Selected Grantee Publications
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- Genetics
- Spectrometry
The Monarch Initiative in 2024: An Analytic Platform Integrating Phenotypes, Genes and Diseases Across Species
Putman et al., Nucleic Acids Research. 2024.
https://pubmed.ncbi.nlm.nih.gov/38000386/
The Monarch Initiative aims to bridge the gap between the genetic variations, environmental determinants, and phenotypic outcomes critical for translational research. The Monarch app provides researchers access to curated data sets with information on genes, phenotypes, and diseases across species and advanced analysis tools for such diverse applications as variant prioritization, deep phenotyping, and patient profile matching. Researchers describe upgrades to the app, including scalable cloud-based infrastructure, simplified data ingestion and knowledge graph integration systems, enhanced data mapping and integration standards, and a new user interface with novel search and graph navigation features. A customized plugin for OpenAI’s ChatGPT allows the use of large language models to interrogate knowledge in the Monarch graph and increase the reliability of the responses of Monarch’s analytic tools. These upgrades will enhance clinical diagnosis and the understanding of disease mechanisms. Supported by ORIP (R24OD011883), NLM, and NHGRI.
Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population
Cruz Cisneros et al., Vaccines. 2024.
https://pubmed.ncbi.nlm.nih.gov/38276675/
The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. Although host genetic factors are known to affect vaccine efficacy for such respiratory pathogens as influenza and tuberculosis, the impact of host genetic variation on vaccine efficacy against COVID-19 is not well understood. Investigators used the diversity outbred mouse model to study the effects of genetic variation on vaccine efficiency. Data indicate that variations in vaccine response in mice are heritable, similar to that in human populations. Supported by ORIP (U42OD010924), NIAID, and NIGMS.
The Landscape of SETBP1 Gene Expression and Transcription Factor Activity Across Human Tissues
Whitlock et al., PLOS One. 2024.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0296328
The SET binding protein 1 (SETBP1) gene encodes a transcription factor (TF) involved in various cellular processes. Variants in SETBP1 can result in different diseases determined by the introduction (i.e., germline vs. somatic) and location of the variant. To better understand the tissue-specific mechanisms involving SETBP1, investigators analyzed publicly available RNA-sequencing data from the Genotype-Tissue Expression project. This study provides insight into the landscape of SETBP1 expression across 31 non-diseased human tissues and reveals tissue-specific expression and activity of SETBP1 and its targets. Supported by ORIP (U54OD030167) and NIGMS.
Stable HIV Decoy Receptor Expression After In Vivo HSC Transduction in Mice and NHPs: Safety and Efficacy in Protection From SHIV
Li, Molecular Therapy. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124088/
Autologous hematopoietic stem cell (HSC) gene therapy offers a promising HIV treatment strategy, but cost, complexity, and toxicity remain significant challenges. Using female mice and female nonhuman primates (NHPs) (i.e., rhesus macaques), researchers developed an approach based on the stable expression of eCD4-Ig, a secreted decoy protein for HIV and simian–human immunodeficiency virus (SHIV) receptors. Their goals were to (1) assess the kinetics and serum level of eCD4-Ig, (2) evaluate the safety of HSC transduction with helper-dependent adenovirus–eCD4-Ig, and (3) test whether eCD4-Ig expression has a protective effect against viral challenge. They found that stable expression of the decoy receptor was achieved at therapeutically relevant levels. These data will guide future in vivo studies. Supported by ORIP (P51OD010425) and NHLBI.
Lymphoid Tissues Contribute to Plasma Viral Clonotypes Early After Antiretroviral Therapy Interruption in SIV-Infected Rhesus Macaques
Solis-Leal et al., Science Translational Medicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/38091409/
Researchers are interested in better understanding the sources, timing, and mechanisms of HIV rebound that occurs after interruption of antiretroviral therapy (ART). Using rhesus macaques (sex not specified), investigators tracked barcoded simian immunodeficiency virus (SIV) clonotypes over time and among tissues. Among the tissues studied, mesenteric lymph nodes, inguinal lymph nodes, and spleen contained viral barcodes detected in plasma. Additionally, the authors reported that CD4+ T cells harbored the most viral RNA after ART interruption. These tissues are likely to contribute to viral reactivation and rebound after ART interruption, but further studies are needed to evaluate the relative potential contributions from other tissues and organs. Supported by ORIP (P51OD011104, P51OD011133, S10OD028732, S10OD028653), NCI, NIMH, and NINDS.
Antiretroviral Therapy Reveals Triphasic Decay of Intact SIV Genomes and Persistence of Ancestral Variants
Fray et al., Cell Host & Microbe. 2023.
https://doi.org/10.1016/j.chom.2023.01.016
Antiretroviral therapy (ART) halts HIV-1 replication but is not curative; a pool of latently infected CD4+ T cells persists, and viremia rapidly rebounds if ART is stopped. Using an intact proviral DNA assay, researchers characterized quantitative and qualitative changes in CD4+ T cells for 4 years following ART initiation in rhesus macaques of both sexes. They found that viruses replicating at ART initiation had mutations conferring antibody escape, and sequences with large numbers of antibody escape mutations became less abundant at later time points. Together, these findings reveal that the population of simian immunodeficiency virus (SIV)–infected CD4+ T cells is dynamic and provide a framework for evaluating and interpreting intervention trials. Supported by ORIP (R01OD011095), NIAID, and NIDCR.
Age-Associated DNA Methylation Changes in Xenopus Frogs
Morselli et al., Epigenetics. 2023.
https://www.tandfonline.com/doi/full/10.1080/15592294.2023.2201517
Age-associated changes in DNA methylation have not been characterized yet in amphibians, which include widely studied model organisms. Here the authors present clear evidence that the aquatic vertebrate species Xenopus tropicalis displays patterns of age-associated changes in DNA methylation. Whole-genome bisulfite sequencing profiles from skin samples of frogs representing young, mature, and old adults demonstrated that many of the methylation features and changes they observed are consistent with what is known in mammalian species, suggesting that the mechanism of age-related changes is conserved. The results of this study will allow researchers to leverage the unique resources available for Xenopus to study how DNA methylation relates to other hallmarks of aging. Supported by ORIP (P40OD010997, R24OD031956, R24OD030008) and NICHD.
Prime Editing–Mediated Correction of the CFTR W1282X Mutation in iPSCs and Derived Airway Epithelial Cells
Li et al., PLOS ONE. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10686454/
Cystic fibrosis (CF) is caused by recessive mutations in the CF transmembrane conductance regulator (CFTR) gene. Correction of nonsense CFTR mutations, which affects 10% of CF patients, via genomic editing represents a promising therapeutic approach. In this study, investigators tested whether prime editing can be applied as a potential therapeutic modality. Induced pluripotent stem cells (iPSCs) from a CF patient homozygous for the CFTR W1282X mutation were used. Studies demonstrated that prime editing corrected mutant allele in iPSCs, which effectively restored CFTR function in iPSC-derived airway epithelial cells and organoids. Supported by ORIP (R01OD01026594).
Broad Receptor Tropism and Immunogenicity of a Clade 3 Sarbecovirus
Lee et al., Cell Host and Microbe. 2023.
https://www.sciencedirect.com/science/article/pii/S1931312823004225
Investigators showed that the S glycoprotein of the clade 3 sarbecovirus PRD-0038 in the African Rhinolophus bat has a broad angiotensin-converting enzyme 2 (ACE2) usage and that receptor-binding domain (RBD) mutations further expand receptor promiscuity and enable human ACE2 utilization. They generated a cryogenic electron microscopy structure of the RBD bound to ACE2, explaining receptor tropism and highlighting differences between SARS-CoV-1 and SARS-CoV-2. PRD‑0038 S vaccination elicits greater titers of antibodies cross-reacting with vaccine-mismatched clade 2 and clade 1a sarbecoviruses, compared with SARS-CoV-2. These findings underline a potential molecular pathway for zoonotic spillover of a clade 3 sarbecovirus, as well as the need to develop pan-sarbecovirus vaccines and countermeasures. Supported by ORIP (S10OD032290, S10OD026959, S10OD021644), NIAID, NCI, and NIGMS.
DAZL Knockout Pigs as Recipients for Spermatogonial Stem Cell Transplantation
Lara et al., Cells. 2023.
https://pubmed.ncbi.nlm.nih.gov/37947660/
Spermatogonial stem cell (SSC) transplantation is a technique that holds potential for addressing male infertility, as well as generation of genetically modified animal models. DAZL (Deleted in Azoospermia–Like) is a conserved RNA-binding protein important for germ cell development, and DAZL knockout (KO) causes defects in germ cell commitment and differentiation. Investigators characterized DAZL-KO pigs as SSC transplantation recipients. DAZL-KO pigs support donor-derived spermatogenesis following SSC transplantation, but low spermatogenic efficiency currently limits their use for the production of offspring. Supported by ORIP (R01OD016575) and NIGMS.