Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, ...collaborating with the Pharmacogenomics Research Network, began eMERGE‐PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of “precision medicine.” The February 2015 eMERGE‐PGx data release includes sequence‐derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation‐Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.
Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) has challenged public health agencies globally. In order to effectively target government responses, it is critical to identify the ...individuals most at risk of coronavirus disease-19 (COVID-19), developing severe clinical signs, and mortality. We undertook a systematic review of the literature to present the current status of scientific knowledge in these areas and describe the need for unified global approaches, moving forwards, as well as lessons learnt for future pandemics.
Medline, Embase and Global Health were searched to the end of April 2020, as well as the Web of Science. Search terms were specific to the SARS-CoV-2 virus and COVID-19. Comparative studies of risk factors from any setting, population group and in any language were included. Titles, abstracts and full texts were screened by two reviewers and extracted in duplicate into a standardised form. Data were extracted on risk factors for COVID-19 disease, severe disease, or death and were narratively and descriptively synthesised.
One thousand two hundred and thirty-eight papers were identified post-deduplication. Thirty-three met our inclusion criteria, of which 26 were from China. Six assessed the risk of contracting the disease, 20 the risk of having severe disease and ten the risk of dying. Age, gender and co-morbidities were commonly assessed as risk factors. The weight of evidence showed increasing age to be associated with severe disease and mortality, and general comorbidities with mortality. Only seven studies presented multivariable analyses and power was generally limited. A wide range of definitions were used for disease severity.
The volume of literature generated in the short time since the appearance of SARS-CoV-2 has been considerable. Many studies have sought to document the risk factors for COVID-19 disease, disease severity and mortality; age was the only risk factor based on robust studies and with a consistent body of evidence. Mechanistic studies are required to understand why age is such an important risk factor. At the start of pandemics, large, standardised, studies that use multivariable analyses are urgently needed so that the populations most at risk can be rapidly protected.
This review was registered on PROSPERO as CRD42020177714 .
Intron retention (IR) occurs when an intron is transcribed into pre-mRNA and remains in the final mRNA. We have developed a program and database called IRFinder to accurately detect IR from mRNA ...sequencing data. Analysis of 2573 samples showed that IR occurs in all tissues analyzed, affects over 80% of all coding genes and is associated with cell differentiation and the cell cycle. Frequently retained introns are enriched for specific RNA binding protein sites and are often retained in clusters in the same gene. IR is associated with lower protein levels and intron-retaining transcripts that escape nonsense-mediated decay are not actively translated.
We present the first results of the Fermilab National Accelerator Laboratory (FNAL) Muon g-2 Experiment for the positive muon magnetic anomaly a_{μ}≡(g_{μ}-2)/2. The anomaly is determined from the ...precision measurements of two angular frequencies. Intensity variation of high-energy positrons from muon decays directly encodes the difference frequency ω_{a} between the spin-precession and cyclotron frequencies for polarized muons in a magnetic storage ring. The storage ring magnetic field is measured using nuclear magnetic resonance probes calibrated in terms of the equivalent proton spin precession frequency ωover ˜_{p}^{'} in a spherical water sample at 34.7 °C. The ratio ω_{a}/ωover ˜_{p}^{'}, together with known fundamental constants, determines a_{μ}(FNAL)=116 592 040(54)×10^{-11} (0.46 ppm). The result is 3.3 standard deviations greater than the standard model prediction and is in excellent agreement with the previous Brookhaven National Laboratory (BNL) E821 measurement. After combination with previous measurements of both μ^{+} and μ^{-}, the new experimental average of a_{μ}(Exp)=116 592 061(41)×10^{-11} (0.35 ppm) increases the tension between experiment and theory to 4.2 standard deviations.
Intron retention (IR) is widely recognized as a consequence of mis-splicing that leads to failed excision of intronic sequences from pre-messenger RNAs. Our bioinformatic analyses of transcriptomic ...and proteomic data of normal white blood cell differentiation reveal IR as a physiological mechanism of gene expression control. IR regulates the expression of 86 functionally related genes, including those that determine the nuclear shape that is unique to granulocytes. Retention of introns in specific genes is associated with downregulation of splicing factors and higher GC content. IR, conserved between human and mouse, led to reduced mRNA and protein levels by triggering the nonsense-mediated decay (NMD) pathway. In contrast to the prevalent view that NMD is limited to mRNAs encoding aberrant proteins, our data establish that IR coupled with NMD is a conserved mechanism in normal granulopoiesis. Physiological IR may provide an energetically favorable level of dynamic gene expression control prior to sustained gene translation.
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•Conserved intron retention (IR) affects 86 genes during granulopoiesis•IR is linked to reduced splicing factor levels and increased intronic GC content•IR triggers nonsense-mediated decay that reduces protein expression•Preventing IR in Lmnb1 reduces granulocyte numbers and alters nuclear volume
Intron retention coupled to nonsense-mediated decay is important not only for the clearance of aberrant transcripts, but also as a conserved regulatory mechanism limiting the expression of dozens of normal genes during granulocyte differentiation.
We describe here the design and initial implementation of the eMERGE‐PGx project. eMERGE‐PGx, a partnership of the Electronic Medical Records and Genomics Network and the Pharmacogenomics Research ...Network, has three objectives: (i) to deploy PGRNseq, a next‐generation sequencing platform assessing sequence variation in 84 proposed pharmacogenes, in nearly 9,000 patients likely to be prescribed drugs of interest in a 1‐ to 3‐year time frame across several clinical sites; (ii) to integrate well‐established clinically validated pharmacogenetic genotypes into the electronic health record with associated clinical decision support and to assess process and clinical outcomes of implementation; and (iii) to develop a repository of pharmacogenetic variants of unknown significance linked to a repository of electronic health record–based clinical phenotype data for ongoing pharmacogenomics discovery. We describe site‐specific project implementation and anticipated products, including genetic variant and phenotype data repositories, novel variant association studies, clinical decision support modules, clinical and process outcomes, approaches to managing incidental findings, and patient and clinician education methods.
Clinical Pharmacology & Therapeutics (2014); 96 4, 482–489. doi:10.1038/clpt.2014.137
While intron retention (IR) is considered a widely conserved and distinct mechanism of gene expression control, its regulation is poorly understood. Here we show that DNA methylation directly ...regulates IR. We also find reduced occupancy of MeCP2 near the splice junctions of retained introns, mirroring the reduced DNA methylation at these sites. Accordingly, MeCP2 depletion in tissues and cells enhances IR. By analysing the MeCP2 interactome using mass spectrometry and RNA co-precipitation, we demonstrate that decreased MeCP2 binding near splice junctions facilitates IR via reduced recruitment of splicing factors, including Tra2b, and increased RNA polymerase II stalling. These results suggest an association between IR and a slower rate of transcription elongation, which reflects inefficient splicing factor recruitment. In summary, our results reinforce the interdependency between alternative splicing involving IR and epigenetic controls of gene expression.
Until recently, retention of introns in mature mRNAs has been regarded as a consequence of mis‐splicing. Intron‐retaining transcripts are thought to be non‐functional because they are readily ...degraded by nonsense‐mediated decay. However, recent advances in next‐generation sequencing technologies have enabled the detection of numerous transcripts that retain introns. As we review herein, intron‐retaining mRNAs play an essential conserved role in normal physiology and an emergent role in diverse diseases. Intron retention should no longer be overlooked as a key mechanism that independently reduces gene expression in normal biology. Exploring its contribution to the development and/or maintenance of diseases is of increasing importance.
Structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is an epigenetic repressor with described roles in X inactivation and genomic imprinting, but Smchd1 is also ...critically involved in the pathogenesis of facioscapulohumeral dystrophy. The underlying molecular mechanism by which Smchd1 functions in these instances remains unknown. Our genome-wide transcriptional and epigenetic analyses show that Smchd1 binds cis -regulatory elements, many of which coincide with CCCTC-binding factor (Ctcf) binding sites, for example, the clustered protocadherin ( Pcdh ) genes, where we show Smchd1 and Ctcf act in opposing ways. We provide biochemical and biophysical evidence that Smchd1âchromatin interactions are established through the homodimeric hinge domain of Smchd1 and, intriguingly, that the hinge domain also has the capacity to bind DNA and RNA. Our results suggest Smchd1 imparts epigenetic regulation via physical association with chromatin, which may antagonize Ctcf-facilitated chromatin interactions, resulting in coordinated transcriptional control.
Intron retention (IR) is a form of alternative splicing that can affect mRNA levels through nonsense-mediated decay or by nuclear mRNA detention. A complex, dynamic IR pattern has been described in ...maturing mammalian granulocytes, but it is unknown whether IR occurs broadly in other hematopoietic lineages. We globally assessed IR in primary maturing mammalian erythroid and megakaryocyte (MK) lineages as well as their common progenitor cells (MEPs). Both lineages exhibit an extensive differential IR program involving hundreds of introns and genes with an overwhelming loss of IR in erythroid cells and MKs compared with MEPs. Moreover, complex IR patterns were seen throughout murine erythroid maturation. Similarly complex patterns were observed in human erythroid differentiation, but not involving the murine orthologous introns or genes. Despite the common origin of erythroid cells and MKs, and overlapping gene expression patterns, the MK IR program is entirely distinct from that of the erythroid lineage with regards to introns, genes, and affected gene ontologies. Importantly, our results suggest that IR serves to broadly regulate mRNA levels. These findings highlight the importance of this understudied form of alternative splicing in gene regulation and provide a useful resource for studies on gene expression in the MK and erythroid lineages.
•Dynamic intron retention programs exist in the murine megakaryocyte and erythroid and human erythroid lineages.•Intron retention inversely correlates with expression levels of a large set of transcripts.
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