Publications by authors named "Francis S Collins"

342 Publications

ARPA-H: Accelerating biomedical breakthroughs.

Science 2021 Jul 22;373(6551):165-167. Epub 2021 Jun 22.

Office of Science and Technology Policy, Executive Office of the President, Washington, DC 20502, USA.

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http://dx.doi.org/10.1126/science.abj8547DOI Listing
July 2021

Affirming NIH's commitment to addressing structural racism in the biomedical research enterprise.

Cell 2021 Jun;184(12):3075-3079

Immediate Office of the Director (IMOD)/OD, NIH, Bethesda, MD 20892, USA.

NIH has acknowledged and committed to ending structural racism. The framework for NIH's approach, summarized here, includes understanding barriers; developing robust health disparities/equity research; improving its internal culture; being transparent and accountable; and changing the extramural ecosystem so that diversity, equity, and inclusion are reflected in funded research and the biomedical workforce.
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http://dx.doi.org/10.1016/j.cell.2021.05.014DOI Listing
June 2021

Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit.

J Infect Dis 2021 Jul;224(Supplement_1):S1-S21

University of Massachusetts Medical School, Worcester, Massachusetts, USA.

The NIH Virtual SARS-CoV-2 Antiviral Summit, held on 6 November 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for coronavirus disease 2019 (COVID-19), including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small-molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development.
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http://dx.doi.org/10.1093/infdis/jiab305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280938PMC
July 2021

SARS-CoV-2 infection induces beta cell transdifferentiation.

Cell Metab 2021 May 19. Epub 2021 May 19.

Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA. Electronic address:

Recent clinical data have suggested a correlation between coronavirus disease 2019 (COVID-19) and diabetes. Here, we describe the detection of SARS-CoV-2 viral antigen in pancreatic beta cells in autopsy samples from individuals with COVID-19. Single-cell RNA sequencing and immunostaining from ex vivo infections confirmed that multiple types of pancreatic islet cells were susceptible to SARS-CoV-2, eliciting a cellular stress response and the induction of chemokines. Upon SARS-CoV-2 infection, beta cells showed a lower expression of insulin and a higher expression of alpha and acinar cell markers, including glucagon and trypsin1, respectively, suggesting cellular transdifferentiation. Trajectory analysis indicated that SARS-CoV-2 induced eIF2-pathway-mediated beta cell transdifferentiation, a phenotype that could be reversed with trans-integrated stress response inhibitor (trans-ISRIB). Altogether, this study demonstrates an example of SARS-CoV-2 infection causing cell fate change, which provides further insight into the pathomechanisms of COVID-19.
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http://dx.doi.org/10.1016/j.cmet.2021.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133495PMC
May 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Genetic effects on liver chromatin accessibility identify disease regulatory variants.

Am J Hum Genet 2021 Jul 25;108(7):1169-1189. Epub 2021 May 25.

Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Identifying the molecular mechanisms by which genome-wide association study (GWAS) loci influence traits remains challenging. Chromatin accessibility quantitative trait loci (caQTLs) help identify GWAS loci that may alter GWAS traits by modulating chromatin structure, but caQTLs have been identified in a limited set of human tissues. Here we mapped caQTLs in human liver tissue in 20 liver samples and identified 3,123 caQTLs. The caQTL variants are enriched in liver tissue promoter and enhancer states and frequently disrupt binding motifs of transcription factors expressed in liver. We predicted target genes for 861 caQTL peaks using proximity, chromatin interactions, correlation with promoter accessibility or gene expression, and colocalization with expression QTLs. Using GWAS signals for 19 liver function and/or cardiometabolic traits, we identified 110 colocalized caQTLs and GWAS signals, 56 of which contained a predicted caPeak target gene. At the LITAF LDL-cholesterol GWAS locus, we validated that a caQTL variant showed allelic differences in protein binding and transcriptional activity. These caQTLs contribute to the epigenomic characterization of human liver and help identify molecular mechanisms and genes at GWAS loci.
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http://dx.doi.org/10.1016/j.ajhg.2021.05.001DOI Listing
July 2021

A Transcription Start Site Map in Human Pancreatic Islets Reveals Functional Regulatory Signatures.

Diabetes 2021 Apr 13. Epub 2021 Apr 13.

Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI

Identifying the tissue-specific molecular signatures of active regulatory elements is critical to understand gene regulatory mechanisms. Here, we identify transcription start sites (TSS) using cap analysis of gene expression (CAGE) across 57 human pancreatic islet samples. We identify 9,954 reproducible CAGE tag clusters (TCs), ∼20% of which are islet specific and occur mostly distal to known gene TSS. We integrated islet CAGE data with histone modification and chromatin accessibility profiles to identify epigenomic signatures of transcription initiation. Using a massively parallel reporter assay, we validated the transcriptional enhancer activity for 2,279 of 3,378 (∼68%) tested islet CAGE elements (5% false discovery rate). TCs within accessible enhancers show higher enrichment to overlap type 2 diabetes genome-wide association study (GWAS) signals than existing islet annotations, which emphasizes the utility of mapping CAGE profiles in disease-relevant tissue. This work provides a high-resolution map of transcriptional initiation in human pancreatic islets with utility for dissecting active enhancers at GWAS loci.
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http://dx.doi.org/10.2337/db20-1087DOI Listing
April 2021

Precision medicine in 2030-seven ways to transform healthcare.

Cell 2021 Mar;184(6):1415-1419

National Institutes of Health, Bethesda, MD, USA.

Precision medicine promises improved health by accounting for individual variability in genes, environment, and lifestyle. Precision medicine will continue to transform healthcare in the coming decade as it expands in key areas: huge cohorts, artificial intelligence (AI), routine clinical genomics, phenomics and environment, and returning value across diverse populations.
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http://dx.doi.org/10.1016/j.cell.2021.01.015DOI Listing
March 2021

A targeted antisense therapeutic approach for Hutchinson-Gilford progeria syndrome.

Nat Med 2021 03 11;27(3):536-545. Epub 2021 Mar 11.

Molecular Genetics Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder characterized by premature death from myocardial infarction or stroke. It is caused by de novo single-nucleotide mutations in the LMNA gene that activate a cryptic splice donor site, resulting in the production of a toxic form of lamin A, which is termed progerin. Here we present a potential genetic therapeutic strategy that utilizes antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to block pathogenic splicing of mutant transcripts. Of several candidates, PPMO SRP-2001 provided the most significant decrease in progerin transcripts in patient fibroblasts. Intravenous delivery of SRP-2001 to a transgenic mouse model of HGPS produced significant reduction of progerin transcripts in the aorta, a particularly critical target tissue in HGPS. Long-term continuous treatment with SRP-2001 yielded a 61.6% increase in lifespan and rescue of vascular smooth muscle cell loss in large arteries. These results provide a rationale for proceeding to human trials.
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http://dx.doi.org/10.1038/s41591-021-01274-0DOI Listing
March 2021

COVID-19 lessons for research.

Science 2021 03;371(6534):1081

Francis S. Collins is the director of the National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1126/science.abh3996DOI Listing
March 2021

In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice.

Nature 2021 01 6;589(7843):608-614. Epub 2021 Jan 6.

Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Hutchinson-Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years. Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates. Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fibroblasts from children with HGPS resulted in 87-91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20-60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause.
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http://dx.doi.org/10.1038/s41586-020-03086-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872200PMC
January 2021

Human Molecular Genetics and Genomics - Important Advances and Exciting Possibilities.

N Engl J Med 2021 Jan 2;384(1):1-4. Epub 2021 Jan 2.

From the National Institutes of Health, Bethesda, MD (F.S.C., C.N.R.); the Department of Molecular and Cell Biology and the Department of Chemistry, University of California, Berkeley, Berkeley (J.A.D.); and the Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA (E.S.L.).

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http://dx.doi.org/10.1056/NEJMp2030694DOI Listing
January 2021

Differentiating Moebius syndrome and other congenital facial weakness disorders with electrodiagnostic studies.

Muscle Nerve 2021 04 19;63(4):516-524. Epub 2021 Jan 19.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Introduction: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW.

Methods: Forty-three subjects enrolled prospectively into a dedicated clinical protocol and had EDx evaluations, including blink reflex and facial and peripheral nerve conduction studies, with optional needle electromyography.

Results: MBS and hereditary congenital facial paresis (HCFP) subjects had low-amplitude cranial nerve 7 responses without other neuropathic or myopathic findings. Carriers of specific pathogenic variants in TUBB3 had, in addition, a generalized sensorimotor axonal polyneuropathy with demyelinating features. Myopathic findings were detected in individuals with Carey-Fineman-Ziter syndrome, myotonic dystrophy, other undefined myopathies, or CFW with arthrogryposis, ophthalmoplegia, and other system involvement.

Discussion: EDx in CFW subjects can assist in characterizing the underlying pathogenesis, as well as guide diagnosis and genetic counseling.
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http://dx.doi.org/10.1002/mus.27159DOI Listing
April 2021

Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D.

Nat Commun 2020 09 30;11(1):4912. Epub 2020 Sep 30.

Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA.

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.
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http://dx.doi.org/10.1038/s41467-020-18581-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528108PMC
September 2020

Recognition of Research Participants' Need for Autonomy: Remembering the Legacy of Henrietta Lacks.

JAMA 2020 Sep;324(11):1027-1028

National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jama.2020.15936DOI Listing
September 2020

Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences.

PLoS Genet 2020 09 11;16(9):e1009019. Epub 2020 Sep 11.

Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America.

Loci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified in the Metabolic Syndrome in Men (METSIM) study. With GWAS data for 9,262 men, four loci were significantly associated with adiponectin: ADIPOQ, CDH13, IRS1, and PBRM1. We performed stepwise conditional analyses to identify distinct association signals, a subset of which are also nearly independent (lead variant pairwise r2<0.01). Two loci exhibited allelic heterogeneity, ADIPOQ and CDH13. Of seven association signals at the ADIPOQ locus, two signals colocalized with adipose tissue expression quantitative trait loci (eQTLs) for three transcripts: trait-increasing alleles at one signal were associated with increased ADIPOQ and LINC02043, while trait-increasing alleles at the other signal were associated with decreased ADIPOQ-AS1. In reporter assays, adiponectin-increasing alleles at two signals showed corresponding directions of effect on transcriptional activity. Putative mechanisms for the seven ADIPOQ signals include a missense variant (ADIPOQ G90S), a splice variant, a promoter variant, and four enhancer variants. Of two association signals at the CDH13 locus, the first signal consisted of promoter variants, including the lead adipose tissue eQTL variant for CDH13, while a second signal included a distal intron 1 enhancer variant that showed ~2-fold allelic differences in transcriptional reporter activity. Fine-mapping and experimental validation demonstrated that multiple, distinct association signals at these loci can influence multiple transcripts through multiple molecular mechanisms.
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http://dx.doi.org/10.1371/journal.pgen.1009019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511027PMC
September 2020

ACE2 expression in adipose tissue is associated with COVID-19 cardio-metabolic risk factors and cell type composition.

medRxiv 2020 Aug 14. Epub 2020 Aug 14.

COVID-19 severity has varied widely, with demographic and cardio-metabolic factors increasing risk of severe reactions to SARS-CoV-2 infection, but the underlying mechanisms for this remain uncertain. We investigated phenotypic and genetic factors associated with subcutaneous adipose tissue expression of Angiotensin I Converting Enzyme 2 ( ), which has been shown to act as a receptor for SARS-CoV-2 cellular entry. In a meta-analysis of three independent studies including up to 1,471 participants, lower adipose tissue expression was associated with adverse cardio-metabolic health indices including type 2 diabetes (T2D) and obesity status, higher serum fasting insulin and BMI, and lower serum HDL levels (P<5.32x10 ). expression levels were also associated with estimated proportions of cell types in adipose tissue; lower expression was associated with a lower proportion of microvascular endothelial cells (P=4.25x10 ) and higher macrophage proportion (P=2.74x10 ), suggesting a link to inflammation. Despite an estimated heritability of 32%, we did not identify any proximal or distal genetic variants (eQTLs) associated with adipose tissue expression. Our results demonstrate that at-risk individuals have lower background levels in this highly relevant tissue. Further studies will be required to establish how this may contribute to increased COVID-19 severity.
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http://dx.doi.org/10.1101/2020.08.11.20171108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430606PMC
August 2020

Recognition of Research Participants' Need for Autonomy: Remembering the Legacy of Henrietta Lacks.

JAMA 2020 Aug 11. Epub 2020 Aug 11.

National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jama.2020.15936DOI Listing
August 2020

Precision Nutrition-the Answer to "What to Eat to Stay Healthy".

JAMA 2020 Aug;324(8):735-736

National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jama.2020.13601DOI Listing
August 2020

Rapid Scaling Up of Covid-19 Diagnostic Testing in the United States - The NIH RADx Initiative.

N Engl J Med 2020 09 22;383(11):1071-1077. Epub 2020 Jul 22.

From the National Institute of Biomedical Imaging and Bioengineering (B.J.T.), the National Institute of Nursing Research (T.A.S.), the Office of the Director (T.A.S., R.A.B., R.L.F., F.S.C.), the National Institute on Minority Health and Health Disparities (E.J.P.-S.), the National Institute on Aging (R.J.H.), and the National Institute of Environmental Health Sciences, National Toxicology Program (R.P.W.), National Institutes of Health, Bethesda, MD.

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http://dx.doi.org/10.1056/NEJMsr2022263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493127PMC
September 2020

Combating sexual harassment.

Science 2020 Jun 11;368(6497):1291. Epub 2020 Jun 11.

Francis S. Collins is the director of the National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1126/science.abd2644DOI Listing
June 2020

Evaluation of musculoskeletal phenotype of the G608G progeria mouse model with lonafarnib, pravastatin, and zoledronic acid as treatment groups.

Proc Natl Acad Sci U S A 2020 06 13;117(22):12029-12040. Epub 2020 May 13.

Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215;

Hutchinson-Gilford progeria syndrome (HGPS) is a uniformly fatal condition that is especially prevalent in skin, cardiovascular, and musculoskeletal systems. A wide gap exists between our knowledge of the disease and a promising treatment or cure. The aim of this study was to first characterize the musculoskeletal phenotype of the homozygous G608G BAC-transgenic progeria mouse model, and to determine the phenotype changes of HGPS mice after a five-arm preclinical trial of different treatment combinations with lonafarnib, pravastatin, and zoledronic acid. Microcomputed tomography and CT-based rigidity analyses were performed to assess cortical and trabecular bone structure, density, and rigidity. Bones were loaded to failure with three-point bending to assess strength. Contrast-enhanced µCT imaging of mouse femurs was performed to measure glycosaminoglycan content, thickness, and volume of the femoral head articular cartilage. Advanced glycation end products were assessed with a fluorometric assay. The changes demonstrated in the cortical bone structure, rigidity, stiffness, and modulus of the HGPS G608G mouse model may increase the risk for bending and deformation, which could result in the skeletal dysplasia characteristic of HGPS. Cartilage abnormalities seen in this HGPS model resemble changes observed in the age-matched WT controls, including early loss of glycosaminoglycans, and decreased cartilage thickness and volume. Such changes might mimic prevalent degenerative joint diseases in the elderly. Lonafarnib monotherapy did not improve bone or cartilage parameters, but treatment combinations with pravastatin and zoledronic acid significantly improved bone structure and mechanical properties and cartilage structural parameters, which ameliorate the musculoskeletal phenotype of the disease.
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http://dx.doi.org/10.1073/pnas.1906713117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275760PMC
June 2020

A strategic approach to COVID-19 vaccine R&D.

Science 2020 05 11;368(6494):948-950. Epub 2020 May 11.

National Institutes of Health, Bethesda, MD 20892, USA.

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http://dx.doi.org/10.1126/science.abc5312DOI Listing
May 2020

Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry.

Brain Commun 2020 14;2(1):fcaa014. Epub 2020 Feb 14.

Quantitative Medical Imaging Section, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, USA.

In this study, we used a novel imaging technique, DTI (diffusion tensor imaging)-driven tensor-based morphometry, to investigate brain anatomy in subjects diagnosed with Moebius syndrome ( = 21), other congenital facial weakness disorders ( = 9) and healthy controls ( = 15). First, we selected a subgroup of subjects who satisfied the minimum diagnostic criteria for Moebius syndrome with only mild additional neurological findings. Compared to controls, in this cohort, we found a small region of highly significant volumetric reduction in the paramedian pontine reticular formation and the medial longitudinal fasciculus, important structures for the initiation and coordination of conjugate horizontal gaze. Subsequently, we tested if volume measurements from this region could help differentiate individual subjects of the different cohorts that were included in our study. We found that this region allowed discriminating Moebius syndrome subjects from congenital facial weakness disorders and healthy controls with high sensitivity (94%) and specificity (89%). Interestingly, this region was normal in congenital facial weakness subjects with oculomotor deficits of myopathic origin, who would have been classified as Moebius on the basis of purely clinical diagnostic criteria, indicating a potential role for diffusion MRI morphometry for differential diagnosis in this condition. When the entire Moebius syndrome cohort was compared to healthy controls, in addition to this 'landmark' region, other areas of significantly reduced volume in the brainstem emerged, including the location of the nuclei and fibres of cranial nerve VI (abducens nerve), and fibres of cranial nerve VII (facial nerve), and a more rostral portion of the medial longitudinal fasciculus. The high sensitivity and specificity of DTI-driven tensor-based morphometry in reliably detecting very small areas of volumetric abnormality found in this study suggest broader applications of this analysis in personalized medicine to detect hypoplasia or atrophy of small pathways and/or brainstem nuclei in other neurological disorders.
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http://dx.doi.org/10.1093/braincomms/fcaa014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158234PMC
February 2020

Single-cell ATAC-Seq in human pancreatic islets and deep learning upscaling of rare cells reveals cell-specific type 2 diabetes regulatory signatures.

Mol Metab 2020 02 20;32:109-121. Epub 2019 Dec 20.

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address:

Objective: Type 2 diabetes (T2D) is a complex disease characterized by pancreatic islet dysfunction, insulin resistance, and disruption of blood glucose levels. Genome-wide association studies (GWAS) have identified > 400 independent signals that encode genetic predisposition. More than 90% of associated single-nucleotide polymorphisms (SNPs) localize to non-coding regions and are enriched in chromatin-defined islet enhancer elements, indicating a strong transcriptional regulatory component to disease susceptibility. Pancreatic islets are a mixture of cell types that express distinct hormonal programs, so each cell type may contribute differentially to the underlying regulatory processes that modulate T2D-associated transcriptional circuits. Existing chromatin profiling methods such as ATAC-seq and DNase-seq, applied to islets in bulk, produce aggregate profiles that mask important cellular and regulatory heterogeneity.

Methods: We present genome-wide single-cell chromatin accessibility profiles in >1,600 cells derived from a human pancreatic islet sample using single-cell combinatorial indexing ATAC-seq (sci-ATAC-seq). We also developed a deep learning model based on U-Net architecture to accurately predict open chromatin peak calls in rare cell populations.

Results: We show that sci-ATAC-seq profiles allow us to deconvolve alpha, beta, and delta cell populations and identify cell-type-specific regulatory signatures underlying T2D. Particularly, T2D GWAS SNPs are significantly enriched in beta cell-specific and across cell-type shared islet open chromatin, but not in alpha or delta cell-specific open chromatin. We also demonstrate, using less abundant delta cells, that deep learning models can improve signal recovery and feature reconstruction of rarer cell populations. Finally, we use co-accessibility measures to nominate the cell-specific target genes at 104 non-coding T2D GWAS signals.

Conclusions: Collectively, we identify the islet cell type of action across genetic signals of T2D predisposition and provide higher-resolution mechanistic insights into genetically encoded risk pathways.
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http://dx.doi.org/10.1016/j.molmet.2019.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961712PMC
February 2020

Single-cell transcriptomics from human pancreatic islets: sample preparation matters.

Biol Methods Protoc 2020 16;5(1):bpz019. Epub 2020 Jan 16.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Single-cell RNA sequencing (scRNA-seq) of human primary tissues is a rapidly emerging tool for investigating human health and disease at the molecular level. However, optimal processing of solid tissues presents a number of technical and logistical challenges, especially for tissues that are only available at autopsy, which includes pancreatic islets, a tissue that is highly relevant to diabetes. To assess the possible effects of different sample preparation protocols on fresh islet samples, we performed a detailed comparison of scRNA-seq data generated with islets isolated from a human donor but processed according to four treatment strategies, including fixation and cryopreservation. We found significant and reproducible differences in the proportion of cell types identified, and more minor effects on cell-specific patterns of gene expression. Fresh islets from a second donor confirmed gene expression signatures of alpha and beta subclusters. These findings may well apply to other tissues, emphasizing the need for careful consideration when choosing processing methods, comparing results between different studies, and/or interpreting data in the context of multiple cell types from preserved tissue.
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http://dx.doi.org/10.1093/biomethods/bpz019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964677PMC
January 2020

Colocalization of GWAS and eQTL signals at loci with multiple signals identifies additional candidate genes for body fat distribution.

Hum Mol Genet 2019 12;28(24):4161-4172

Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.

Integration of genome-wide association study (GWAS) signals with expression quantitative trait loci (eQTL) studies enables identification of candidate genes. However, evaluating whether nearby signals may share causal variants, termed colocalization, is affected by the presence of allelic heterogeneity, different variants at the same locus impacting the same phenotype. We previously identified eQTL in subcutaneous adipose tissue from 770 participants in the Metabolic Syndrome in Men (METSIM) study and detected 15 eQTL signals that colocalized with GWAS signals for waist-hip ratio adjusted for body mass index (WHRadjBMI) from the Genetic Investigation of Anthropometric Traits consortium. Here, we reevaluated evidence of colocalization using two approaches, conditional analysis and the Bayesian test COLOC, and show that providing COLOC with approximate conditional summary statistics at multi-signal GWAS loci can reconcile disagreements in colocalization classification between the two tests. Next, we performed conditional analysis on the METSIM subcutaneous adipose tissue data to identify conditionally distinct or secondary eQTL signals. We used the two approaches to test for colocalization with WHRadjBMI GWAS signals and evaluated the differences in colocalization classification between the two tests. Through these analyses, we identified four GWAS signals colocalized with secondary eQTL signals for FAM13A, SSR3, GRB14 and FMO1. Thus, at loci with multiple eQTL and/or GWAS signals, analyzing each signal independently enabled additional candidate genes to be identified.
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http://dx.doi.org/10.1093/hmg/ddz263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202621PMC
December 2019

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019