Search NASA⌕ Search

SEARCH · Search NASA

Results for “Disease genetics”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

PyPop: a mature open-source software pipeline for population genomics

Python for Population Genomics (PyPop) is a software package that processes genotype and allele data and performs large-scale population genetic analyses on highly polymorphic multi-locus genotype data. In particular, PyPop tests data conformity to Hardy-Weinberg equilibrium expectations, performs Ewens-Watterson tests for selection, estimates haplotype frequencies, measures linkage disequilibrium, and tests significance. Standardized means of performing these tests is key for contemporary studies of evolutionary biology and population genetics, and these tests are central to genetic studies of disease association as well. Here, we present PyPop 1.0.0, a new major release of the package, which implements new features using the more robust infrastructure of GitHub, and is distributed via the industry-standard Python Package Index. New features include implementation of the asymmetric linkage disequilibrium measures and, of particular interest to the immunogenetics research communities, support for modern nomenclature, including colon-delimited allele names, and improvements to meta-analysis features for aggregating outputs for multiple populations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Characterizing the Defense Hierarchy of Populus trichocarpa

The U.S. Departments of Energy and Agriculture are developing bioenergy crops as a sustainable alternative to traditional fossil fuels. Plant disease threatens this effort by inhibiting the efficient production of plant feedstocks for bioenergy. In particular, biotrophic Melampsora leaf rust pathogens can increase morbidity in Populus trichocarpa and its hybrids (aka poplars), the primary woody feedstocks for bioenergy. Controlling rust disease in plantations is thus critical to the success of the poplar bioenergy program. Current efforts to control rust disease focus on plant genetic resistance. However, with novel pathogenic variation generated by the global movement of pathogens and their hybridization, it is increasingly clear that controlling rust disease in a long-lived plant like Populus depends on our ability to understand and manage not only genes for rust resistance, but also short-lived plant microorganisms that contribute to defense against rust (aka “defense mutualists”). Our proposed research thus seeks to develop an integrative, hierarchical model of P. trichocarpa defense that integrates genetic resistance and defense mutualists. Our overarching hypothesis is that defense against Melampsora rust is biologically degenerate, with major and minor plant resistance genes, plant defense compounds, and defense mutualists within the microbiome each contributing to rust resistance under different circumstances. The specific aims of our study will test the placement of each of these factors in the defense hierarchy. Ultimately, it is our hope that disease management strategies harnessing both resistance genes and naturally occurring defense mutualists of P. trichocarpa, and an appreciation of the ecological circumstances in which each is effective, will maximize plant resistance and productivity while minimizing impacts on the surrounding ecological landscape.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2002

Insulin secretion and sensitivity in space flight: diabetogenic effects

Nearly three decades of space flight research have suggested that there are subclinical diabetogenic changes that occur in microgravity. Alterations in insulin secretion, insulin sensitivity, glucose tolerance, and metabolism of protein and amino acids support the hypothesis that insulin plays an essential role in the maintenance of muscle mass in extended-duration space flight. Experiments in flight and after flight and ground-based bedrest studies have associated microgravity and its experimental paradigms with manifestations similar to those of diabetes, physical inactivity, and aging. We propose that these manifestations are characterized best by an etiology that falls into the clinical category of "other" causes of diabetes, including, but not restricted to, genetic beta-cell defects, insulin action defects, diseases of the endocrine pancreas, endocrinopathies, drug or chemically induced diabetes, infections, immune-mediated metabolic alteration, and a host of genetic related diseases. We present data showing alterations in tumor necrosis factor-alpha production, insulin secretion, and amino acid metabolism in pancreatic islets of Langerhans cultured in a ground-based cell culture bioreactor that mimics some of the effects of microgravity. Taken together, space flight research, ground-based studies, and bioreactor studies of pancreatic islets of Langerhans support the hypothesis that the pancreas is unable to overcome peripheral insulin resistance and amino acid dysregulation during space flight. We propose that measures of insulin secretion and insulin action will be necessary to design effective countermeasures against muscle loss, and we advance the "disposition index" as an essential model to be used in the clinical management of space flight-induced muscle loss.

Review↗
DOE OSTI2022

Disentangling Alzheimer’s disease neurodegeneration from typical brain ageing using machine learning

Abstract Neuroimaging biomarkers that distinguish between changes due to typical brain ageing and Alzheimer’s disease are valuable for determining how much each contributes to cognitive decline. Supervised machine learning models can derive multivariate patterns of brain change related to the two processes, including the Spatial Patterns of Atrophy for Recognition of Alzheimer’s Disease (SPARE-AD) and of Brain Aging (SPARE-BA) scores investigated herein. However, the substantial overlap between brain regions affected in the two processes confounds measuring them independently. We present a methodology, and associated results, towards disentangling the two. T1-weighted MRI scans of 4054 participants (48–95 years) with Alzheimer’s disease, mild cognitive impairment (MCI), or cognitively normal (CN) diagnoses from the Imaging-based coordinate SysTem for AGIng and NeurodeGenerative diseases (iSTAGING) consortium were analysed. Multiple sets of SPARE scores were investigated, in order to probe imaging signatures of certain clinically or molecularly defined sub-cohorts. First, a subset of clinical Alzheimer’s disease patients (n = 718) and age- and sex-matched CN adults (n = 718) were selected based purely on clinical diagnoses to train SPARE-BA1 (regression of age using CN individuals) and SPARE-AD1 (classification of CN versus Alzheimer’s disease) models. Second, analogous groups were selected based on clinical and molecular markers to train SPARE-BA2 and SPARE-AD2 models: amyloid-positive Alzheimer’s disease continuum group (n = 718; consisting of amyloid-positive Alzheimer’s disease, amyloid-positive MCI, amyloid- and tau-positive CN individuals) and amyloid-negative CN group (n = 718). Finally, the combined group of the Alzheimer’s disease continuum and amyloid-negative CN individuals was used to train SPARE-BA3 model, with the intention to estimate brain age regardless of Alzheimer’s disease-related brain changes. The disentangled SPARE models, SPARE-AD2 and SPARE-BA3, derived brain patterns that were more specific to the two types of brain changes. The correlation between the SPARE-BA Gap (SPARE-BA minus chronological age) and SPARE-AD was significantly reduced after the decoupling (r = 0.56–0.06). The correlation of disentangled SPARE-AD was non-inferior to amyloid- and tau-related measurements and to the number of APOE ε4 alleles but was lower to Alzheimer’s disease-related psychometric test scores, suggesting the contribution of advanced brain ageing to the latter. The disentangled SPARE-BA was consistently less correlated with Alzheimer’s disease-related clinical, molecular and genetic variables. By employing conservative molecular diagnoses and introducing Alzheimer’s disease continuum cases to the SPARE-BA model training, we achieved more dissociable neuroanatomical biomarkers of typical brain ageing and Alzheimer’s disease.

Hwang, Gyujoon↗
DOE OSTI2020

A Microbe Associated with Sleep Revealed by a Novel Systems Genetic Analysis of the Microbiome in Collaborative Cross Mice

The microbiome influences health and disease through complex networks of host genetics, genomics, microbes, and environment. Identifying the mechanisms of these interactions has remained challenging. Systems genetics in laboratory mice (Mus musculus) enables data-driven discovery of biological network components and mechanisms of host–microbial interactions underlying disease phenotypes. To examine the interplay among the whole host genome, transcriptome, and microbiome, we mapped QTL and correlated the abundance of cecal messenger RNA, luminal microflora, physiology, and behavior in a highly diverse Collaborative Cross breeding population. One such relationship, regulated by a variant on chromosome 7, was the association of Odoribacter (Bacteroidales) abundance and sleep phenotypes. In a test of this association in the BKS.Cg-Dock7 m +/+ Lepr db /J mouse model of obesity and diabetes, known to have abnormal sleep and colonization by Odoribacter, treatment with antibiotics altered sleep in a genotype-dependent fashion. The many other relationships extracted from this study can be used to interrogate other diseases, microbes, and mechanisms.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Utilizing plant synthetic biology to accelerate plant-microbe interactions research

Plant-microbe interactions are critical to ecosystem resilience and substantially influence crop production. From the perspective of plant science, two important focus areas concerning plant-microbe interactions include: 1) understanding plant molecular mechanisms involved in plant-microbe interfaces and 2) engineering plants for increasing plant disease resistance or enhancing beneficial interactions with microbes to increase their resilience to biotic and abiotic stress conditions. Molecular biology and genetics approaches have been used to investigate the molecular mechanisms underlying plant responses to various beneficial and pathogenic microbes. While these approaches are valuable for elucidating the functions of individual genes and pathways, they fall short of unraveling the complex cross-talk across pathways or systems that plants employ to respond and adapt to environmental stresses. Also, genetic engineering of plants to increase disease resistance or enhance symbiosis with microbes has mainly been attempted or conducted through targeted manipulation of single genes/pathways of plants. Recent advancements in synthetic biology tool development are paving the way for multi-gene characterization and engineering in plants in relation to plant-microbe interactions. Here, we briefly summarize the current understanding of plant molecular pathways involved in plant interactions with beneficial and pathogenic microorganisms. Then, we highlight the progress in applying plant synthetic biology to elucidate the molecular basis of plant responses to microbes, enhance plant disease resistance, engineer synthetic symbiosis, and conduct in situ microbiome engineering. Lastly, we discuss the challenges, opportunities, and future directions for advancing plant-microbe interactions research using the capabilities of plant synthetic biology.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

The role of memory in non-genetic inheritance and its impact on cancer treatment resistance

Intra-tumour heterogeneity is a leading cause of treatment failure and disease progression in cancer. While genetic mutations have long been accepted as a primary mechanism of generating this heterogeneity, the role of phenotypic plasticity is becoming increasingly apparent as a driver of intra-tumour heterogeneity. Consequently, understanding the role of this plasticity in treatment resistance and failure is a key component of improving cancer therapy. We develop a mathematical model of stochastic phenotype switching that tracks the evolution of drug-sensitive and drug-tolerant subpopulations to clarify the role of phenotype switching on population growth rates and tumour persistence. By including cytotoxic therapy in the model, we show that, depending on the strategy of the drug-tolerant subpopulation, stochastic phenotype switching can lead to either transient or permanent drug resistance. We study the role of phenotypic heterogeneity in a drug-resistant, genetically homogeneous population of non-small cell lung cancer cells to derive a rational treatment schedule that drives population extinction and avoids competitive release of the drug-tolerant sub-population. This model-informed therapeutic schedule results in increased treatment efficacy when compared against periodic therapy, and, most importantly, sustained tumour decay without the development of resistance.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Parabacteroides distasonis : intriguing aerotolerant gut anaerobe with emerging antimicrobial resistance and pathogenic and probiotic roles in human health

Parabacteroides distasonis is the type strain for the genus Parabacteroides, a group of gram-negative anaerobic bacteria that commonly colonize the gastrointestinal tract of numerous species. First isolated in the 1930s from a clinical specimen as Bacteroides distasonis, the strain was re-classified to form the new genus Parabacteroides in 2006. Currently, the genus consists of 15 species, 10 of which are listed as 'validly named' (P. acidifaciens, P. chartae, P. chinchillae, P. chongii, P. distasonis, P. faecis, P. goldsteinii, P. gordonii, P. johnsonii, and P. merdae) and 5 'not validly named' (P. bouchesdurhonensis, P. massiliensis, P. pacaensis, P. provencensis, and P. timonensis) by the List of Prokaryotic names with Standing in Nomenclature. The Parabacteroides genus has been associated with reports of both beneficial and pathogenic effects in human health. Herein, we review the literature on the history, ecology, diseases, antimicrobial resistance, and genetics of this bacterium, illustrating the effects of P. distasonis on human and animal health.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Template and target-site recognition by human LINE-1 in retrotransposition

The long interspersed element-1 (LINE-1, hereafter L1) retrotransposon has generated nearly one-third of the human genome and serves as an active source of genetic diversity and human disease. L1 spreads through a mechanism termed target-primed reverse transcription, in which the encoded enzyme (ORF2p) nicks the target DNA to prime reverse transcription of its own or non-self RNAs. Here we purified full-length L1 ORF2p and biochemically reconstituted robust target-primed reverse transcription with template RNA and target-site DNA. We report cryo-electron microscopy structures of the complete human L1 ORF2p bound to structured template RNAs and initiating cDNA synthesis. The template polyadenosine tract is recognized in a sequence-specific manner by five distinct domains. Among them, an RNA-binding domain bends the template backbone to allow engagement of an RNA hairpin stem with the L1 ORF2p C-terminal segment. Moreover, structure and biochemical reconstitutions demonstrate an unexpected target-site requirement: L1 ORF2p relies on upstream single-stranded DNA to position the adjacent duplex in the endonuclease active site for nicking of the longer DNA strand, with a single nick generating a staggered DNA break. Our research provides insights into the mechanism of ongoing transposition in the human genome and informs the engineering of retrotransposon proteins for gene therapy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant Acinetobacter baumannii

New antimicrobials are needed for the treatment of extensively drug-resistantAcinetobacter baumannii. The de novo pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated drug target for malaria and human autoimmune diseases. Here, we provide genetic evidence thatA. baumanniiDHODH (AbDHODH) is essential for bacterial survival in rodent infection models. We chemically validate the target by repurposing a unique library of ~450 triazolopyrimidine/imidazopyrimidine analogs developed for our malaria DHODH program to identify 21 compounds with submicromolar activity onAbDHODH. The most potent (DSM186, DHODH IC 50 28 nM) had a minimal inhibitory concentration of ≤1 µg/ml against geographically diverseA. baumanniistrains, including meropenem-resistant isolates. A structurally related analog (DSM161) with a long in vivo half-life conferred significant protection in the neutropenic mouse thigh infection model. Encouragingly, the development of resistance to these compounds was not identified in vitro or in vivo. Lastly, the X-ray structure ofAbDHODH bound to DSM186 was solved to 1.4 Å resolution. These data support the potential ofAbDHODH as a drug target for the development of antimicrobials for the treatment ofA. baumanniiand potentially other high-risk bacterial infections.

Acinetobacter baumannii↗
DOE OSTI2023

Mass Spectrometry–Based Proteogenomics: New Therapeutic Opportunities for Precision Medicine

Proteogenomics refers to the integration of comprehensive genomic, transcriptomic, and proteomic measurements from the same samples with the goal of fully understanding the regulatory processes converting genotypes to phenotypes, often with an emphasis on gaining a deeper understanding of disease processes. Although specific genetic mutations have long been known to drive the development of multiple cancers, gene mutations alone do not always predict prognosis or response to targeted therapy. The benefit of proteogenomics research is that information obtained from proteins and their corresponding pathways provides insight into therapeutic targets that can complement genomic information by providing an additional dimension regarding the underlying mechanisms and pathophysiology of tumors. This review describes the novel insights into tumor biology and drug resistance derived from proteogenomic analysis while highlighting the clinical potential of proteogenomic observations and advances in technique and analysis tools.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Short incubation periods of atypical H-type BSE in cattle with EK211 and KK211 prion protein genotypes after intracranial inoculation

In 2006, a case of atypical H-type BSE (H-BSE) was found to be associated with a germline mutation in the PRNP gene that resulted in a lysine substitution for glutamic acid at codon 211 (E211K). The E211K amino acid substitution in cattle is analogous to E200K in humans, which is associated with the development of genetic Creutzfeldt-Jakob disease (CJD). In the present study, we aimed to determine the effect of the EK211 prion protein genotype on incubation time in cattle inoculated with the agent of H-BSE; to characterize the molecular profile of H-BSE in KK211 and EK211 genotype cattle; and to assess the influence of serial passage on BSE strain. Eight cattle, representing three PRNP genotype groups (EE211, EK211, and KK211), were intracranially inoculated with the agent of H-BSE originating from either a case in a cow with the EE211 prion protein genotype or a case in a cow with E211K amino acid substitution. All inoculated animals developed clinical disease; post-mortem samples were collected, and prion disease was confirmed through enzyme immunoassay, anti-PrP Sc immunohistochemistry, and western blot. Western blot molecular analysis revealed distinct patterns in a steer with KK211 H-BSE compared to EK211 and EE211 cattle. Incubation periods were significantly shorter in cattle with the EK211 and KK211 genotypes compared to the EE211 genotype. Inoculum type did not significantly influence the incubation period. This study demonstrates a shorter incubation period for H-BSE in cattle with the K211 genotype in both the homozygous and heterozygous forms.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2000

Realizing the potential of rapid-cycling Brassica as a model system for use in plant biology research

Rapid-cycling Brassica populations were initially developed as a model for probing the genetic basis of plant disease. Paul Williams and co-workers selected accessions of the six main species for short time to flower and rapid seed maturation. Over multiple generations of breeding and selection, rapid-cycling populations of each of the six species were developed. Because of their close relationship with economically important Brassica species, rapid-cycling Brassica populations, especially those of B. rapa (RCBr) and B. oleracea, have seen wide application in plant and crop physiology investigations. Adding to the popularity of these small, short-lived plants for research applications is their extensive use in K-12 education and outreach.

Review, Tutorial↗
DOE OSTI2024

Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Tomato deploys defence and growth simultaneously to resist bacterial wilt disease

Abstract Plant disease limits crop production, and host genetic resistance is a major means of control. Plant pathogenic Ralstonia causes bacterial wilt disease and is best controlled with resistant varieties. Tomato wilt resistance is multigenic, yet the mechanisms of resistance remain largely unknown. We combined metaRNAseq analysis and functional experiments to identify core Ralstonia ‐responsive genes and the corresponding biological mechanisms in wilt‐resistant and wilt‐susceptible tomatoes. While trade‐offs between growth and defence are common in plants, wilt‐resistant plants activated both defence responses and growth processes. Measurements of innate immunity and growth, including reactive oxygen species production and root system growth, respectively, validated that resistant plants executed defence‐related processes at the same time they increased root growth. In contrast, in wilt‐susceptible plants roots senesced and root surface area declined following Ralstonia inoculation. Wilt‐resistant plants repressed genes predicted to negatively regulate water stress tolerance, while susceptible plants repressed genes predicted to promote water stress tolerance. Our results suggest that wilt‐resistant plants can simultaneously promote growth and defence by investing in resources that act in both processes. Infected susceptible plants activate defences, but fail to grow and so succumb to Ralstonia , likely because they cannot tolerate the water stress induced by vascular wilt.

Meline, Valerian↗
DOE OSTI2023

The Monarch Initiative in 2024: an analytic platform integrating phenotypes, genes and diseases across species

Abstract Bridging the gap between genetic variations, environmental determinants, and phenotypic outcomes is critical for supporting clinical diagnosis and understanding mechanisms of diseases. It requires integrating open data at a global scale. The Monarch Initiative advances these goals by developing open ontologies, semantic data models, and knowledge graphs for translational research. The Monarch App is an integrated platform combining data about genes, phenotypes, and diseases across species. Monarch's APIs enable access to carefully curated datasets and advanced analysis tools that support the understanding and diagnosis of disease for diverse applications such as variant prioritization, deep phenotyping, and patient profile-matching. We have migrated our system into a scalable, cloud-based infrastructure; simplified Monarch's data ingestion and knowledge graph integration systems; enhanced data mapping and integration standards; and developed a new user interface with novel search and graph navigation features. Furthermore, we advanced Monarch's analytic tools by developing a customized plugin for OpenAI’s ChatGPT to increase the reliability of its responses about phenotypic data, allowing us to interrogate the knowledge in the Monarch graph using state-of-the-art Large Language Models. The resources of the Monarch Initiative can be found at monarchinitiative.org and its corresponding code repository at github.com/monarch-initiative/monarch-app.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Genetics and Genomics of Pathogen Resistance in Switchgrass

This project investigates the genetic and genomic bases of resistance/tolerance to disease in switchgrass (Panicum virgatum) populations developed as bioenergy feedstock. The focus is placed populations adapted to the Central Great Plains derived from the hybridization of upland and lowland ecotypes, represented by cultivars Summer and Kanlow, respectively. Resistance was investigated against the rust disease caused by the fungus Puccinia novo-panici (syn. P emaculata) and mosaic disease caused by the virus complex of Panicum mosaic virus and its satellite. Objectives of the project were: 1) to elucidate the genetic and genomic bases of resistance/tolerance in locally adapted upland and lowland switchgrass breeding populations with contrasting disease symptoms under field conditions; 2) determine the molecular underpinnings of why cv Kanlow has broad resistance/tolerance to pathogens; and 3) discover the molecular differences that permit systemic viral infections in some switchgrass plants but not in other genetically-related plants.

09 BIOMASS FUELS↗