Publications by authors named "Greg Barsh"

12 Publications

  • Page 1 of 1

Genetic regulation of nonsense-mediated decay underlies association with risk of severe COVID-19.

medRxiv 2021 Jul 13. Epub 2021 Jul 13.

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of . We suggest that genetically-regulated loss of expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the risk haplotypes.
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http://dx.doi.org/10.1101/2021.07.09.21260221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288155PMC
July 2021

Verifying nomenclature of DNA variants in submitted manuscripts: Guidance for journals.

Hum Mutat 2021 Jan 10;42(1):3-7. Epub 2020 Dec 10.

Department of Genetic Medicine, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Documenting variation in our genomes is important for research and clinical care. Accuracy in the description of DNA variants is therefore essential. To address this issue, the Human Variome Project convened a committee to evaluate the feasibility of requiring authors to verify that all variants submitted for publication complied with a widely accepted standard for description. After a pilot study of two journals, the committee agreed that requiring authors to verify that variants complied with Human Genome Variation Society nomenclature is a reasonable step toward standardizing the worldwide inventory of human variation.
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http://dx.doi.org/10.1002/humu.24144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961887PMC
January 2021

Melanoma to Vitiligo: The Melanocyte in Biology & Medicine-Joint Montagna Symposium on the Biology of Skin/PanAmerican Society for Pigment Cell Research Annual Meeting.

J Invest Dermatol 2020 02 23;140(2):269-274. Epub 2019 Jul 23.

Department of Dermatology, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.03.1164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981008PMC
February 2020

Return of raw data in genomic testing and research: ownership, partnership, and risk-benefit.

Genet Med 2020 01 17;22(1):12-14. Epub 2019 Jul 17.

HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.

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http://dx.doi.org/10.1038/s41436-019-0607-xDOI Listing
January 2020

Eliciting preferences on secondary findings: the Preferences Instrument for Genomic Secondary Results.

Genet Med 2017 03 25;19(3):337-344. Epub 2016 Aug 25.

Center for Biomedical Ethics and Society, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Purpose: Eliciting and understanding patient and research participant preferences regarding return of secondary test results are key aspects of genomic medicine. A valid instrument should be easily understood without extensive pretest counseling while still faithfully eliciting patients' preferences.

Methods: We conducted focus groups with 110 adults to understand patient perspectives on secondary genomic findings and the role that preferences should play. We then developed and refined a draft instrument and used it to elicit preferences from parents participating in a genomic sequencing study in children with intellectual disabilities.

Results: Patients preferred filtering of secondary genomic results to avoid information overload and to avoid learning what the future holds, among other reasons. Patients preferred to make autonomous choices about which categories of results to receive and to have their choices applied automatically before results are returned to them and their clinicians. The Preferences Instrument for Genomic Secondary Results (PIGSR) is designed to be completed by patients or research participants without assistance and to guide bioinformatic analysis of genomic raw data. Most participants wanted to receive all secondary results, but a significant minority indicated other preferences.

Conclusions: Our novel instrument-PIGSR-should be useful in a wide variety of clinical and research settings.Genet Med 19 3, 337-344.
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http://dx.doi.org/10.1038/gim.2016.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326612PMC
March 2017

A candidate mechanism underlying the variance of interictal spike propagation.

J Neurosci 2012 Feb;32(9):3009-21

Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Synchronous activation of neural networks is an important physiological mechanism, and dysregulation of synchrony forms the basis of epilepsy. We analyzed the propagation of synchronous activity through chronically epileptic neural networks. Electrocorticographic recordings from epileptic patients demonstrate remarkable variance in the pathways of propagation between sequential interictal spikes (IISs). Calcium imaging in chronically epileptic slice cultures demonstrates that pathway variance depends on the presence of GABAergic inhibition and that spike propagation becomes stereotyped following GABA receptor blockade. Computer modeling suggests that GABAergic quenching of local network activations leaves behind regions of refractory neurons, whose late recruitment forms the anatomical basis of variability during subsequent network activation. Targeted path scanning of slice cultures confirmed local activations, while ex vivo recordings of human epileptic tissue confirmed the dependence of interspike variance on GABA-mediated inhibition. These data support the hypothesis that the paths by which synchronous activity spreads through an epileptic network change with each activation, based on the recent history of localized activity that has been successfully inhibited.
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http://dx.doi.org/10.1523/JNEUROSCI.5853-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319688PMC
February 2012

Tabby pattern genetics - a whole new breed of cat.

Pigment Cell Melanoma Res 2010 Aug 26;23(4):514-6. Epub 2010 May 26.

Department of Genetics, Stanford University, Stanford, CA, USA.

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http://dx.doi.org/10.1111/j.1755-148X.2010.00723.xDOI Listing
August 2010

How hair gets its pigment.

Cell 2007 Sep;130(5):779-81

Department of Genetics, Stanford School of Medicine, Stanford, CA 94305, USA.

Mutations in the transcription factor Foxn1 cause the nude phenotype in mice, which is characterized by a lack of visible hair. New work by Weiner et al. (2007) in this issue of Cell now shows that Foxn1 also contributes to hair color by marking which cells are to receive pigment from melanocytes.
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http://dx.doi.org/10.1016/j.cell.2007.08.032DOI Listing
September 2007

Genitopatellar syndrome: expanding the phenotype and excluding mutations in LMX1B and TBX4.

Am J Med Genet A 2006 Jul;140(14):1567-72

Division of Medical Genetics, Department of Preventive Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Genitopatellar syndrome is a newly described disorder characterized by absent/hypoplastic patellae, lower extremity contractures, urogenital anomalies, dysmorphic features, skeletal anomalies, and agenesis of the corpus callosum. More recently, cardiac anomalies and ectodermal dysplasia have been suggested as additional features of this syndrome. We report on two additional patients with genitopatellar syndrome and expand the spectrum of anomalies to include radio-ulnar synostosis. Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail-patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed. Although there still does not appear to be an identifiable molecular etiology in genitopatellar syndrome, mutations in these two candidate genes have been excluded in our patients. Since both LMX1B and TBX4 are involved in a common molecular pathway, it is likely that the causative gene of genitopatellar syndrome functions within the same developmental process.
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http://dx.doi.org/10.1002/ajmg.a.31258DOI Listing
July 2006

Microarray profiling of human skeletal muscle reveals that insulin regulates approximately 800 genes during a hyperinsulinemic clamp.

J Biol Chem 2003 May 5;278(20):18063-8. Epub 2003 Mar 5.

INSERM U.449 and Human Nutrition Research Center of Lyon, Faculty of Medicine R. Laennec, Lyon Cédex 08, France.

Insulin action in target tissues involved precise regulation of gene expression. To define the set of insulin-regulated genes in human skeletal muscle, we analyzed the global changes in mRNA levels during a 3-h hyperinsulinemic euglycemic clamp in vastus lateralis muscle of six healthy subjects. Using 29,308 cDNA element microarrays, we found that the mRNA expression of 762 genes, including 353 expressed sequence tags, was significantly modified during insulin infusion. 478 were up-regulated and 284 down-regulated. Most of the genes with known function are novel targets of insulin. They are involved in the transcriptional and translational regulation (29%), intermediary and energy metabolisms (14%), intracellular signaling (12%), and cytoskeleton and vesicle traffic (9%). Other categories consisted of genes coding for receptors, carriers, and transporters (8%), components of the ubiquitin/proteasome pathways (7%) and elements of the immune response (5.5%). These results thus define a transcriptional signature of insulin action in human skeletal muscle. They will help to better define the mechanisms involved in the reduction of insulin effectiveness in pathologies such as type 2 diabetes mellitus, a disease characterized by defective regulation of gene expression in response to insulin.
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http://dx.doi.org/10.1074/jbc.M300293200DOI Listing
May 2003

The mouse Kreisler (Krml1/MafB) segmentation gene is required for differentiation of glomerular visceral epithelial cells.

Dev Biol 2002 Sep;249(1):16-29

Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada.

Molecular components of the glomerular filtration mechanism play critical roles in renal diseases. Many of these components are produced during the final stages of differentiation of glomerular visceral epithelial cells, also known as podocytes. While basic domain leucine zipper (bZip) transcription factors of the Maf subfamily have been implicated in cellular differentiation processes, Kreisler (Krml1/MafB), the gene affected in the mouse kreisler (kr) mutation, is known for its role in hindbrain patterning. Here we show that mice homozygous for the kr(enu) mutation develop renal disease and that Kreisler is essential for cellular differentiation of podocytes. Consistent with abnormal podocyte differentiation, kr(enu) homozygotes show proteinuria, and fusion and effacement of podocyte foot processes, which are also observed in the nephrotic syndrome. Kreisler acts during the final stages of glomerular development-the transition between the capillary loop and mature stages-and downstream of the Pod1 basic domain helix-loop-helix transcription factor. The levels of Podocin, the gene mutated in autosomal recessive steroid-resistant nephrotic syndrome (NPHS2), and Nephrin, the gene mutated in congenital nephrotic syndrome of the Finnish type (NPHS1), are slightly reduced in kr(enu)/kr(enu) podocytes. However, these observations alone are unlikely to account for the aberrant podocyte foot process formation. Thus, Kreisler must regulate other unknown genes required for podocyte function and with possible roles in kidney disease.
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http://dx.doi.org/10.1006/dbio.2002.0751DOI Listing
September 2002

In vivo regulation of human skeletal muscle gene expression by thyroid hormone.

Genome Res 2002 Feb;12(2):281-91

Department of Pediatrics and Genetics, Howard Hughes Medical Institute, Beckman Center, Stanford University School of Medicine, Stanford, California 94305, USA.

Thyroid hormones are key regulators of metabolism that modulate transcription via nuclear receptors. Hyperthyroidism is associated with increased metabolic rate, protein breakdown, and weight loss. Although the molecular actions of thyroid hormones have been studied thoroughly, their pleiotropic effects are mediated by complex changes in expression of an unknown number of target genes. Here, we measured patterns of skeletal muscle gene expression in five healthy men treated for 14 days with 75 microg of triiodothyronine, using 24,000 cDNA element microarrays. To analyze the data, we used a new statistical method that identifies significant changes in expression and estimates the false discovery rate. The 381 up-regulated genes were involved in a wide range of cellular functions including transcriptional control, mRNA maturation, protein turnover, signal transduction, cellular trafficking, and energy metabolism. Only two genes were down-regulated. Most of the genes are novel targets of thyroid hormone. Cluster analysis of triiodothyronine-regulated gene expression among 19 different human tissues or cell lines revealed sets of coregulated genes that serve similar biologic functions. These results define molecular signatures that help to understand the physiology and pathophysiology of thyroid hormone action.
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http://dx.doi.org/10.1101/gr.207702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC155277PMC
February 2002
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