scholarly journals Promoter CpG density predicts downstream gene loss-of-function intolerance

2020 ◽  
Author(s):  
Leandros Boukas ◽  
Hans T. Bjornsson ◽  
Kasper D. Hansen
Keyword(s):  
Predictive Model ◽  
Gene Loss ◽  
Cpg Islands ◽  
Joint Analysis ◽  
Loss Of Function ◽  
Large Numbers ◽  
Human Genes ◽  
Individual Contributions ◽  
The Individual ◽  
Prevailing View

AbstractThe aggregation and joint analysis of large numbers of exome sequences has recently made it possible to de-rive estimates of intolerance to loss-of-function (LoF) variation for human genes. Here, we demonstrate strong and widespread coupling between genic LoF-intolerance and promoter CpG density across the human genome. Genes downstream of the most CpG-rich pro-moters (top 10% CpG density) have a 67.2% probability of being highly LoF-intolerant, using the LOEUF metric from gnomAD. This is in contrast to 7.4% of genes downstream of the most CpG-poor (bottom 10% CpG density) promoters. Combining promoter CpG density with exonic and promoter conservation explains 33.4% of the variation in LOEUF, and the contribution of CpG density exceeds the individual contributions of exonic and promoter conservation. We leverage this to train a simple and easily interpretable predictive model that out-performs other existing predictors and allows us to classify 1,760 genes – which currently lack reliable LOEUF estimates – as highly LoF-intolerant or not. These predictions have the potential to aid in the interpretation of novel patient variants. Moreover, our results reveal that high CpG density is not merely a generic feature of human promoters, but is preferentially encountered at the promoters of the most selectively constrained genes, calling into question the prevailing view that CpG islands are not subject to selection.

scholarly journals Optically splitting symmetric neuron pairs in C. elegans

2020 ◽  
Author(s):  
Lloyd Davis ◽  
Inja Radman ◽  
Angeliki Goutou ◽  
Ailish Tynan ◽  
Kieran Baxter ◽  
...  
Keyword(s):  
Genetic Code ◽  
Single Cell ◽  
Symmetric Pair ◽  
C Elegans ◽  
Large Numbers ◽  
Individual Contributions ◽  
Touch Response ◽  
Expansion System ◽  
Genetic Code Expansion ◽  
The Individual

AbstractTwo thirds of the 302 neurons in C. elegans form bilaterally symmetric pairs in its physical connectome, and similar gross morphological symmetries are seen in the nervous systems of many other animals. A central question is whether and how this morphological symmetry is broken to produce functional asymmetry. Addressing this question, in all but two cases, has been impossible because no promoters are known that can direct gene expression to a single cell within a symmetric pair. Here we develop an efficient genetic code expansion system in C. elegans and use this system to create a photo-activatable version of Cre recombinase. Using this system, we target single neurons within a bilaterally symmetric pair (PLMR and PLML) with a laser. This turns on Cre and thereby switches on expression of an optogenetic channel in a single cell. We hereby overcome the limitation that these neurons cannot be targeted by genetic means. Our approach enables the generation of large numbers of animals for downstream experiments. By globally illuminating groups of freely moving animals to stimulate the targeted neurons that express an optogenetic channel we dissect the individual contributions of PLMR and PLML to the C. elegans touch response. Our results reveal that the individual neurons make asymmetric contributions to this behaviour, and suggest distinct roles for PLMR and PLML in the habituation to repeated stimulation. Our results demonstrate how genetic code expansion and optical targeting can be combined to break the symmetry of neuron pairs in C. elegans and thereby dissect the contributions of individual neurons to behaviour.

scholarly journals Heterozygous gene truncation delineates the human haploinsufficient genome

2014 ◽  
Author(s):  
István Bartha ◽  
Antonio Rausell ◽  
Paul McLaren ◽  
Manuel Tardaguila ◽  
Pejman Mohammadi ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Mutation ◽  
Phenotypic Traits ◽  
Incomplete Penetrance ◽  
Heterozygous State ◽  
Loss Of Function ◽  
Protein Coding ◽  
Large Numbers ◽  
Human Genes ◽  
Compensatory Mutations

Sequencing projects have identified large numbers of rare stop-gain and frameshift variants in the human genome. As most of these are observed in the heterozygous state, they test a gene?s tolerance to haploinsufficiency and dominant loss of function. We analyzed the distribution of truncating variants across 16,260 protein coding autosomal genes in 11,546 individuals. We observed 39,893 truncating variants affecting 12,062 genes, which significantly differed from an expectation of 12,916 genes under a model of neutral de novo mutation (p<1E-4). Extrapolating this to increasing numbers of sequenced individuals, we estimate that 10.8% of human genes do not tolerate heterozygous truncating variants. An additional 10 to 15% of truncated genes may be rescued by incomplete penetrance or compensatory mutations, or because the truncating variants are of limited functional impact. The study of protein truncating variants delineates the essential genome and, more generally, identifies rare heterozygous variants as an unexplored source of diversity of phenotypic traits and diseases.

scholarly journals Modeling C9orf72-Related Frontotemporal Dementia and Amyotrophic Lateral Sclerosis in Drosophila

2021 ◽  
Vol 15 ◽  
Author(s):  
Joanne L. Sharpe ◽  
Nikki S. Harper ◽  
Duncan R. Garner ◽  
Ryan J. H. West
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Dipeptide Repeat Proteins ◽  
Repeat Proteins ◽  
Individual Contributions ◽  
The Individual ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

An intronic hexanucleotide (GGGGCC) expansion in the C9orf72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In the decade following its discovery, much progress has been made in enhancing our understanding of how it precipitates disease. Both loss of function caused by reduced C9orf72 transcript levels, and gain of function mechanisms, triggered by the production of repetitive sense and antisense RNA and dipeptide repeat proteins, are thought to contribute to the toxicity. Drosophila models, with their unrivaled genetic tractability and short lifespan, have played a key role in developing our understanding of C9orf72-related FTD/ALS. There is no C9orf72 homolog in fly, and although this precludes investigations into loss of function toxicity, it is useful for elucidating mechanisms underpinning gain of function toxicity. To date there are a range of Drosophila C9orf72 models, encompassing different aspects of gain of function toxicity. In addition to pure repeat transgenes, which produce both repeat RNA and dipeptide repeat proteins (DPRs), RNA only models and DPR models have been generated to unpick the individual contributions of RNA and each dipeptide repeat protein to C9orf72 toxicity. In this review, we discuss how Drosophila models have shaped our understanding of C9orf72 gain of function toxicity, and address opportunities to utilize these models for further research.

A Handbook to Eddic Poetry: Myths and Legends of Early Scandinavia, ed. Carolyne Larrington, Judy Quinn, and Brittany Schorn. Cambridge: Cambridge University Press, 2016, xii, 413 pp., 12 b/w ill.

Mediaevistik ◽  
2018 ◽  
Vol 31 (1) ◽  
pp. 366-366
Author(s):  
Albrecht Classen
Keyword(s):  
Old Norse ◽  
Entire Volume ◽  
Cambridge University ◽  
Critical Studies ◽  
Individual Contributions ◽  
The Many ◽  
The Individual ◽  
Made In ◽  
Scandinavian Literature

Eddic poetry constitutes one of the most important genres in Old Norse or Scandinavian literature and has been studied since the earliest time of modern-day philology. The progress we have made in that field is impressive, considering the many excellent editions and translations, not to mention the countless critical studies in monographs and articles. Nevertheless, there is always a great need to revisit, to summarize, to review, and to digest the knowledge gained so far. The present handbook intends to address all those goals and does so, to spell it out right away, exceedingly well. But in contrast to traditional concepts, the individual contributions constitute fully developed critical article, each with a specialized topic elucidating it as comprehensively as possible, and concluding with a section of notes. Those are kept very brief, but the volume rounds it all off with an inclusive, comprehensive bibliography. And there is also a very useful index at the end. At the beginning, we find, following the table of contents, a list of the contributors, unfortunately without emails, a list of translations and abbreviations of the titles of Eddic poems in the Codex Regius and then elsewhere, and a very insightful and pleasant introduction by Carolyne Larrington. She briefly introduces the genre and then summarizes the essential points made by the individual authors. The entire volume is based on the Eddic Network established by the three editors in 2012, and on two workshops held at St. John’s College, Oxford in 2013 and 2014.

Employee Surveys and Sensing

2020 ◽  
Keyword(s):  
Organizational Performance ◽  
Employee Engagement ◽  
Computational Linguistics ◽  
Full Range ◽  
Organization Culture ◽  
Employee Survey ◽  
Passive Data ◽  
Individual Contributions ◽  
Action Taking ◽  
The Individual

This volume comprises 27 chapters focused on the design and execution of employee survey programs. These chapters reflect the latest advances in technology and analytics and a pervasive emphasis on driving organizational performance and effectiveness. The individual chapters represent the full range of survey-related topics, including design, administration, analysis, feedback, and action-taking. The latest methodological trends and capabilities are discussed including computational linguistics, applications of artificial intelligence, and the use of qualitative methods such as focus groups. Extending beyond traditional employee surveys, contributions include the role of passive data collection as an alternative or supplement in a comprehensive employee listening system. Unique contextual factors are discussed including the use of surveys in a unionized environment. Individual contributions also reflect increasing stakeholder concerns for the protection of privacy among other ethical considerations. Finally, significant clarifications to the literature are provided on the use of surveys for measuring organization culture, strategic climate, and employee engagement.

Knowledge First

2017 ◽  
Author(s):  
J. Adam Carter ◽  
Emma C. Gordon ◽  
Benjamin W. Jarvis
Keyword(s):  
Philosophy Of Mind ◽  
Theoretical Background ◽  
Contemporary Research ◽  
Timothy Williamson ◽  
Research Themes ◽  
New Directions ◽  
Individual Contributions ◽  
The Individual

In this introductory chapter, the volume’s editors provide a theoretical background to the volume’s topic and a brief overview of the papers included. The chapter is divided into five parts: Section 1 explains the main contours of the knowledge-first approach, as it was initially advanced by Timothy Williamson in Knowledge and its Limits. In Sections 2–3, some of the key philosophical motivations for the knowledge-first approach are reviewed, and several key contemporary research themes associated with this approach in epistemology, the philosophy of mind and elsewhere are outlined and briefly discussed. The volume’s papers are divided into two broad categories: foundational issues and applications and new directions. Section 4 discusses briefly the scope and aim of the volume as the editors have conceived it, and Section 5 offers an overview of each of the individual contributions in the volume.

scholarly journals A Mild Phenotype Caused by Two Novel Compound Heterozygous Mutations in CEP290

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1240
Author(s):  
Agnieszka Rafalska ◽  
Anna M. Tracewska ◽  
Anna Turno-Kręcicka ◽  
Milena J. Szafraniec ◽  
Marta Misiuk-Hojło
Keyword(s):  
Vision Loss ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Mild Phenotype ◽  
Cone Function ◽  
Retinal Disorders ◽  
Molecular Inversion Probes ◽  
Disease Experience ◽  
The Individual ◽  
Inherited Retinal Disorders

CEP290 is a ciliary gene frequently mutated in ciliopathies, resulting in a broad range of phenotypes, ranging from isolated inherited retinal disorders (IRDs) to severe or lethal syndromes with multisystemic involvement. Patients with non-syndromic CEP290-linked disease experience profound and early vision loss due to cone-rod dystrophy, as in Leber congenital amaurosis. In this case report, we describe two novel loss-of-function heterozygous alterations in the CEP290 gene, discovered in a patient suffering from retinitis pigmentosa using massive parallel sequencing of a molecular inversion probes library constructed for 108 genes involved in IRDs. A milder phenotype than expected was found in the individual, which serves to prove that some CEP290-associated disorders may display preserved cone function.

scholarly journals Of Visions and Visionaries: Information and Communication Technologies (ICT) in China

2021 ◽  
Vol 50 (1) ◽  
pp. 3-11
Author(s):  
Barbara Schulte ◽  
Marina Svensson
Keyword(s):  
Information And Communication Technologies ◽  
Communication Technologies ◽  
Special Issue ◽  
Empirical Reality ◽  
Information And Communication ◽  
Individual Contributions ◽  
State Governance ◽  
Different Dimensions ◽  
Chinese State ◽  
The Individual

This special issue approaches information and communication technologies (ICT) visions and their realisation/implementation at various levels, among different actors and from various perspectives. Conceptually, we distinguish three different dimensions, even though those overlap in the individual contributions as well as in empirical reality – namely ideational, instrumental, and relational. The different contributions address both visions formulated by the Chinese state and by individual actors such as entrepreneurs. Even though the conditions for the use of ICT in China are deeply affected by state governance, this governance is in no way tantamount to one single government. As this issue’s contributions show, state attempts at building a stable cyber-governance are in need of allies and, depending on the allies’ visions and other, competitive visions, the outcomes of these dynamics are seldom truthful realisations of one original grand masterplan.

Outcomes of Microneurovascular Facial Reanimation Using Masseteric Innervation in Patients With Long-Standing Facial Palsy Resulting From Cured Brainstem Lesions

Neurosurgery ◽  
2010 ◽  
Vol 67 (3) ◽  
pp. 663-674 ◽  
Author(s):  
Kartik G. Krishnan ◽  
Gabriele Schackert ◽  
Volker Seifert
Keyword(s):  
Loss Of Function ◽  
Muscle Flaps ◽  
Self Evaluation ◽  
Möbius Syndrome ◽  
Evaluation Scores ◽  
Facial Nerves ◽  
Facial Reanimation ◽  
Masseteric Nerve ◽  
Natural Emotion ◽  
The Individual

Abstract BACKGROUND The functions of the human face are not only of esthetic significance but also extend into metaphoric nuances of psychology. The loss of function of one or both facial nerves has a remarkable impact on patients' lives. OBJECTIVE To retrospectively analyze the functional outcomes of microneurovascular facial reanimation using masseteric innervation. METHODS Seventeen patients with irreparable facial paralysis resulting from benign lesions involving the facial nuclei (n = 14) or Möbius syndrome (n = 3) were treated with free muscle flaps for oral commissural reanimation using ipsilateral masseteric innervation and using temporalis muscle transfer for eyelid reanimation. Results were analyzed by the absolute commissural excursion and commissural excursion index and by a patient self-evaluation score. Presence of synkinesis was documented. Follow-up ranged from 8 to 48 months (mean, 26.4 months). RESULTS Normalization of the commissural excursion index was observed in 8 of 17 patients (47%), an improvement was seen in 7 of 17 (41%), and failure was observed in 2 of 17 (12%). The individual dynamics of absolute commissural excursion and commissural excursion index changes are presented. A natural smiling response was observed in 10 of 17 patients (59%) but not in the remaining 7 (41%). This response reflected the patient's ability to relay the natural emotion of smiling through the masseteric nerve. Patients' self-evaluation scores were a level higher than objective indices. CONCLUSIONS Innervation of free muscle flaps with the masseteric nerve for oral commissure reanimation might play an important role in patients with lesions of the facial nuclei (as in Möbius syndrome). Synkinesis persists for long periods after surgery. However, most of the patients learned to express their emotions by overcoming this phenomenon. Despite hypercorrection or inadequate correction, patients evaluated themselves favorably.

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