitions in networks where certain level of edge frustration exists. We apply this method to detect the “best” k-partitions in 15 real-world networks, finding partitions with a very low level of “edge frustration”. Most of these partitions correspond to bipartitions but tri- and pentapartite structures of real-world networks are also reported.
TRACE-Seq Reveals Clonal Reconstitution Dynamics of Gene Targeted Human Hematopoietic Stem Cells
Authors: Sharma Rajiv , Dever Daniel P , Lee Ciaran M , Azizi Armon , Pan Yidan , Camarena Joab , Köhnke Thomas , Bao Gang , Porteus Matthew H , Majeti Ravindra 
Published: May 2020

AbstractTargeted DNA correction of disease-causing mutations in hematopoietic stem and progenitor cells (HSPCs) may usher in a new class of medicines to treat genetic diseases of the blood and immune system. With state-of-the-art methodologies, it is now possible to correct disease-causing mutations at high frequencies in HSPCs by combining ribonucleoprotein (RNP) delivery of Cas9 and chemically modified sgRNAs with homologous DNA donors via recombinant adeno-associated viral vector serotype six (AAV6). However, because of the precise nucleotide-resolution nature of gene correction, these current approaches do not allow for clonal tracking of gene targeted HSPCs. Here, we describeTrackingRecombinationAlleles inClonalEngraftment usingsequencing (TRACE-Seq), a novel methodology that utilizes barcoded AAV6 donor template libraries, carrying either in-frame silent mutations or semi-randomized nucleotide sequences outside the coding region, to track thein vivolineage contribution of gene targeted HSPC clones. By targeting theHBBgene with an AAV6 donor template library consisting of ∼20,000 possible unique exon 1 in-frame silent mutations, we track the hematopoietic reconstitution ofHBBtargeted myeloid-skewed, lymphoid-skewed, and balanced multi-lineage repopulating human HSPC clones in immunodeficient mice. We anticipate that this methodology has the potential to be used for HSPC clonal tracking of Cas9 RNP and AAV6-mediated gene targeting outcomes in translational and basic research settings.
Content-Based Similarity Search in Large-Scale DNA Data Storage Systems
Authors: Bee Callista , Chen Yuan-Jyue , Ward David , Liu Xiaomeng , Seelig Georg , Strauss Karin , Ceze Luis 
Published: May 2020

AbstractSynthetic DNA has the potential to store the world’s continuously growing amount of data in an extremely dense and durable medium. Current proposals for DNA-based digital storage systems include the ability to retrieve individual files by their unique identifier, but not by their content. Here, we demonstrate content-based retrieval from a DNA database by learning a mapping from images to DNA sequences such that an encoded query image will retrieve visually similar images from the database via DNA hybridization. We encoded and synthesized a database of 1.6 million images and queried it with a variety of images, showing that each query retrieves a sample of the database containing visually similar images are retrieved at a rate much greater than chance. We compare our results with several algorithms for similarity search in electronic systems, and demonstrate that our molecular approach is competitive with state-of-the-art electronics.One Sentence SummaryLearned encodings enable content-based image similarity search from a database of 1.6 million images encoded in synthetic DNA.
Changes in arthropod community but not plant quality benefit a specialist herbivore on plant under reduced water availability
Authors: Lin Po-An , Liu Chia-Ming , Ou Jia-Ang , Sun Cheng-Han , Chuang Wen-Po , Ho Chuan-Kai , Kinoshita Natsuko , Felton Gary W. 
Published: May 2020

AbstractPlants grow under reduced water availability can have divergent effects on insect herbivores, in some instances producing benefits to them. However, the forces mediating these positive impacts remain mostly unclear. We conducted a manipulative field study using a specialist herbivorePieris rapae, and its host plant,Rorippa indica, in two populations to identify how water availability impacts overall plant quality and multitrophic interactions. We observed thatR. indicagrowing under low water availability led to higher survival ofP. rapaelarvae. The increase in survival of eggs and larvae was related to the reduced abundance of other herbivores and natural enemies. Water availability had differential impacts on members of the herbivore community through changes in plant quality. Low water availability decreased the quality ofR. indicato most herbivores as indicated by reduced abundance in the field and decreased relative growth rate in feeding assays. In contrast, the performance ofP. rapaelarvae were not affected by differences in sympatricR. indicagrown under different water availability. These results indicate that localP. rapaepossess some physiological adaptation to overcome fluctuations in host quality. Our findings illustrate that reduced water availability is beneficial to a specialist herbivore, but detrimental to most other herbivores. Our work highlights the complex roles of the arthropod communities associated with plants in determining the impacts of water availability on insect herbivores.
Characterization of systemic genomic instability in budding yeast
Authors: Sampaio Nadia M. V. , Ajith V. P. , Watson Ruth A. , Heasley Lydia R. , Chakraborty Parijat , Rodrigues-Prause Aline , Malc Ewa P. , Mieczkowski Piotr A. , Nishant Koodali T. , Argueso Juan Lucas 
Published: May 2020

ABSTRACTConventional models of genome evolution are centered around the principle that mutations form independently of each other and build up slowly over time. We characterized the occurrence of bursts of genome-wide loss-of-heterozygosity (LOH) inSaccharomyces cerevisiae, providing support for an additional non-independent and faster mode of mutation accumulation. We initially characterized a yeast clone isolated for carrying an LOH event at a specific chromosome site, and surprisingly, found that it also carried multiple unselected rearrangements elsewhere in its genome. Whole genome analysis of over 100 additional clones selected for carrying primary LOH tracts revealed that they too contained unselected structural alterations more often than control clones obtained without any selection. We also measured the rates of coincident LOH at two different chromosomes and found that double LOH formed at rates 14-150 fold higher than expected if the two underlying single LOH events occurred independently of each other. These results were consistent across different strain backgrounds, and in mutants incapable of entering meiosis. Our results indicate that a subset of mitotic cells within a population can experience discrete episodes of systemic genomic instability, when the entire genome becomes vulnerable and multiple chromosomal alterations can form over a narrow time window. They are reminiscent of early reports from the classic yeast genetics literature, as well as recent studies in humans, both in the cancer and genomic disorder contexts. The experimental model we describe provides a system to further dissect the fundamental biological processes responsible for punctuated bursts of structural genomic variation.SIGNIFICANCE STATEMENTMutations are generally thought to accumulate independently and gradually over many generations. Here, we combined complementary experimental approaches in budding yeast to track the appearance of chromosomal changes resulting in loss-of-heterozygosity (LOH). In contrast to the prevailing model, our results provide evidence for the existence of a path for non-independent accumulation of multiple chromosomal alteration events over few generations. These results are analogous to recent reports of bursts of genomic instability in human cells. The experimental model we describe provides a system to further dissect the fundamental biological processes underlying such punctuated bursts of mutation accumulation.
Peptide recognition and dephosphorylation by the vaccinia VH1 phosphatase
Authors: Zhao Bryan M. , Hogan Megan , Lee Michael S , Dyas Beverly K. , Ulrich Robert G. 
Published: May 2020

ABSTRACTThe VH1 protein encoded by the highly conserved H1 locus of orthopoxviruses is a dual-specificity phosphatase (DUSPs) that hydrolyzes phosphate groups from phosphorylated tyrosine, serine, and threonine residues of viral and host cell proteins. Because the DUSP activities are required for virus replication, VH1 is a prime target for the development of therapeutic inhibitors. However, the presentation of a shallow catalytic site has thwarted all drug development efforts. As an alternative to direct targeting of catalytic pockets, we describe surface contacts between VH1 and substrates that are essential for full activity and provide a new pathway for developing inhibitors of protein-protein interactions. Critical amino acid residues were manipulated by site-directed mutagenesis of VH1, and perturbation of peptide substrate interactions based on these mutations were assessed by high-throughput assays that employed surface plasmon resonance and phosphatase activities. Two positively-charged residues (Lys-20 and Lys-22) and the hydrophobic side chain of Met-60 appear to orient the polarity of the pTyr peptide on the VH1 surface, while additional amino acid residues that flank the catalytic site contribute to substrate recognition and productive dephosphorylation. We propose that the enzyme-substrate contact residues described here may serve as molecular targets for the development of inhibitors that specifically block VH1 catalytic activity and thus poxvirus replication.
ModelingIKZF1lesions in B-ALL reveals distinct chemosensitivity patterns and potential therapeutic vulnerabilities
Authors: Rogers Jason H. , Gupta Rohit , Reyes Jaime M. , Gundry Michael C. , Medrano Geraldo , Guzman Anna , Song Tidie , Johnson Cade , Barnes Sean , Cristobal Carlo D. D. , Brunetti Lorenzo , Goodell Margaret A. , Rau Rachel E. 
Published: May 2020

AbstractIKAROS family zinc finger 1 (IKZF1) alterations represent a diverse group of genetic lesions that are associated with an increased risk of relapse in B-lymphoblastic leukemia (B-ALL). Due to the heterogeneity of concomitant lesions it remains unclear howIKZF1abnormalities directly affect cell function and therapy resistance and whether their consideration as a prognostic indicator is valuable in improving outcome. We used CRISPR/Cas9 to engineer multiple panels of isogeneic lymphoid leukemia cell lines with a spectrum ofIKZF1lesions in order to measure changes in chemosensitivity, gene expression, cell cycle, and in vivo engraftment dynamics that can be directly linked to loss of IKAROS protein.IKZF1knockout and heterozygous null cells displayed relative resistance to a number of commonly employed therapies for B-ALL including dexamethasone, vincristine, asparaginase, and daunorubicin. Transcription profiling revealed a stem/myeloid cell-like phenotype and JAK/STAT upregulation after IKAROS loss. We also used a CRISPR homology-directed repair (HDR) strategy to knock-in the dominant-negative IK6 isoform tagged with GFP into the endogenous locus and observed a similar drug resistance profile with the exception of retained sensitivity to dexamethasone. Interestingly,IKZF1knockout and IK6 knock-in cells both have significantly increased sensitivity to cytarabine, suggesting intensification of nucleoside analog therapy may be specifically effective forIKZF1-deleted B-ALL. Both types ofIKZF1lesions decreased survival time of xenograft mice, with higher numbers of circulating blasts and increased organ infiltration. Given these findings, exact specification ofIKZF1status in patients may be a beneficial addition to risk stratification and could inform therapy.Key pointsEngineeredIKZF1perturbations result in a stem-cell like expression signature, enhanced engraftment in vivo, and multi-drug resistanceLoss of IKAROS may result in new vulnerabilities due to increased sensitivity to cytarabine and upregulation of JAK/STAT and mAb targets
The Perfect Storm: Gene Tree Estimation Error, Incomplete Lineage Sorting, and Ancient Gene Flow Explain the Most Recalcitrant Ancient Angiosperm Clade, Malpighiales
Authors: Cai Liming , Xi Zhenxiang , Lemmon Emily Moriarty , Lemmon Alan R. , Mast Austin , Buddenhagen Christopher E. , Liu Liang , Davis Charles C. 
Published: May 2020

ABSTRACTThe genomic revolution offers renewed hope of resolving rapid radiations in the Tree of Life. The development of the multispecies coalescent (MSC) model and improved gene tree estimation methods can better accommodate gene tree heterogeneity caused by incomplete lineage sorting (ILS) and gene tree estimation error stemming from the short internal branches. However, the relative influence of these factors in species tree inference is not well understood. Using anchored hybrid enrichment, we generated a data set including 423 single-copy loci from 64 taxa representing 39 families to infer the species tree of the flowering plant order Malpighiales. This order alone includes nine of the top ten most unstable nodes in angiosperms, and the recalcitrant relationships along the backbone of the order have been hypothesized to arise from the rapid radiation during the Cretaceous. Here, we show that coalescent-based methods do not resolve the backbone of Malpighiales and concatenation methods yield inconsistent estimations, providing evidence that gene tree heterogeneity is high in this clade. Despite high levels of ILS and gene tree estimation error, our simulations demonstrate that these two factors alone are insufficient to explain the lack of resolution in this order. To explore this further, we examined triplet frequencies among empirical gene trees and discovered some of them deviated significantly from those attributed to ILS and estimation error, suggesting gene flow as an additional and previously unappreciated phenomenon promoting gene tree variation in Malpighiales. Finally, we applied a novel method to quantify the relative contribution of these three primary sources of gene tree heterogeneity and demonstrated that ILS, gene tree estimation error, and gene flow contributed to 15%, 52%, and 32% of the variation, respectively. Together, our results suggest that a perfect storm of factors likely influence this lack of resolution, and further indicate that recalcitrant phylogenetic relationships like the backbone of Malpighiales may be better represented as phylogenetic networks. Thus, reducing such groups solely to existing models that adhere strictly to bifurcating trees greatly oversimplifies reality, and obscures our ability to more clearly discern the process of evolution.
A non-linear relation between levels of adult hippocampal neurogenesis and expression of the immature neuron marker doublecortin
Authors: Mendez-David Indira , David Denis J , Deloménie Claudine , Beaulieu Jean-Martin , Gardier Alain M. , Hen René 
Published: May 2020

ABSTRACTWe investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule β2-arrestin is required for the antidepressant-like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and on survival of adult-born granule cells are absent in the β2-arrestin knockout (β2-Arr KO) mice. To our surprise fluoxetine induced a dramatic upregulation of doublecortin (DCX) in the β2-Arr KO mice, indicating that DCX expression can be increased even though AHN is not. We discovered two other conditions where DCX expression is regulated non linearly compared to levels of AHN: a chronic stress model where DCX is upregulated and an inflammation model where DCX is down regulated. We conclude that assessing DCX expression alone to quantify levels of AHN can be misleading and that caution should be applied when label retention techniques are not available.HIGHLIGHTSβ2-arrestin (β-Arr2) is required for the antidepressant-like effects of fluoxetine.A dramatic upregulation of doublecortin (DCX) is observed in the β2-Arr KO mice after antidepressant treatment whereas its effects on proliferation of neural progenitors and on survival of adult-born granule cells are absent.DCX is more upregulated than the number of young neurons in a mouse model of depression.DCX is more down regulated than the number of young neurons in a model of inflammation.microRNAs (miRs) may contribute to the regulation of DCX mRNA expression.
Conscious processing of narrative stimuli synchronizes heart rate between individuals
Authors: Pérez Pauline , Madsen Jens , Banellis Leah , Türker Başak , Raimondo Federico , Perlbarg Vincent , Valente Melanie , Niérat Marie-Cécile , Puybasset Louis , Naccache Lionel , Similowski Thomas , Cruse Damian , Parra Lucas C , Sitt Jacobo D 
Published: May 2020

AbstractHeart rate has natural fluctuations that are typically ascribed to autonomic function. Recent evidence suggests that conscious processing can affect the timing of the heartbeat. We hypothesized that heart rate is modulated by conscious processing and therefore dependent on attentional focus. To test this, we leverage the observation that neural processes can be synchronized between subjects by presenting an identical narrative stimulus. As predicted, we find significant inter-subject correlation of the heartbeat (ISC-HR) when subjects are presented with an auditory or audiovisual narrative. Consistent with the conscious processing hypothesis, we find that ISC-HR is reduced when subjects are distracted from the narrative, and that higher heart rate synchronization predicts better recall of the narrative. Finally, patients with disorders of consciousness who are listening to a story have lower ISC-HR, as compared to healthy individuals, and that individual ISC-HR might predict a patients’ prognosis.. We conclude that heart rate fluctuations are partially driven by conscious processing, depend on attentional state, and may represent a simple metric to assess conscious state in unresponsive patients.
Reduced reproductive success is associated with selective constraint on human genes
Authors: Gardner Eugene J. , Neville Matthew D. C. , Samocha Kaitlin E. , Barclay Kieron , Kolk Martin , Niemi Mari E. K. , Kirov George , Martin Hilary C. , Hurles Matthew E. 
Published: May 2020

SummaryGenome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants1. While genes under the strongest selective constraint are highly enriched for associations with Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known2. Here we show that genetic variants that damage these genes are associated with markedly reduced reproductive success, primarily due to increased childlessness, with a stronger effect in males than in females. We present evidence that increased childlessness is likely mediated by genetically associated cognitive and behavioural traits, which may mean male carriers are less likely to find reproductive partners. This reduction in reproductive success may account for 20% of purifying selection against heterozygous variants that ablate protein-coding genes. While this genetic association could only account for a very minor fraction of the overall likelihood of being childless (less than 1%), especially when compared to more influential sociodemographic factors, it may influence how genes evolve over time.
Nonspecific Cleavages Arising from Reconstitution of Trypsin under Mildly Acidic Conditions
Authors: Niu Ben , Martinelli Michael , Jiao Yang , Meinke Eric , Cao Mingyan , Wang Jihong 
Published: May 2020

AbstractTryptic digestion of proteins followed by liquid chromatography with tandem mass spectrometry analysis is an extensively used approach in proteomics research and biopharmaceutical product characterization, owing to the high level of cleavage fidelity produced with this technique. However, nonspecific trypsin cleavages have been frequently reported and shown to be related to a number of digestion conditions and predigestion sample treatments. In this work, we reveal that, for a number of commercial trypsins, reconstitution and storage conditions can have a significant impact on the occurrence of trypsin nonspecific cleavages. We analyzed the tryptic digestion of a variety of biotherapeutics, using trypsins reconstituted under different conditions. The results indicate that, for many commercial trypsins, commonly recommended reconstitution/storage conditions (mildly acidic, e.g., 50 mM acetic acid, 1 mM HCl) can actually promote nonspecific trypsin activities, which are time dependent and can be as high as 20% in total relative abundance. In contrast, using water for reconstitution and storage can effectively limit nonspecific cleavages to 1%. Interestingly, the performances of different commercial trypsins were found to be quite distinct in their levels of nonspecific cleavages and responses to the two reconstitution conditions. Our findings demonstrate the importance of choosing the appropriate trypsin for tryptic digestion and the necessity of assessing the impact of trypsin reconstitution and storage on nonspecific cleavages. We advocate for manufacturers of commercial trypsins to reevaluate manufacturing processes and reconstitution/storage conditions to provide good cleavage specificity.