Selected Grantee Publications
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- 266 results found
- Genetics
- Preservation
Rapid Joule Heating Improves Vitrification Based Cryopreservation
Zhan et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-33546-9
Cryopreservation by vitrification is an effective approach for long-term preservation of biosystems, but effective vitrification often requires high concentrations of cryoprotective agent (CPA), which can be toxic. The investigators described a joule heating–based platform technology for rapid rewarming of biosystems, which allows the use of low concentrations of CPA. They demonstrated the success of this platform in cryopreservation of three model systems: adherent cells, Drosophila melanogaster embryos, and rat kidney slices with low CPA concentrations. This work provides a general solution to cryopreserve a broad spectrum of cells, tissues, organs, and organisms. Supported by ORIP (R21OD028758), NIDDK, NHLBI, and NIGMS.
Mendelian Gene Identification through Mouse Embryo Viability Screening
Cacheiro et al., Genome Medicine. 2022.
https://www.doi.org/10.1186/s13073-022-01118-7
The investigators dissected phenotypic similarities between patients and model organisms by assessing the embryonic stage at which homozygous loss of function results in lethality in mice of both sexes obtained from the International Mouse Phenotyping Consortium. Information on knockout mouse embryo lethality can be used to prioritize candidate genes associated with certain disorders. Access to unsolved cases from rare-disease genome sequencing programs allows for the screening of those genes for potentially pathogenic variants, which could lead to a diagnosis and new potential treatment options to inform the management of human disease. Supported by ORIP (UM1OD023221, UM1OD023222, U42OD011174) and NHGRI.
Canine Reference Genome Accuracy Impacts Variant Calling: Lessons Learned from Investigating Embryonic Lethal Variant
Kinsey et al., Animal Genetics. 2022.
https://www.doi.org/10.1111/age.13241
With increasingly affordable whole-genome sequencing, hundreds of canine genomes now can be analyzed for embryonic lethal mutations. Investigators examined whole-genome sequence data from 675 dogs of both sexes to investigate for variants with missing homozygosity and high predicted impact. They identified 45 likely embryonic lethal mutations in 32 genes but found that all but one of those were labeled incorrectly and were artifacts associated with a widely utilized canine reference genome. This effect is a major obstacle to studies focusing on loci with high heterozygosity. The investigators propose that by using newer, multiple reference genomes, researchers could reduce artifacts and identify variants more accurately. Supported by ORIP (K01OD027051, K01OD019912).
De Novo Variants in EMC1 Lead to Neurodevelopmental Delay and Cerebellar Degeneration and Affect Glial Function in Drosophila
Chung et al., Human Molecular Genetics. 2022.
https://www.doi.org/10.1093/hmg/ddac053
Variants in EMC1, which encodes a subunit of the endoplasmic reticulum (ER)–membrane protein complex (EMC), are associated with developmental delay in children. Functional consequences of these variants are poorly understood. The investigators identified de novo variants in EMC1 in three children affected by global developmental delay, hypotonia, seizures, visual impairment, and cerebellar atrophy. They demonstrated in Drosophila that these variants are loss-of-function alleles and lead to lethality when expressed in glia but not in neurons. This work suggests the causality of EMC variants in disease. Supported by ORIP (R24OD022005, R24OD031447), NINDS, and NICHD.
Pharmacogenetic Gene–Drug Associations in Pediatric Burn and Surgery Patients
Grimsrud et al., Journal of Burn Care & Research. 2022.
https://www.doi.org/10.1093/jbcr/irac062
Simultaneous administration of many medications is common in management of critically ill patients. The researchers investigated drug–drug interactions in these treatments during hospitalization, which might decrease drug efficacy or increase adverse reactions. Genetic and medication data from 30 pediatric burn and surgery patients were analyzed to identify pharmacogene–drug associations. Nineteen patients were identified with predicted altered gene functions. Approximately one-third of the patients tested had functionally impactful genotypes in each of the primary drug metabolizing pathways. This study suggests that the vast variability in drug efficacy is partly due to genetic variants and that pharmacogenetic analysis may help optimize dosing regimens. Supported by ORIP (K01OD026608) and NCI.
Lesion Environments Direct Transplanted Neural Progenitors Towards a Wound Repair Astroglial Phenotype in Mice
O’Shea et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-33382-x
Neural progenitor cells (NPCs) are potential cell transplantation therapies for central nervous system (CNS) injuries. Investigators derived NPCs expressing a ribosomal protein-hemagglutinin tag (RiboTag) for transcriptional profiling. Their findings reveal similarities between the transcriptional profiles, cellular morphologies, and functional features of cells transplanted into subacute CNS lesions and host astroglia. The astroglia are stimulated by injuries to proliferate and adopt a naturally occurring, border-forming wound repair phenotype in mice of both sexes. Understanding the autonomous cues instructing NPCs transplanted in CNS host tissue will be fundamental to therapeutic NPC transplantation. Supported by ORIP (U42OD010921,U42OD011174, UM1OD023222) and NINDS.
Profiling Development of Abdominal Organs in the Pig
Gabriel et al., Scientific Reports. 2022.
https://www.doi.org/10.1038/s41598-022-19960-5
The pig is a model system for studying human development and disease due to its similarities to human anatomy, physiology, size, and genome. Moreover, advances in CRISPR gene editing have made genetically engineered pigs a viable model for the study of human pathologies and congenital anomalies. However, a detailed atlas illustrating pig development is necessary for identifying and modeling developmental defects. Here, the authors describe normal development of the pig abdominal system (i.e., kidney, liver, pancreas, spleen, adrenal glands, bowel, gonads) and compare them with congenital defects that can arise in gene-edited SAP130 mutant pigs. This atlas and the methods described here can be used as tools for identifying developmental pathologies of the abdominal organs in the pig at different stages of development. Supported by ORIP (U42OD011140), NHLBI, NIAID, NIBIB, NICHD, and NINDS.
Molecular and Cellular Evolution of the Primate Dorsolateral Prefrontal Cortex
Ma et al., Science. 2022.
https://www.doi.org/10.1126/science.abo7257
The dorsolateral prefrontal cortex (dlPFC) exists only in primates, lies at the center of high-order cognition, and is a locus of pathology underlying many neuropsychiatric diseases. The investigators generated single-nucleus transcriptome data profiling more than 600,000 nuclei from the dlPFC of adult humans, chimpanzees, rhesus macaques, and common marmosets of both sexes. Postmortem human samples were obtained from tissue donors. The investigators’ analyses delineated dlPFC cell-type homology and transcriptomic conservation across species and identified species divergence at the molecular and cellular levels, as well as potential epigenomic mechanisms underlying these differences. Expression patterns of more than 900 genes associated with brain disorders revealed a variety of conserved, divergent, and group-specific patterns. The resulting data resource will help to vertically integrate marmoset and macaque models with human-focused efforts to develop treatments for neuropsychiatric conditions. Supported by ORIP (P51OD011133), NIA, NICHD, NIDA, NIGMS, NHGRI, NIMH, and NINDS.
X Chromosome Agents of Sexual Differentiation
Arnold et al., Nature Reviews Endocrinology. 2022.
https://www.doi.org/10.1038/s41574-022-00697-0
Many diseases affect one sex disproportionately. A major goal of biomedical research is to understand which sex-biasing factors influence disease severity and to develop therapeutic strategies to target these factors. Two groups of such agents are sex chromosome genes and gonadal hormones. Researchers use the “four core genotypes” model to enable comparisons among animals with different sex chromosomes but the same type of sex hormones, which allows investigators to distinguish disease mechanisms influenced by the sex chromosomes. Supported by ORIP (R01OD030496, R21OD026560), NICHD, NIDDK, and NHLBI.
Wastewater Sequencing Reveals Early Cryptic SARS-CoV-2 Variant Transmission
Karthikeyan et al., Nature. 2022.
https://www.doi.org/10.1038/s41586-022-05049-6
The investigators explored the use of SARS-CoV-2 RNA concentration in wastewater as a practical approach to estimate community prevalence of COVID-19, detect emerging variants, and track regional infection dynamics. Two obstacles must be overcome to leverage wastewater-based genomic surveillance: low-quality sequence data and inability to estimate relative lineage abundance in mixed samples. The investigators developed and deployed improved virus concentration protocols and deconvolution software to fully resolve multiple virus strains from wastewater. Results indicate that emerging variants of concern were detected up to 14 days earlier in wastewater samples, and multiple instances of virus spread that were not captured by clinical genomic surveillance were identified by wastewater-based genomic surveillance. The study provides a scalable solution for wastewater genomic surveillance that allows early detection of SARS-CoV-2 variants and identification of cryptic transmission. The work suggests a critical, urgently needed methodology for early detection of emerging variants and early public health interventions. Supported by ORIP (S10OD026929), and NIAID.