Selected Grantee Publications
Identification of Constrained Sequence Elements Across 239 Primate Genomes
Kuderna et al., Nature. 2024.
https://pubmed.ncbi.nlm.nih.gov/38030727/
Functional genomic elements that have acquired selective constraints specific to the primate order are prime candidates for understanding evolutionary changes in humans, but the selective constraints specific to the phylogenetic branch from which the human species ultimately emerged remain largely unidentified. Researchers constructed a genome-wide multiple sequence alignment of 239 primate species to better characterize constraint at noncoding regulatory sequences in the human genome. Their work reveals noncoding regulatory elements that are under selective constraint in primates but not in other placental mammals and are enriched for variants that affect human gene expression and complex traits in diseases. These findings highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals. Supported by ORIP (P40OD024628), NHGRI, NIA, and NICHD.
GenomeMUSter Mouse Genetic Variation Service Enables Multitrait, Multipopulation Data Integration and Analysis
Ball et al., Genome Research. 2024.
https://genome.cshlp.org/content/34/1/145.long
Advances in genetics, including transcriptome-wide and phenome-wide association analysis methods, create compelling new opportunities for using fully reproducible and widely studied inbred mouse strains to characterize the polygenetic basis for individual differences in disease-related traits. Investigators developed an imputation approach and implemented data service to provide a broad and more comprehensive mouse variant resource. They evaluated the strain-specific imputation accuracy on a “held-out” test set that was not used in the imputation process. The authors present its application to multipopulation and multispecies analyses of complex trait variation in type 2 diabetes and substance use disorders and compare these results to human genetics studies. Supported by ORIP (U42OD010921, P40OD011102, R24OD035408), NCI, NIAAA, NIDA, and NIDCD.
Preclinical Safety and Biodistribution of CRISPR Targeting SIV in Non-Human Primates
Burdo et al., Gene Therapy. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11090835/
Nonhuman primates have served as a valuable resource for evaluating novel eradication and cure strategies for HIV infection. Using a male rhesus macaque model, researchers demonstrated the safety and utility of CRISPR gene-editing technology for targeting integrated simian immunodeficiency virus (SIV). Their work suggests that a single intravenous inoculation for HIV gene editing can be utilized to reach viral reservoirs throughout the body. Additionally, no off-target effects or abnormal pathology were observed. Together, these findings support the continued development of HIV eradicative cure strategies using CRISPR technology in humans. Supported by ORIP (P40OD012217, U42OD021458).
The Gene Expression Profile and Cell of Origin of Canine Peripheral T-Cell Lymphoma
Owens et al., BMC Cancer. 2024.
https://pubmed.ncbi.nlm.nih.gov/38166662/
Peripheral T-cell lymphoma (PTCL) refers to a heterogenous group of T-cell neoplasms with poor treatment responses and survival times. Canine PTCL clinically and immunophenotypically resembles the most common human subtype, PTCL-NOS (PTCL-not otherwise specified), and is a naturally occurring model for human PTCL. Gene expression profiling in human PTCL-NOS has helped characterize this ambiguous diagnosis into distinct subtypes, but similar gene expression profiling in canine PTCL is lacking. Canine CD4+ PTCL most closely resembles the GATA3-PTCL subtype of PTCL-NOS and may originate from an earlier stage of T-cell development than the more conventionally posited mature T-helper cell origin. Supported by ORIP (T32OD010437).
Newly Identified Roles for PIEZO1 Mechanosensor in Controlling Normal Megakaryocyte Development and in Primary Myelofibrosis
Abbonante et al., American Journal of Hematology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38165047/
Mechanisms through which mature megakaryocytes (Mks) and their progenitors sense the bone marrow extracellular matrix to promote lineage differentiation are only partially understood. The authors report that PIEZO1, a mechanosensitive cation channel, is expressed in mouse and human Mks, and activation of PIEZO1 increased the number of immature Mks in mice. Piezo1/2 knockout mice show an increase in Mk size and platelet count, both at basal state and upon marrow regeneration. Together, these data suggest that PIEZO1 places a brake on Mk maturation and platelet formation in physiology, and its upregulation might contribute to aggravating disease. Supported by ORIP (K01OD025290), NHGRI, NHLBI, and NCATS.
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.
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.