Incomplete annotation has a disproportionate impact on our understanding of Mendelian and complex neurogenetic disorders

Growing evidence suggests that human gene annotation remains incomplete; however, it is unclear how this affects different tissues and our understanding of different disorders. Here, we detect previously unannotated transcription from Genotype-Tissue Expression RNA sequencing data across 41 human tissues. We connect this unannotated transcription to known genes, confirming that human gene annotation remains incomplete, even among well-studied genes including 63% of the Online Mendelian Inheritance in Man–morbid catalog and 317 neurodegeneration-associated genes. We find the greatest abundance of unannotated transcription in brain and genes highly expressed in brain are more likely to be reannotated. We explore examples of reannotated disease genes, such as SNCA, for which we experimentally validate a previously unidentified, brain-specific, potentially protein-coding exon. We release all tissue-specific transcriptomes through vizER: http://rytenlab.com/browser/app/vizER. We anticipate that this resource will facilitate more accurate genetic analysis, with the greatest impact on our understanding of Mendelian and complex neurogenetic disorders

recount3: summaries and queries for large-scale RNA-seq expression and splicing

We present recount3, a resource consisting of over 750,000 publicly available human and mouse RNA sequencing (RNA-seq) samples uniformly processed by our new Monorail analysis pipeline. To facilitate access to the data, we provide the recount3 and snapcount R/Bioconductor packages as well as complementary web resources. Using these tools, data can be downloaded as study-level summaries or queried for specific exon-exon junctions, genes, samples, or other features. Monorail can be used to process local and/or private data, allowing results to be directly compared to any study in recount3. Taken together, our tools help biologists maximize the utility of publicly available RNA-seq data, especially to improve their understanding of newly collected data. recount3 is available from http://rna.recount.bio

Pure-glue hidden valleys through the Higgs portal

We consider the possibility that the Higgs boson can act as a link to a hidden sector in the context of pure-glue hidden valley models. In these models the standard model is weakly coupled, through loops of heavy messengers fields, to a hidden sector whose low energy dynamics is described by a pure-Yang-Mills theory. Such a hidden sector contains several metastable hidden glueballs. In this work we shall extend earlier results on hidden valleys to include couplings of the messengers to the standard model Higgs sector. The effective interactions at one-loop couple the hidden gluons to the standard model particles through the Higgs sector. These couplings in turn induce hidden glueball decays to fermion pairs, or cascade decays with multiple Higgs emission. The presence of effective operators of different mass dimensions, often competing with each other, together with a great diversity of states, leads to a great variability in the lifetimes and decay modes of the hidden glueballs. We find that most of the operators considered in this paper are not heavily constrained by precision electroweak physics, therefore leaving plenty of room in the parameter space to be explored by the future experiments at the LHC.Comment: 44 pages, 16 figures. Major revision for JHEP, corrected an error in Eq. 5.1, comments adde

Weinberg like sum rules revisited

The generalized Weinberg sum rules containing the difference of isovector vector and axial-vector spectral functions saturated by both finite and infinite number of narrow resonances are considered. We summarize the status of these sum rules and analyze their overall agreement with phenomenological Lagrangians, low-energy relations, parity doubling, hadron string models, and experimental data.Comment: 31 pages, noticed misprints are corrected, references are added, and other minor corrections are mad

Institutional logics and interorganizational learning in technological arenas: Evidence from standard-setting organizations in the mobile handset industry

© 2015, INFORMS. Conceptualizing standard-setting organizations (SSOs) as technological arenas within which firms from different countries interact and learn, we offer insights into the interplay between firms' institutional logics and their interorganizational learning outcomes. We suggest that firms' interorganizational learning is embedded in their macrolevel country contexts, characterized by more corporatist versus less corporatist (pluralist) institutional logics. Whereas corporatism spurs coordinated approaches, pluralism engenders competitive interactions that affect the extent to which firms span organizational and technological boundaries and learn from each other. We test our theory using longitudinal analysis of 181 dyads involving 26 firms participating in 17 SSOs in the global mobile handset industry. We find that interorganizational learning, as measured by patent citations, involving corporatist firm dyads significantly increases when the dominant logic within the arena is also corporatist. By making cooperative schemas more accessible, a dominant corporatist logic also enhances interorganizational learning across technologically distant dyads. When a pluralist logic dominates the arena, corporatist dyads learn less because firms in the dyad activate a contradictory logic that decouples them from their natural processes for interorganizational learning. These findings highlight the implications of institutional logics for interorganizational learning outcomes and provide insights into how firms attend to institutional contradictions in arenas that provide opportunities for interorganizational learning

Identification, replication and characterization of epigenetic remodelling in the aging genome:A cross population analysis

Aging is a complex biological process regulated by multiple cellular pathways and molecular mechanisms including epigenetics. Using genome-wide DNA methylation data measured in a large collection of Scottish old individuals, we performed discovery association analysis to identify age-methylated CpGs and replicated them in two independent Danish cohorts. The double-replicated CpGs were characterized by distribution over gene regions and location in relation to CpG islands. The replicated CpGs were further characterized by involvement in biological pathways to study their functional implications in aging. We identified 67,604 age-associated CpG sites reaching genome-wide significance of FWE

Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD