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Results for “single nucleotide polymorphism (SNP)”

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.

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All sourcesNASA NTRSDOE OSTI
NASA NTRSDate not supplied

A Dominant Arabidopsis Thaliana ACTIN7 Mutant for Studies of Cytoskeletal-Mediated Root Gravity and Spaceflight Stress Responses

A forward genetic screen for Arabidopsis thaliana mutants that exhibited differential sensitivity to the actin-disrupting compound, latrunculin B (LatB), was conducted to uncover new players involved in actin-mediated root gravity responses. This to the isolation of a mutant that exhibited robust primary root growth at 100 nM LatB, which is a concentration that severely inhibits wild-type root elongation. Phenotypic analysis revealed that hypocotyl elongation in the dark and root hair tip growth in the mutant could tolerate LatB concentrations that impaired these processes in wild type. A cross between the mutant and wild type resulted in progeny resistance to LatB, which indicated that the mutant is dominant (hereafter referred to as LBR1 for LatB Resistant1). Filamentous-actin (F-actin) organization in LBR1 primary roots remained intact at 100 nM LatB, while that of wild type exhibited fragmented F-actin. Next generation sequencing revealed that LBR1 had a single nucleotide polymorphism (SNP) in the AT5G09810 gene that changed cytosine to a thiamine at the first exon. AT5G09810 encodes ACTIN7 (ACT7), which is one of three vegetative actin isoforms in A. thaliana. The SNP in the ACT7 gene led to a change in a single amino acid from proline at position 32 to a serine. Transgenic complementation of LBR1 plants with wild-type ACT7 under the control of the ACT7 promoter (pACT7:ACT7) and wild-type plants with LBR1, which contained the proline to serine mutation, also under the ACT7 promoter (pACT7:LBR1) confirmed that LBR1 is ACT7. The pACT7:LBR1 construct was also able to confer LatB resistance to the act7-5 and act2-3 vegetative ACT mutants. Moreover, LBR1 exhibited partial tolerance to salt and low phosphate, and enhanced root skewing on a clinostat, suggesting that site-directed engineering of vegetative ACT presents a strategy for generating stress-tolerant plants for spaceflight applications and studies of actin-mediated gravity responses.

Plant Space Biology↗
NASA NTRSDate not supplied

A Dominant Arabidopsis Thaliana ACTIN7 Mutant for Studies of Cytoskeletal-Mediated Root Gravity and Spaceflight Stress Responses

A forward genetic screen for Arabidopsis thaliana mutants that exhibited differential sensitivity to the actin-disrupting compound, latrunculin B (LatB), was conducted to uncover new players involved in actin-mediated root gravity responses. This led to the isolation of a mutant that exhibited robust primary root growth at 100 nM LatB, which is a concentration that severely inhibits wild-type root elongation. Phenotypic analysis revealed that hypocotyl elongation in the dark and root hair tip growth in the mutant could tolerate LatB concentrations that impaired these processes in wild type. A cross between the mutant and wild type resulted in progeny resistance to LatB, which indicated that the mutant is dominant (hereafter referred to as LBR1 for LatB Resistant1). Filamentous-actin (F-actin) organization in LBR1 primary roots remained intact at 100 nM LatB, while that of wild type exhibited fragmented F-actin. Next generation sequencing revealed that LBR1 had a single nucleotide polymorphism (SNP) in the AT5G09810 gene that changed cytosine to a thiamine at the first exon. AT5G09810 encodes ACTIN7 (ACT7), which is one of three vegetative actin isoforms in A. thaliana. The SNP in the ACT7 gene led to a change in a single amino acid from proline at position 32 to a serine. Transgenic complementation of LBR1 plants with wild-type ACT7 under the control of the ACT7 promoter (pACT7:ACT7) and wild-type plants with LBR1, which contained the proline to serine mutation, also under the ACT7 promoter (pACT7:LBR1) confirmed that LBR1 is ACT7. The pACT7:LBR1 construct was also able to confer LatB resistance to the act7-5 and act2-3 vegetative ACT mutants. Moreover, LBR1 exhibited partial tolerance to salt and low phosphate, and enhanced root skewing on a clinostat, suggesting that site-directed engineering of vegetative ACT presents a strategy for generating stress-tolerant plants for spaceflight applications and studies of actin-mediated gravity responses.

Plant Space Biology↗
NASA NTRS2003

The Single Nucleotide Polymorphism Consortium

I want to discuss both the Single Nucleotide Polymorphism (SNP) Consortium and the Human Genome Project. I am afraid most of my presentation will be thin on law and possibly too high on rhetoric. Having been engaged in a personal and direct way with these issues as a trained scientist, I find it quite difficult to be always as objective as I ought to be.

Morgan, Michael↗
NASA NTRS2004

Microelectronic DNA assay for the detection of BRCA1 gene mutations

Mutations in BRCA1 are characterized by predisposition to breast cancer, ovarian cancer and prostate cancer as well as colon cancer. Prognosis for this cancer survival depends upon the stage at which cancer is diagnosed. Reliable and rapid mutation detection is crucial for the early diagnosis and treatment. We developed an electronic assay for the detection of a representative single nucleotide polymorphism (SNP), deletion and insertion in BRCA1 gene by the microelectronics microarray instrumentation. The assay is rapid, and it takes 30 minutes for the immobilization of target DNA samples, hybridization, washing and readout. The assay is multiplexing since it is carried out at the same temperature and buffer conditions for each step. The assay is also highly specific, as the signal-to-noise ratio is much larger than recommended value (72.86 to 321.05 vs. 5) for homozygotes genotyping, and signal ratio close to the perfect value 1 for heterozygotes genotyping (1.04).

Validation Studies↗
NASA NTRSDate not supplied

Exploring Endothelial Function Risk Factors and Optic Disc Edema Changes During Strict 6º Head-Down Tilt Bed Rest

Approximately 20% of astronauts on International Space Station missions experience ophthalmic pathologies including optic disc edema, part of what is characterized as Spaceflight Associated Neuro-ocular Syndrome (SANS). While the cause of SANS is unknown, there are likely multiple contributing factors, including genetics, that may affect the response to spaceflight in affected individuals. B-vitamin status and the presence of specific one-carbon pathway single nucleotide polymorphism (SNP) alleles predicted the incidence of SANS pathologies in astronauts and in bed rest subjects. There are several hypotheses for how genetic variants could lead to SANS, specifically related to endothelial function. The biochemical pathway to which these genes are associated is intimately involved in maintaining endothelial function via nitric oxide synthase (eNOS) coupling and nitric oxide (NO) production. Furthermore, eNOS uncoupling can impair the functional status of the endothelial glycocalyx, which lines the entirety of the vascular lumen and affects endothelial function. Vascular distension, stasis and altered shear forces, which are associated with headward fluid shifts, may also contribute to glycocalyx dysfunction and shedding, resulting in endothelial dysfunction and increased vascular permeability and tissue edema, potentially contributing to optic nerve and optic disc edema in affected individuals. Given the findings relating genetics and the risk of optic disc edema in astronauts during flight and subjects during bed rest, further investigation is warranted. In this study, we will assess the same genetic variants in another bed rest study: AGBRESA. Some of the AGBRESA subjects developed optic disc edema, but their genetics have not been studied. Furthermore, we will test available urine samples from prior bed rest studies (VaPER and AGBRESA) for markers of glycocalyx degradation to expand our understanding of factors contributing to SANS.

S R Zwart↗
NASA NTRSDate not supplied

B Complex 5-Methyltetrahydrofolate, Riboflavin, Pyridoxine, and Methylcobalamin Supplementation as a Non-Mechanical Countermeasure to Mitigate Optic Disc Edema Changes During Strict 6º Head-Down Tilt Bed Rest

A subset of astronauts on International Space Station missions have experienced optic disc edema, part of what is characterized as Spaceflight Associated Neuro-ocular Syndrome (SANS). While the precise cause of SANS is unknown, it is likely that there are multiple contributing factors, including genetic and environmental factors. Our recent work has shown that crewmembers with SANS have higher concentrations of metabolic biomarkers of impairments in the one-carbon metabolic pathway compared to unaffected astronauts - before, during, and after f light (1). B-vitamin status and the presence of one-carbon pathway single nucleotide polymorphism (SNP) variants predicted the incidence of SANS pathologies, including optic disc edema (2). Specifically, the G allele of methionine synthase reductase (MTRR) A66G and the C allele of serine hydroxymethyltransferase-1 (SHMT1) C1420T were associated with increased incidence of SANS pathologies (2). In a recent 30-d bed rest head-down tilt study with 0.5% CO2 exposure, 5 of 11 subjects developed optic disc edema (4) and the same SHMT1 C1420T and MTRR A66G genetic variants were associated with a larger increase in total retina thickness, a quantitative measure of optic disc edema (5). We published a multi-hit hypothesis of how genetics represents an indispensable element of SANS, which is a multifactorial problem (6). In brief: endothelial dysfunction secondary to genetic, biochemical/nutritional, and physiological (e.g., cardiovascular/fluid shift) f actors could lead to optic disc edema and the other ocular changes that occur in SANS. We expanded this hypothesis to include the possibility that genetic effects on B-vitamin status can alter nitric oxide synthesis and oxidative stress in the endothelium. This in turn could alter the turnover of structural components of the sclera, making it more susceptible to pathologic changes when faced with stressors related to the unrelenting headward fluid shift that occurs in weightlessness and strict head-down tilt bed rest (5). If the relationships that we have observed in flight and ground-based research hold true for the SANS Countermeasure Study, these genetic factors could predict who will be more susceptible to the development of SANS, and more importantly could also provide countermeasure options. As has been shown extensively in the literature, vitamin supplementation can serve to overcome genetic hindrances to one-carbon biochemistry and vascular physiology. Thus, based on our findings, publications, and hypotheses, supported by extensive supporting literature, we had hoped to test in the SANS Countermeasure Study the efficacy of a bioactive B-vitamin complex as a countermeasure to optimize function of the one-carbon pathway and prevent or mitigate optic disc edema during strict 6-degree head down tilt bed rest, and ultimately in space f light. While the supplement is no longer planned to be tested in the SANS Countermeasure Study because of laws regulating supplementation studies like this costing much more than initially planned, we will assess the contribution of one-carbon pathway genetics and B-vitamin status to SANS risk.

S R Zwart↗
NASA NTRSDate not supplied

One-Carbon Metabolism and SANS 2022 Update

Spaceflight Associated Neuro-ocular Syndrome, or SANS, affects a subset of astronauts (1, 2), and biochemical evidence has documented differences in those astronauts (3). Specifically, they had higher circulating concentrations of metabolites of the one-carbon metabolic pathway (1C), including homocysteine, and these concentrations were higher before flight (3). After ruling out many potential confounding factors in these otherwise healthy individuals (e.g., sex, kidney function, vitamin status, coffee consumption), a study of genetics was warranted. In an initial pilot effort, we documented a genetic predisposition to develop ophthalmic changes after long-duration space flight (4). That is, from a limited study of 5 single-nucleotide polymorphisms (SNPs), we found that the G allele for the MTRR A66G SNP was associated with a greater risk of choroidal folds and cotton-wool spots after flight, and the C allele for SHMT1 C1420T was protective against optic disc edema (4). These data provide a potential pathway for understanding why some individuals develop SANS, while others do not. The initial pilot study of 5 SNPs yielded striking findings, but the 1C pathway is far more complex. An effort was undertaken to examine more than 500 1C SNPs to see if a broader examination could help illuminate this association. That work is ongoing. The astronaut findings led us to advocate for the inclusion of 1C pathway genetic and biochemistry testing on other SANS-related projects, noting that genetics might help identify responders, non-responders, or outliers. The first such effort yielded evidence of an association of specific forms of the MTRR and SHMT-1 SNPs and vitamin B12 status with end-tidal CO2 after acute carbon dioxide exposure (5). The second such effort led to the identification that individuals exposed to strict head-down tilt and CO2 for 30-d who developed optic disc edema also had risk alleles for the two SNPs described above (6). Additionally, we identified a clinical population with many characteristics either attributed or purported to be involved in the ocular changes seen in affected astronauts: women with polycystic ovary syndrome (PCOS). PCOS is a condition of androgen excess and anovulatory menstrual cycles. The shared characteristics and clinical findings between SANS and PCOS generally include higher circulating homocysteine concentrations, increased retinal nerve fiber layer thickness, increased androgen concentrations (or responses), and altered carbohydrate metabolism. To our knowledge, no study has examined whether women with PCOS have asymptomatic ophthalmic anomalies observed in astronauts with SANS. While researchers have evaluated the one-carbon metabolism pathway polymorphisms of PCOS patients, and initial studies show an association with certain one-carbon polymorphisms, none have looked at the set of SNPs identified in our studies that are associated with ophthalmic changes in astronauts. Accordingly, we designed a study to evaluate the association of one-carbon pathway SNPs and ophthalmic findings in patients with PCOS and/or IIH compared to controls. Subjects provided blood samples for vitamin and one carbon biochemistry analyses, an extensive analysis of >500 SNPs associated with one carbon metabolism and had eye examinations and ocular imaging. Data analysis are underway. The data collected to date have shown associations between one carbon pathway biochemistry and genetics and incidence of SANS. The mechanisms for SANS has yet to be identified, although many hypotheses exist. Based on our data, we have developed (8, 9) and expanded (6) a multi-hit hypothesis for how these seemingly disparate findings could be linked. While intriguing, the hypothesis represents the starting point for further research. We aim to clarify the relationship between B-vitamin status and genetics with regard to the risk of SANS. Ultimately, understanding the mechanism(s) behind this will provide a means to predict, prevent, or treat these ophthalmologic pathologies in astronauts, and terrestrial populations.

S M Smith↗