bluuebunny/crossref_metadata_2025 huggingface dataset:
WEVar: a novel statistical learning framework for predicting noncoding regulatory variants
Authors: Wang Ye , Jiang Yuchao , Yao Bing , Huang Kun , Liu Yunlong , Wang Yue , Qin Xiao , Saykin Andrew J , Chen Li
Published: April 2021

Understanding the functional consequence of noncoding variants is of great interest. Though genome-wide association studies or quantitative trait locus analyses have identified variants associated with traits or molecular phenotypes, most of them are located in the noncoding regions, making the identification of causal variants a particular challenge. Existing computational approaches developed for prioritizing noncoding variants produce inconsistent and even conflicting results. To address these challenges, we propose a novel statistical learning framework, which directly integrates the precomputed functional scores from representative scoring methods. It will maximize the usage of integrated methods by automatically learning the relative contribution of each method and produce an ensemble score as the final prediction. The framework consists of two modes. The first ‘context-free’ mode is trained using curated causal regulatory variants from a wide range of context and is applicable to predict regulatory variants of unknown and diverse context. The second ‘context-dependent’ mode further improves the prediction when the training and testing variants are from the same context. By evaluating the framework via both simulation and empirical studies, we demonstrate that it outperforms integrated scoring methods and the ensemble score successfully prioritizes experimentally validated regulatory variants in multiple risk loci.
Clustering single-cell RNA-seq data by rank constrained similarity learning
Authors: Mei Qinglin , Li Guojun , Su Zhengchang
Published: April 2021

Motivation

Recent breakthroughs of single-cell RNA sequencing (scRNA-seq) technologies offer an exciting opportunity to identify heterogeneous cell types in complex tissues. However, the unavoidable biological noise and technical artifacts in scRNA-seq data as well as the high dimensionality of expression vectors make the problem highly challenging. Consequently, although numerous tools have been developed, their accuracy remains to be improved.

Results

Here, we introduce a novel clustering algorithm and tool RCSL (Rank Constrained Similarity Learning) to accurately identify various cell types using scRNA-seq data from a complex tissue. RCSL considers both local similarity and global similarity among the cells to discern the subtle differences among cells of the same type as well as larger differences among cells of different types. RCSL uses Spearman’s rank correlations of a cell’s expression vector with those of other cells to measure its global similarity, and adaptively learns neighbor representation of a cell as its local similarity. The overall similarity of a cell to other cells is a linear combination of its global similarity and local similarity. RCSL automatically estimates the number of cell types defined in the similarity matrix, and identifies them by constructing a block-diagonal matrix, such that its distance to the similarity matrix is minimized. Each block-diagonal submatrix is a cell cluster/type, corresponding to a connected component in the cognate similarity graph. When tested on 16 benchmark scRNA-seq datasets in which the cell types are well-annotated, RCSL substantially outperformed six state-of-the-art methods in accuracy and robustness as measured by three metrics.

Availability and implementation

The RCSL algorithm is implemented in R and can be freely downloaded at https://cran.r-project.org/web/packages/RCSL/index.html.

Supplementary information

Supplementary data are available at Bioinformatics online.
Metaball skinning of synthetic astroglial morphologies into realistic mesh models for in silico simulations and visual analytics
Authors: Abdellah Marwan , Foni Alessandro , Zisis Eleftherios , Guerrero Nadir Román , Lapere Samuel , Coggan Jay S , Keller Daniel , Markram Henry , Schürmann Felix
Published: April 2021

Motivation

Astrocytes, the most abundant glial cells in the mammalian brain, have an instrumental role in developing neuronal circuits. They contribute to the physical structuring of the brain, modulating synaptic activity and maintaining the blood–brain barrier in addition to other significant aspects that impact brain function. Biophysically, detailed astrocytic models are key to unraveling their functional mechanisms via molecular simulations at microscopic scales. Detailed, and complete, biological reconstructions of astrocytic cells are sparse. Nonetheless, data-driven digital reconstruction of astroglial morphologies that are statistically identical to biological counterparts are becoming available. We use those synthetic morphologies to generate astrocytic meshes with realistic geometries, making it possible to perform these simulations.

Results

We present an unconditionally robust method capable of reconstructing high fidelity polygonal meshes of astroglial cells from algorithmically-synthesized morphologies. Our method uses implicit surfaces, or metaballs, to skin the different structural components of astrocytes and then blend them in a seamless fashion. We also provide an end-to-end pipeline to produce optimized two- and three-dimensional meshes for visual analytics and simulations, respectively. The performance of our pipeline has been assessed with a group of 5000 astroglial morphologies and the geometric metrics of the resulting meshes are evaluated. The usability of the meshes is then demonstrated with different use cases.

Availability and implementation

Our metaball skinning algorithm is implemented in Blender 2.82 relying on its Python API (Application Programming Interface). To make it accessible to computational biologists and neuroscientists, the implementation has been integrated into NeuroMorphoVis, an open source and domain specific package that is primarily designed for neuronal morphology visualization and meshing.

Supplementary information

Supplementary data are available at Bioinformatics online.
Tauroursodeoxycholic acid/TGR5 signaling promotes survival and early development of glucose-stressed porcine embryos
Authors: Dicks Naomi , Gutierrez Karina , Currin Luke , de Macedo Mariana P , Glanzner Werner G , Mondadori Rafael G , Michalak Marek , Agellon Luis B , Bordignon Vilceu
Published: April 2021

Conditions of impaired energy and nutrient homeostasis, such as diabetes and obesity, are associated with infertility. Hyperglycemia increases endoplasmic reticulum stress as well as oxidative stress and reduces embryo development and quality. Oxidative stress also causes deoxyribonucleic acid damage, which impairs embryo quality and development. The natural bile acid tauroursodeoxycholic acid reduces endoplasmic reticulum stress and rescues developmentally incompetent late-cleaving embryos, as well as embryos subjected to nuclear stress, suggesting the endoplasmic reticulum stress response, or unfolded protein response, and the genome damage response are linked. Tauroursodeoxycholic acid acts via the Takeda-G-protein-receptor-5 to alleviate nuclear stress in embryos. To evaluate the role of tauroursodeoxycholic acid/Takeda-G-protein-receptor-5 signaling in embryo unfolded protein response, we used a model of glucose-induced endoplasmic reticulum stress. Embryo development was impaired by direct injection of tauroursodeoxycholic acid into parthenogenetically activated oocytes, whereas it was improved when tauroursodeoxycholic acid was added to the culture medium. Attenuation of the Takeda-G-protein-receptor-5 precluded the positive effect of tauroursodeoxycholic acid supplementation on development of parthenogenetically activated and fertilized embryos cultured under standard conditions and parthenogenetically activated embryos cultured with excess glucose. Moreover, attenuation of tauroursodeoxycholic acid/Takeda-G-protein-receptor-5 signaling induced endoplasmic reticulum stress, oxidative stress and cell survival genes, but decreased expression of pluripotency genes in parthenogenetically activated embryos cultured under excess glucose conditions. These data suggest that Takeda-G-protein-receptor-5 signaling pathways link the unfolded protein response and genome damage response. Furthermore, this study identifies Takeda-G-protein-receptor-5 signaling as a potential target for mitigating fertility issues caused by nutrient excess-associated blastomere stress and embryo death.
MicroRNAs in amniotic fluid and maternal blood plasma associated with sex determination and early gonad differentiation in cattle
Authors: Sánchez José María , Gómez-Redondo Isabel , Browne John A , Planells Benjamín , Gutiérrez-Adán Alfonso , Lonergan Pat
Published: April 2021

We hypothesized that sexually dimorphic differences exist in the expression of miRNAs in amniotic fluid (AF) and maternal blood plasma (MP) in association with the process of sex determination and gonad differentiation in cattle. Amniotic fluid and MP were collected from six pregnant heifers (three carrying a single male and three a single female embryo) following slaughter on Day 39 postinsemination, coinciding with the peak of SRY expression. Samples (six AF and six MP) were profiled using an miRNA Serum/Plasma Focus PCR Panel. Differentially expressed (DE) miRNAs were identified in AF (n = 5) and associated MP (n = 56) of male vs. female embryos (P < 0.05). Functional analysis showed that inflammatory and immune response were among the 13 biological processes enriched by miRNAs DE in MP in the male group (FDR < 0.05), suggesting that these sex-dependent DE miRNAs may be implicated in modulating the receptivity of the dam to a male embryo. Further, we compared the downstream targets of the sex-dependent DE miRNAs detected in MP with genes previously identified as DE in male vs. female genital ridges. The analyses revealed potential targets that might be important during this developmental stage such as SHROOM2, DDX3Y, SOX9, SRY, PPP1CB, JARID2, USP9X, KDM6A, and EIF2S3. Results from this study highlight novel aspects of sex determination and embryo–maternal communication in cattle such as the potential role of miRNAs in gonad development as well as in the modulation of the receptivity of the dam to a male embryo.
The cost to see the Wizard: buy-ins and trade-offs in neurological rehabilitation
Authors: Doogan Catherine , Leff Alex P
Published: April 2021

This scientific commentary refers to ‘A decision-neuroscientific intervention to improve cognitive recovery after stroke’ by Studer et al. (doi:10.1093/brain/awab128).
Adjunctive Corticosteroids for Lyme Neuroborreliosis Peripheral Facial Palsy—A Prospective Study With Historical Controls
Authors: Avellan Sanna , Bremell Daniel
Published: April 2021

Background

Lyme neuroborreliosis peripheral facial palsy (LNB PFP) and idiopathic PFP, Bell’s palsy (BP), are the most common causes of facial palsy in borrelia-endemic areas and are clinically similar. Early treatment with corticosteroids has been shown to be effective in Bell’s palsy, and antibiotics improve the outcome in LNB. However, there is a lack of knowledge on how the addition of corticosteroids to standard antibiotic treatment affects the outcome in LNB PFP.

Methods

This prospective, open trial with historical controls was conducted at 2 large hospitals in western Sweden between 2011 and 2018. Adults who presented with LNB PFP were included in the study group and were treated with oral doxycycline 200 mg twice daily for 10 days and prednisolone 60 mg once daily for 5 days, then tapered over 5 days. The historical controls were adult patients with LNB PFP included in previous studies and treated with oral doxycycline. Both groups underwent a follow-up lumbar puncture and were followed until complete recovery or for 12 months.

Results

Fifty-seven patients were included, 27 in the study group and 30 in the control group. Two patients (7%) in the study group and 6 patients (20%) in the control group suffered from sequelae at the end follow-up. There was no statistically significant difference between the groups, either in the proportion of patients with sequelae or in the decline in cerebrospinal fluid mononuclear cell count.

Conclusions

Adjunctive corticosteroids neither improve nor impair the outcome for patients with LNB PFP treated with doxycycline.
Does Teacher Self-Efficacy Predict Writing Practices of Teachers of Deaf and Hard of Hearing Students?
Authors: Graham Steve , Wolbers Kimberly , Dostal Hannah , Holcomb Leala
Published: April 2021

Forty-four elementary grade teachers of deaf and hard of hearing students were surveyed about how they taught writing and their beliefs about writing. Beliefs about writing included their self-efficacy to teach writing, attitude toward writing, and epistemological beliefs about writing. These teachers from fifteen different states in the United States slightly agreed that they were efficacious writing teachers and they were slightly positive about their writing. They slightly agreed that learning to write involves effort and process, moderately disagreed that writing development is innate or fixed, slightly disagreed that knowledge about writing is certain, and were equally split about whether writing knowledge comes from authorities and experts. On average, teachers applied the twenty-two instructional writing practices surveyed at least once a month. They reported their students wrote weekly, and their writing was supported through goal setting, feedback, and prewriting activities. Writing instruction mostly focuses on teaching grammar and how to plan compositions. Teacher self-efficacy uniquely and statistically predicted reported teaching practices after attitude toward writing, and epistemological beliefs were first controlled. Recommendations for future research and implications for practice are presented.
Exact computation of maximum rank correlation estimator
Authors: Shin Youngki , Todorov Zvezdomir
Published: April 2021

In this paper we provide a computation algorithm to get a global solution for the maximum rank correlation estimator using the mixed integer programming (MIP) approach. We construct a new constrained optimization problem by transforming all indicator functions into binary parameters to be estimated and show that it is equivalent to the original problem. We also consider an application of the best subset rank prediction and show that the original optimization problem can be reformulated as MIP. We derive the nonasymptotic bound for the tail probability of the predictive performance measure. We investigate the performance of the MIP algorithm by an empirical example and Monte Carlo simulations.
Fitness Cost of Chlorpyrifos Resistance in Spodoptera frugiperda (Lepidoptera: Noctuidae) on Different Host Plants
Authors: Garlet Cínthia G , Moreira Rafaella P , Gubiani Patricia da S , Palharini Ramon B , Farias Juliano R , Bernardi Oderlei
Published: April 2021

Spodoptera frugiperda (J. E. Smith, 1797) is a polyphagous pest of global relevance due to the damage it inflicts on agricultural crops. In South American countries, this species is one of the principal pests of maize and cotton. Currently, S. frugiperda is also emerging as an important pest of soybeans and winter cereals in Brazil. Chemical control is one of the main control tactics against S. frugiperda, even though resistance against numerous modes of action insecticides has been reported. To support insect resistance management programs, we evaluated the fitness costs of resistance of S. frugiperda to the acetylcholinesterase inhibitor chlorpyrifos. Fitness costs were quantified by comparing biological parameters of chlorpyrifos-resistant and -susceptible S. frugiperda and their F1 hybrids (heterozygotes) on non-Bt cotton, non-Bt maize, non-Bt soybean, and oats. The results revealed that the chlorpyrifos-resistant genotype showed lower pupa-to-adult and egg-to-adult survivorship and reduced larval weights on oats; longer neonate-to-pupa and egg-to-adult developmental periods, and lower pupal weights and fecundity on maize; lower pupal weights on soybean; and reduced fecundity on cotton compared with the chlorpyrifos-susceptible genotype. Fitness costs also affected fertility life table parameters of the resistant genotype, increasing the mean length of a generation on cotton and maize and reducing the potential for population growth on all hosts. These findings suggest fitness costs at the individual and population levels of chlorpyrifos resistance in S. frugiperda, indicating that removal of the selective agent from the environment would result in reduced resistance and opportunities for the restoration of susceptibility.
Peak oxygen consumption achieved at the end of cardiac rehabilitation predicts long-term survival in patients with coronary heart disease
Authors: Carbone Salvatore , Kim Youngdeok , Kachur Sergey , Billingsley Hayley , Kenyon Jonathan , De Schutter Alban , Milani Richard V , Lavie Carl J
Published: April 2021

Aims

Cardiac rehabilitation (CR) improves survival in patients with coronary heart disease (CHD), which is largely mediated by the improvements in cardiorespiratory fitness (CRF) defined as peak oxygen consumption (VO2). Therefore, measuring CRF is essential to predict long-term outcomes in this population. It is unclear, however, whether peak VO2 achieved at the end of CR (END-peak VO2) predicts survival or whether the changes of CRF achieved during CR provide a greater prognostic value. To determine whether END-peak VO2 independently predicts long-term survival in patients with CHD undergoing CR. We also aimed at identifying cut-offs for END-peak VO2 that could be used in clinical practice.

Methods and results

Retrospective analysis of 853 patients with CHD referred to CR who completed a maximal cardiopulmonary exercise test. Survival analysis was performed to examine the risk of all-cause mortality (average follow-up years: 6.65) based on peak VO2. The Contal and O’Quigley’s method was used to determine the optimal cut-off of END-peak VO2 based on the log-rank statistic. END-peak VO2 was inversely associated with mortality risk [hazard ratio (HR) = 0.84; 95% confidence interval (CI) = 0.78–0.90], independent of changes in peak VO2 adjusted for the baseline peak VO2. The estimated cut-off of END-peak VO2 at ≥17.6 mL/kg/min best predicted the survival with high predictive accuracy and patients with END-peak VO2 under the cut-off had a greater risk of mortality (HR = 2.93; 95% CI = 1.81–4.74).

Conclusions

In patient with CHD undergoing CR, END-peak VO2 is an independent predictor for long-term survival. Studies utilizing higher intensity CR programmes, with and without pharmacologic strategies, to increase peak VO2 to a greater degree in those achieving a suboptimal END-peak VO2, are urgently needed.
Pragmatic Adjudication of Election Cases in the European Court of Human Rights
Authors: Kurnosov Dmitry
Published: April 2021

During the past 30 years, the European Court of Human Rights (ECtHR) has been constantly expanding its footprint in the area of democratic rights. However, the Court’s approach to election cases has been arguably more cautious compared to its jurisprudence on freedom of speech, association and assembly. Despite a growing body of scholarship on the ECtHR and democratic processes, this caution is yet to be adequately contextualized. This article aims to fill the gap by developing a normative model of how external considerations affect the ECtHR election jurisprudence. American judge-scholar Richard Posner has proposed pragmatic adjudication as a blueprint for incorporating external considerations into political disputes before the courts. I rely on this blueprint to gauge the level of deference to respondent governments in election cases at the ECtHR between 1987 and 2020. I find that, while the Court gives states wide leeway over political competition, it is less deferential when cases concern access to political process. At the same time, the ECtHR increasingly relies on procedural oversight to detect unfair electoral practices without changing the general distribution of competences.
Perspectives on Epigenetics Alterations Associated with Smoking and Vaping
Authors: Xie Zidian , Rahman Irfan , Goniewicz Maciej L , Li Dongmei
Published: April 2021

Epigenetic alterations, including DNA methylation, microRNA, and long noncoding RNA, play important roles in the pathogenesis of numerous respiratory health conditions and diseases. Exposure to tobacco smoking has been found to be associated with epigenetic changes in the respiratory tract. Marketed as a less harmful alternative to combustible cigarettes, electronic cigarette (e-cigarette) has rapidly gained popularity in recent years, especially among youth and young adults. Accumulative evidence from both animal and human studies has shown that e-cigarette use (vaping) is also linked to similar respiratory health conditions as observed with cigarette smoking, including wheezing, asthma, and COPD. This review aims to provide an overview of current studies on associations of smoking and vaping with epigenetic alterations in respiratory cells and provide future research directions in epigenetic studies related to vaping.
A Transcriptomic Pipeline Adapted for Genomic Sequence Discovery of Germline-Restricted Sequence in Zebra Finch,Taeniopygia guttata
Authors: Asalone Kathryn C , Takkar Ajuni K , Saldanha Colin J , Bracht John R
Published: April 2021

Songbirds have an unusual genomic element which is only found in their germline cells, known as the germline-restricted chromosome (GRC). Because germ cells contain both GRC and non-GRC (or A-chromosome) sequences, confidently identifying the GRC-derived elements from genome assemblies has proven difficult. Here, we introduce a new application of a transcriptomic method for GRC sequence identification. By adapting the Stringtie/Ballgown pipeline to use somatic and germline DNA reads, we find that the ratio of fragments per kilobase per million mapped reads can be used to confidently assign contigs to the GRC. Using this comparative coverage analysis, we successfully identify 733 contigs as high confidence GRC sequences (720 newly identified in this study) and 51 contigs which were validated using quantitative polymerase chain reaction. We also identified two new GRC genes, one hypothetical protein and one gene encoding an RNase H-like domain, and placed 16 previously identified but unplaced genes onto their host contigs. With the current focus on sequencing GRCs from different songbirds, our work adds to the genomic toolkit to identify GRC elements, and we provide a detailed protocol and GitHub repository at https://github.com/brachtlab/Comparative_Coverage_Analysis (last accessed May 12, 2021).
The Ca2+-Calmodulin-Activated Protein Phosphatase Calcineurin Negatively Regulates Egf Receptor Signaling in Drosophila Development
Authors: Sullivan Kathleen M C , Rubin Gerald M
Published: April 2021

Calcineurin is a Ca2+-calmodulin-activated, Ser-Thr protein phosphatase that is essential for the translation of Ca2+ signals into changes in cell function and development. We carried out a dominant modifier screen in the Drosophila eye using an activated form of the catalytic subunit to identify new targets, regulators, and functions of calcineurin. An examination of 70,000 mutagenized flies yielded nine specific complementation groups, four that enhanced and five that suppressed the activated calcineurin phenotype. The gene canB2, which encodes the essential regulatory subunit of calcineurin, was identified as a suppressor group, demonstrating that the screen was capable of identifying genes relevant to calcineurin function. We demonstrated that a second suppressor group was sprouty, a negative regulator of receptor tyrosine kinase signaling. Wing and eye phenotypes of ectopic activated calcineurin and genetic interactions with components of signaling pathways suggested a role for calcineurin in repressing Egf receptor/Ras signal transduction. On the basis of our results, we propose that calcineurin, upon activation by Ca2+-calmodulin, cooperates with other factors to negatively regulate Egf receptor signaling at the level of sprouty and the GTPase-activating protein Gap1.
Physical and Genetic Mapping in the Grasses Lolium perenne and Festuca pratensis
Authors: King J , Armstead I P , Donnison I S , Thomas H M , Jones R N , Kearsey M J , Roberts L A , Thomas A , Morgan W G , King I P
Published: April 2021

A single chromosome of the grass species Festuca pratensis has been introgressed into Lolium perenne to produce a diploid monosomic substitution line (2n = 2x = 14). In this line recombination occurs throughout the length of the F. pratensis/L. perenne bivalent. The F. pratensis chromosome and recombinants between it and its L. perenne homeologue can be visualized using genomic in situ hybridization (GISH). GISH junctions represent the physical locations of sites of recombination, enabling a range of recombinant chromosomes to be used for physical mapping of the introgressed F. pratensis chromosome. The physical map, in conjunction with a genetic map composed of 104 F. pratensis-specific amplified fragment length polymorphisms (AFLPs), demonstrated: (1) the first large-scale analysis of the physical distribution of AFLPs; (2) variation in the relationship between genetic and physical distance from one part of the F. pratensis chromosome to another (e.g., variation was observed between and within chromosome arms); (3) that nucleolar organizer regions (NORs) and centromeres greatly reduce recombination; (4) that coding sequences are present close to the centromere and NORs in areas of low recombination in plant species with large genomes; and (5) apparent complete synteny between the F. pratensis chromosome and rice chromosome 1.
Adaptive Divergence in Experimental Populations ofPseudomonas fluorescens. I. Genetic and Phenotypic Bases of Wrinkly Spreader Fitness
Authors: Spiers Andrew J , Kahn Sophie G , Bohannon John , Travisano Michael , Rainey Paul B
Published: April 2021

A central feature of all adaptive radiations is morphological divergence, but the phenotypic innovations that are responsible are rarely known. When selected in a spatially structured environment, populations of the bacterium Pseudomonas fluorescens rapidly diverge. Among the divergent morphs is a mutant type termed “wrinkly spreader” (WS) that colonizes a new niche through the formation of self-supporting biofilms. Loci contributing to the primary phenotypic innovation were sought by screening a WS transposon library for niche-defective (WS-) mutants. Detailed analysis of one group of mutants revealed an operon of 10 genes encoding enzymes necessary to produce a cellulose-like polymer (CLP). WS genotypes overproduce CLP and overproduction of the polymer is necessary for the distinctive morphology of WS colonies; it is also required for biofilm formation and to maximize fitness in spatially structured microcosms, but overproduction of CLP alone is not sufficient to cause WS. A working model predicts that modification of cell cycle control of CLP production is an important determinant of the phenotypic innovation. Analysis of >30 kb of DNA encoding traits required for expression of the WS phenotype, including a regulatory locus, has not revealed the mutational causes, indicating a complex genotype-phenotype map.
Genetic Analysis of Traits Distinguishing Outcrossing and Self-Pollinating Forms of Currant Tomato, Lycopersicon pimpinellifolium (Jusl.) Mill.
Authors: Georgiady Michael S , Whitkus Richard W , Lord Elizabeth M
Published: April 2021

The evolution of inbreeding is common throughout the angiosperms, although little is known about the developmental and genetic processes involved. Lycopersicon pimpinellifolium (currant tomato) is a self-compatible species with variation in outcrossing rate correlated with floral morphology. Mature flowers from inbreeding and outcrossing populations differ greatly in characters affecting mating behavior (petal, anther, and style lengths); other flower parts (sepals, ovaries) show minimal differences. Analysis of genetic behavior, including quantitative trait locus (QTL) mapping, was performed on representative selfing and outcrossing plants derived from two contrasting natural populations. Six morphological traits were analyzed: flowers per inflorescence; petal, anther, and style lengths; and lengths of the fertile and sterile portions of anthers. All traits were smaller in the selfing parent and had continuous patterns of segregation in the F2. Phenotypic correlations among traits were all positive, but varied in strength. Quantitative trait locus mapping was done using 48 RFLP markers. Five QTL total were found involving four of the six traits: total anther length, anther sterile length, style length, and flowers per inflorescence. Each of these four traits had a QTL of major (>25%) effect on phenotypic variance.
A Reaction-Diffusion Model for Interference in Meiotic Crossing Over
Authors: Fujitani Youhei , Mori Shintaro , Kobayashi Ichizo
Published: April 2021

One crossover point between a pair of homologous chromosomes in meiosis appears to interfere with occurrence of another in the neighborhood. It has been revealed that Drosophila and Neurospora, in spite of their large difference in the frequency of crossover points, show very similar plots of coincidence—a measure of the interference—against the genetic distance of the interval, defined as one-half the average number of crossover points within the interval. We here propose a simple reaction-diffusion model, where a “randomly walking” precursor becomes immobilized and matures into a crossover point. The interference is caused by pair-annihilation of the random walkers due to their collision and by annihilation of a random walker due to its collision with an immobilized point. This model has two parameters—the initial density of the random walkers and the rate of its processing into a crossover point. We show numerically that, as the former increases and/or the latter decreases, plotted curves of the coincidence vs. the genetic distance converge on a unique curve. Thus, our model explains the similarity between Drosophila and Neurospora without parameter values adjusted finely, although it is not a “genetic model” but is a “physical model,” specifying explicitly what happens physically.
A Neutral Model With Fluctuating Population Size and Its Effective Size
Authors: Iizuka Masaru , Tachida Hidenori , Matsuda Hirotsugu
Published: April 2021

We consider a diffusion model with neutral alleles whose population size is fluctuating randomly. For this model, the effects of fluctuation of population size on the effective size are investigated. The effective size defined by the equilibrium average heterozygosity is larger than the harmonic mean of population size but smaller than the arithmetic mean of population size. To see explicitly the effects of fluctuation of population size on the effective size, we investigate a special case where population size fluctuates between two distinct states. In some cases, the effective size is very different from the harmonic mean. For this concrete model, we also obtain the stationary distribution of the average heterozygosity. Asymptotic behavior of the effective size is obtained when the population size is large and/or autocorrelation of the fluctuation is weak or strong.
Population, Evolutionary and Genomic Consequences of Interference Selection
Authors: Comeron Josep M , Kreitman Martin
Published: April 2021

Weakly selected mutations are most likely to be physically clustered across genomes and, when sufficiently linked, they alter each others’ fixation probability, a process we call interference selection (IS). Here we study population genetics and evolutionary consequences of IS on the selected mutations themselves and on adjacent selectively neutral variation. We show that IS reduces levels of polymorphism and increases low-frequency variants and linkage disequilibrium, in both selected and adjacent neutral mutations. IS can account for several well-documented patterns of variation and composition in genomic regions with low rates of crossing over in Drosophila. IS cannot be described simply as a reduction in the efficacy of selection and effective population size in standard models of selection and drift. Rather, IS can be better understood with models that incorporate a constant “traffic” of competing alleles. Our simulations also allow us to make genome-wide predictions that are specific to IS. We show that IS will be more severe at sites in the center of a region containing weakly selected mutations than at sites located close to the edge of the region. Drosophila melanogaster genomic data strongly support this prediction, with genes without introns showing significantly reduced codon bias in the center of coding regions. As expected, if introns relieve IS, genes with centrally located introns do not show reduced codon bias in the center of the coding region. We also show that reasonably small differences in the length of intermediate “neutral” sequences embedded in a region under selection increase the effectiveness of selection on the adjacent selected sequences. Hence, the presence and length of sequences such as introns or intergenic regions can be a trait subject to selection in recombining genomes. In support of this prediction, intron presence is positively correlated with a gene’s codon bias in D. melanogaster. Finally, the study of temporal dynamics of IS after a change of recombination rate shows that nonequilibrium codon usage may be the norm rather than the exception.
Pleiotropic Model of Maintenance of Quantitative Genetic Variation at Mutation-Selection Balance
Authors: Zhang Xu-Sheng , Wang Jinliang , Hill William G
Published: April 2021

A pleiotropic model of maintenance of quantitative genetic variation at mutation-selection balance is investigated. Mutations have effects on a metric trait and deleterious effects on fitness, for which a bivariate gamma distribution is assumed. Equations for calculating the strength of apparent stabilizing selection (Vs) and the genetic variance maintained in segregating populations (VG) were derived. A large population can hold a high genetic variance but the apparent stabilizing selection may or may not be relatively strong, depending on other properties such as the distribution of mutation effects. If the distribution of mutation effects on fitness is continuous such that there are few nearly neutral mutants, or a minimum fitness effect is assumed if most mutations are nearly neutral, VG increases to an asymptote as the population size increases. Both VG and Vs are strongly affected by the shape of the distribution of mutation effects. Compared with mutants of equal effect, allowing their effects on fitness to vary across loci can produce a much higher VG but also a high Vs (Vs in phenotypic standard deviation units, which is always larger than the ratio VP/Vm), implying weak apparent stabilizing selection. If the mutational variance Vm is ∼10-3  Ve (Ve, environmental variance), the model can explain typical values of heritability and also apparent stabilizing selection, provided the latter is quite weak as suggested by a recent review.
Frequentist Estimation of Coalescence Times From Nucleotide Sequence Data Using a Tree-Based Partition
Authors: Tang Hua , Siegmund David O , Shen Peidong , Oefner Peter J , Feldman Marcus W
Published: April 2021

This article proposes a method of estimating the time to the most recent common ancestor (TMRCA) of a sample of DNA sequences. The method is based on the molecular clock hypothesis, but avoids assumptions about population structure. Simulations show that in a wide range of situations, the point estimate has small bias and the confidence interval has at least the nominal coverage probability. We discuss conditions that can lead to biased estimates. Performance of this estimator is compared with existing methods based on the coalescence theory. The method is applied to sequences of Y chromosomes and mtDNAs to estimate the coalescent times of human male and female populations.
Levels of DNA Polymorphism Vary With Mating System in the Nematode Genus Caenorhabditis
Authors: Graustein Andrew , Gaspar John M , Walters James R , Palopoli Michael F
Published: April 2021

Self-fertilizing species often harbor less genetic variation than cross-fertilizing species, and at least four different models have been proposed to explain this trend. To investigate further the relationship between mating system and genetic variation, levels of DNA sequence polymorphism were compared among three closely related species in the genus Caenorhabditis: two self-fertilizing species, Caenorhabditis elegans and C. briggsae, and one cross-fertilizing species, C. remanei. As expected, estimates of silent site nucleotide diversity were lower in the two self-fertilizing species. For the mitochondrial genome, diversity in the selfing species averaged 42% of diversity in C. remanei. Interestingly, the reduction in genetic variation was much greater for the nuclear than for the mitochondrial genome. For two nuclear genes, diversity in the selfing species averaged 6 and 13% of diversity in C. remanei. We argue that either population bottlenecks or the repeated action of natural selection, coupled with high levels of selfing, are likely to explain the observed reductions in species-wide genetic diversity.
Characterization of Essential Genes by Parasexual Genetics in the Human Fungal Pathogen Aspergillus fumigatus: Impact of Genomic Rearrangements Associated With Electroporation of DNA
Authors: Firon Arnaud , Beauvais Anne , Latgé Jean-Paul , Couvé Elisabeth , Grosjean-Cournoyer Marie-Claire , d'Enfert Christophe
Published: April 2021

We have evaluated the usefulness of parasexual genetics in the identification of genes essential for the growth of the human fungal pathogen Aspergillus fumigatus. First, essentiality of the A. fumigatus AfFKS1 gene, encoding the catalytic subunit of the β-(1,3)-glucan synthase complex, was assessed by inactivating one allele of AfFKS1 in a diploid strain of A. fumigatus obtained using adequate selectable markers in spore color and nitrate utilization pathways and by performing haploidization under conditions that select for the occurrence of the disrupted allele. Haploid progeny could not be obtained, demonstrating that AfFKS1 and, hence, β-(1,3)-glucan synthesis are essential in A. fumigatus. Second, random heterozygous insertional mutants were generated by electroporation of diploid conidia with a heterologous plasmid. A total of 4.5% of the transformants failed to produce haploid progeny on selective medium. Genomic analysis of these heterozygous diploids led in particular to the identification of an essential A. fumigatus gene encoding an SMC-like protein resembling one in Schizosacccharomyces pombe involved in chromosome condensation and cohesion. However, significant plasmid and genomic DNA rearrangements were observed at many of the identified genomic loci where plasmid integration had occurred, thus suggesting that the use of electroporation to build libraries of A. fumigatus insertional mutants has relatively limited value and cannot be used in an exhaustive search of essential genes.
Dominant Alleles of the Basic Helix-Loop-Helix Transcription Factor ATR2 Activate Stress-Responsive Genes in Arabidopsis
Authors: Smolen Gromoslaw A , Pawlowski Laura , Wilensky Sharon E , Bender Judith
Published: April 2021

Members of the R/B basic helix-loop-helix (bHLH) family of plant transcription factors are involved in a variety of growth and differentiation processes. We isolated a dominant mutation in an R/B-related bHLH transcription factor in the course of studying Arabidopsis tryptophan pathway regulation. This mutant, atr2D, displayed increased expression of several tryptophan genes as well as a subset of other stress-responsive genes. The atr2D mutation creates an aspartate to asparagine change at a position that is highly conserved in R/B factors. Substitutions of other residues with uncharged side chains at this position also conferred dominant phenotypes. Moreover, overexpression of mutant atr2D, but not wild-type ATR2, conferred pleiotropic effects, including reduced size, dark pigmentation, and sterility. Therefore, atr2D is likely to be an altered-function allele that identifies a key regulatory site in the R/B factor coding sequence. Double-mutant analysis with atr1D, an overexpression allele of the ATR1 Myb factor previously isolated in tryptophan regulation screens, showed that atr2D and atr1D have additive effects on tryptophan regulation and are likely to act through distinct mechanisms to activate tryptophan genes. The dominant atr mutations thus provide tools for altering tryptophan metabolism in plants.
Two O-Linked N-Acetylglucosamine Transferase Genes of Arabidopsis thaliana L. Heynh. Have Overlapping Functions Necessary for Gamete and Seed Development
Authors: Hartweck Lynn M , Scott Cheryl L , Olszewski Neil E
Published: April 2021

The Arabidopsis SECRET AGENT (SEC) and SPINDLY (SPY) proteins are similar to animal O-linked N-acetylglucosamine transferases (OGTs). OGTs catalyze the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to Ser/Thr residues of proteins. In animals, O-GlcNAcylation has been shown to affect protein activity, stability, and/or localization. SEC protein expressed in Escherichia coli had autocatalytic OGT activity. To determine the function of SEC in plants, two tDNA insertional mutants were identified and analyzed. Although sec mutant plants did not exhibit obvious phenotypes, sec and spy mutations had a synthetic lethal interaction. This lethality was incompletely penetrant in gametes and completely penetrant postfertilization. The rate of both female and male sec spy gamete transmission was higher in plants heterozygous for both mutations than in plants heterozygous for sec and homozygous for spy. Double-mutant embryos aborted at various stages of development and no double-mutant seedlings were obtained. These results indicate that OGT activity is required during gametogenesis and embryogenesis with lethality occurring when parentally derived SEC, SPY, and/or O-GlcNAcylated proteins become limiting.
A Combined Amplified Fragment Length Polymorphism and Randomly Amplified Polymorphism DNA Genetic Linkage Map of Mycosphaerella graminicola, the Septoria Tritici Leaf Blotch Pathogen of Wheat
Authors: Kema Gert H J , Goodwin Stephen B , Hamza Sonia , Verstappen Els C P , Cavaletto Jessica R , Van der Lee Theo A J , de Weerdt Marjanne , Bonants Peter J M , Waalwijk Cees
Published: April 2021

An F1 mapping population of the septoria tritici blotch pathogen of wheat, Mycosphaerella graminicola, was generated by crossing the two Dutch field isolates IPO323 and IPO94269. AFLP and RAPD marker data sets were combined to produce a high-density genetic linkage map. The final map contained 223 AFLP and 57 RAPD markers, plus the biological traits mating type and avirulence, in 23 linkage groups spanning 1216 cM. Many AFLPs and some RAPD markers were clustered. When markers were reduced to 1 per cluster, 229 unique positions were mapped, with an average distance of 5.3 cM between markers. Because M. graminicola probably has 17 or 18 chromosomes, at least 5 of the 23 linkage groups probably will need to be combined with others once additional markers are added to the map. This was confirmed by pulsed-field gel analysis; probes derived from 2 of the smallest linkage groups hybridized to two of the largest chromosome-sized bands, revealing a discrepancy between physical and genetic distance. The utility of the map was demonstrated by identifying molecular markers tightly linked to two genes of biological interest, mating type and avirulence. Bulked segregant analysis was used to identify additional molecular markers closely linked to these traits. This is the first genetic linkage map for any species in the genus Mycosphaerella or the family Mycosphaerellaceae.
The bantam Gene Regulates Drosophila Growth
Authors: Hipfner David R , Weigmann Katrin , Cohen Stephen M
Published: April 2021

We report here the consequences of mutations of a novel locus, named bantam, whose product is involved in the regulation of growth in Drosophila. bantam mutant animals are smaller than wild type, due to a reduction in cell number but not cell size, and do not have significant disruptions in patterning. Conversely, overexpression of the bantam product using the EP element EP(3)3622 causes overgrowth of wing and eye tissue. Overexpression in clones of cells results in an increased rate of cell proliferation and a matched increase in cellular growth rate, such that the resulting tissue is composed of more cells of a size comparable to wild type. These effects are strikingly similar to those associated with alterations in the activity of the cyclinD-cdk4 complex. However, epistasis and genetic interaction analyses indicate that bantam and cyclinD-cdk4 operate independently. Thus, the bantam locus represents a novel regulator of tissue growth.
A Targeted RNAi Screen for Genes Involved in Chromosome Morphogenesis and Nuclear Organization in the Caenorhabditis elegans Germline
Authors: Colaiácovo M P , Stanfield G M , Reddy K C , Reinke V , Kim S K , Villeneuve A M
Published: April 2021

We have implemented a functional genomics strategy to identify genes involved in chromosome morphogenesis and nuclear organization during meiotic prophase in the Caenorhabditis elegans germline. This approach took advantage of a gene-expression survey that used DNA microarray technology to identify genes preferentially expressed in the germline. We defined a subset of 192 germline-enriched genes whose expression profiles were similar to those of previously identified meiosis genes and designed a screen to identify genes for which inhibition by RNA interference (RNAi) elicited defects in function or development of the germline. We obtained strong germline phenotypes for 27% of the genes tested, indicating that this targeted approach greatly enriched for genes that function in the germline. In addition to genes involved in key meiotic prophase events, we identified genes involved in meiotic progression, germline proliferation, and chromosome organization and/or segregation during mitotic growth.
Courtship and Other Behaviors Affected by a Heat-Sensitive, Molecularly Novel Mutation in the cacophony Calcium-Channel Gene of Drosophila
Authors: Chan Betty , Villella Adriana , Funes Pablo , Hall Jeffrey C
Published: April 2021

The cacophony (cac) locus of Drosophila melanogaster, which encodes a calcium-channel subunit, has been mutated to cause courtship-song defects or abnormal responses to visual stimuli. However, the most recently isolated cac mutant was identified as an enhancer of a comatose mutation’s effects on general locomotion. We analyzed the cacTS2 mutation in terms of its intragenic molecular change and its effects on behaviors more complex than the fly’s elementary ability to move. The molecular etiology of this mutation is a nucleotide substitution that causes a proline-to-serine change in a region of the polypeptide near its EF hand. Given that this motif is involved in channel inactivation, it was intriguing that cacTS2 males generate song pulses containing larger-than-normal numbers of cycles—provided that such males are exposed to an elevated temperature. Similar treatments caused only mild visual-response abnormalities and generic locomotor sluggishness. These results are discussed in the context of calcium-channel functions that subserve certain behaviors and of defects exhibited by the original cacophony mutant. Despite its different kind of amino-acid substitution, compared with that of cacTS2, cacS males sing abnormally in a manner that mimics the new mutant’s heat-sensitive song anomaly.