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All sourcesNASA NTRSDOE OSTI
NASA NTRS2015

Space Biophysics: Accomplishments, Trends, Challenges

Physics and biology are inextricably linked. All the chemical and biological processes of life are dutifully bound to follow the rules and laws of physics. In space, these physical laws seem to turn on their head and biological systems, from microbes to humans, adapt and evolve in myriad ways to cope with the changed physical influences of the space environment. Gravity is the most prominent change in space that influences biology. In microgravity, the physical processes of sedimentation, density-driven convective flow, influence of surface tension and fluid pressure profoundly influence biology at the molecular and cellular level as well as at the whole-body level. Gravity sensing mechanisms are altered, structural and functional components of biology (such as bone and muscle) are reduced and changes in the way fluids and gasses behave also drive the way microbial systems and biofilms grow as well as the way plants and animals adapt. The radiation environment also effects life in space. Solar particle events and high energy cosmic radiation can cause serious damage to DNA and other biomolecules. The results can cause mutation, cellular damage or death, leading to health consequences of acute radiation damage or long-term health consequences such as increased cancer risk. Space Biophysics is the study and utilization of physical changes in space that cause changes in biological systems. The unique physical environment in space has been used successfully to grow high-quality protein crystals and 3D tissue cultures that could not be grown in the presence of unidirectional gravitational acceleration here on Earth. All biological processes that change in space have their root in a biophysical alteration due to microgravity and/or the radiation environment of space. In order to fully-understand the risks to human health in space and to fully-understand how humans, plants, animals and microbes can safely and effectively travel and eventually live for long periods beyond the protective environment of Earth, the biophysical properties underlying these changes must be studied, characterized and understood. This lecture reviews the current state of NASA biophysics research accomplishments and identifies future trends and challenges for biophysics research on the International Space Station and beyond.

Space Biophysics: Accomplishments↗
NASA NTRS2017

Field Exploration and Life Detection Sampling Through Planetary Analogue Sampling (FELDSPAR).

Exploration missions to Mars rely on rovers to perform analyses over small sampling areas; however, landing sites for these missions are selected based on large-scale, low-resolution remote data. The use of Earth analogue environments to estimate the multi-scale spatial distributions of key signatures of habitability can help ensure mission science goals are met. A main goal of FELDSPAR is to conduct field operations analogous to Mars sample return in its science, operations, and technology from landing site selection, to in-field sampling location selection, remote or stand-off analysis, in situ analysis, and home laboratory analysis. Lava fields and volcanic regions are relevant analogues to Martian landscapes due to desiccation, low nutrient availability, and temperature extremes. Operationally, many Icelandic lava fields are remote enough to require that field expeditions address several sampling constraints that are experienced in robotic exploration, including in situ and sample return missions. The Fimmvruhls lava field was formed by a basaltic effusive eruption associated with the 2010 Eyjafjallajkull eruption. Mlifellssandur is a recently deglaciated plain to the north of the Myrdalsjkull glacier. Holuhraun was formed by a 2014 fissure eruptions just north of the large Vatnajkull glacier. Dyngjusandur is an alluvial plain apparently kept barren by repeated mechanical weathering. Informed by our 2013 expedition, we collected samples in nested triangular grids every decade from the 10 cm scale to the 1 km scale (as permitted by the size of the site). Satellite imagery is available for older sites, and for Mlifellssandur, Holuhraun, and Dyngjusandur we obtained overhead imagery at 1 m to 200 m elevation. PanCam-style photographs were taken in the field by sampling personnel. In-field reflectance spectroscopy was also obtained with an ASD spectrometer in Dyngjusandur. All sites chosen were 'homogeneous' in apparent color, morphology, moisture, grain size, and reflectance spectra at all scales greater than 10 cm. Field lab assays were conducted to monitor microbial habitation, including ATP quantification, qPCR for fungal, bacterial, and archaeal DNA, and direct cell imaging using fluorescence microscopy. Home laboratory analyses include Raman spectroscopy and community sequencing. ATP appeared to be significantly more sensitive to small changes in sampling location than qPCR or fluorescence microscopy. Bacterial and archaeal DNA content were more consistent at the smaller scales, but similarly variable across more distant sites. Conversely, cell counts and fungal DNA content have significant local variation but appear relatively homogeneous over scales of 1 km. ATP, bacterial DNA, and archaeal DNA content were relatively well correlated at many spatial scales. While we have observed spatial variation at various scales and are beginning to observe how that variation fluctuates over time as biodiversity recovers after an eruption, we do not yet fully understand what parameters lead to the observed spatial variation. Home laboratory analyses will help us further understand the elemental and structural composition of the basaltic matrices, but further field analyses are vital for the understanding how temperature, moisture, incident radiation, and so forth influence the habitability of a microclimate.

Field↗
DOE OSTI2023

Drug discovery efforts at George Mason University

With over 39,000 students, and research expenditures in excess of $200 million, George Mason University (GMU) is the largest R1 (Carnegie Classification of very high research activity) university in Virginia. Mason scientists have been involved in the discovery and development of novel diagnostics and therapeutics in areas as diverse as infectious diseases and cancer. Below are highlights of the efforts being led by Mason researchers in the drug discovery arena. To enable targeted cellular delivery, and non-biomedical applications, Veneziano and colleagues have developed a synthesis strategy that enables the design of self-assembling DNA nanoparticles (DNA origami) with prescribed shape and size in the 10 to 100 nm range. The nanoparticles can be loaded with molecules of interest such as drugs, proteins and peptides, and are a promising new addition to the drug delivery platforms currently in use. The investigators also recently used the DNA origami nanoparticles to fine tune the spatial presentation of immunogens to study the impact on B cell activation. These studies are an important step towards the rational design of vaccines for a variety of infectious agents. To elucidate the parameters for optimizing the delivery efficiency of lipid nanoparticles (LNPs), Buschmann, Paige and colleagues have devised methods for predicting and experimentally validating the pKa of LNPs based on the structure of the ionizable lipids used to formulate the LNPs. These studies may pave the way for the development of new LNP delivery vehicles that have reduced systemic distribution and improved endosomal release of their cargo post administration. To better understand protein-protein interactions and identify potential drug targets that disrupt such interactions, Luchini and colleagues have developed a methodology that identifies contact points between proteins using small molecule dyes. The dye molecules noncovalently bind to the accessible surfaces of a protein complex with very high affinity, but are excluded from contact regions. When the complex is denatured and digested with trypsin, the exposed regions covered by the dye do not get cleaved by the enzyme, whereas the contact points are digested. The resulting fragments can then be identified using mass spectrometry. The data generated can serve as the basis for designing small molecules and peptides that can disrupt the formation of protein complexes involved in disease processes. For example, using peptides based on the interleukin 1 receptor accessory protein (IL-1RAcP), Luchini, Liotta, Paige and colleagues disrupted the formation of IL-1/IL-R/IL-1RAcP complex and demonstrated that the inhibition of complex formation reduced the inflammatory response to IL-1B. Working on the discovery of novel antimicrobial agents, Bishop, van Hoek and colleagues have discovered a number of antimicrobial peptides from reptiles and other species. DRGN-1, is a synthetic peptide based on a histone H1-derived peptide that they had identified from Komodo Dragon plasma. DRGN-1 was shown to disrupt bacterial biofilms and promote wound healing in an animal model. The peptide, along with others, is being developed and tested in preclinical studies. Other research by van Hoek and colleagues focuses on in silico antimicrobial peptide discovery, screening of small molecules for antibacterial properties, as well as assessment of diffusible signal factors (DFS) as future therapeutics. The above examples provide insight into the cutting-edge studies undertaken by GMU scientists to develop novel methodologies and platform technologies important to drug discovery.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Improving CRISPR/Cas9-mediated genome editing efficiency in Yarrowia lipolytica using direct tRNA-sgRNA fusions

We report Yarrowia lipolytica is an important oleaginous yeast currently used in the production of specialty chemicals and has a great potential for further applications in lipid biotechnology. Harnessing the full potential of Y. lipolytica is, however, limited by its inherent recalcitrance to genetic manipulation. In contrast to Saccharomyces cerevisiae, Y. lipolytica is poor in homology-mediated DNA repair and thus in homologous recombination, which limits site-specific gene editing in this yeast. Recently developed CRISPR/Cas9-based methods using tRNA-sgRNA fusions succeeded in editing some genomic loci in Y. lipolytica. Nonetheless, the majority of other tested loci either failed editing or editing was achieved but at very low efficiency using these methods. Using tools of secondary RNA structure prediction, we were able to improve the design of the tRNA-sgRNA fusions used for the expression of single guide RNA (sgRNA) in such methods. This resulted in high efficiency CRISPR/cas9 gene editing at chromosomal loci that failed gene editing or were edited at very low efficiencies with previous methods. In addition, we characterized the gene editing performance of our newly designed tRNA-sgRNA fusions for both chromosomal gene integration and deletion. As such, this study presents an efficient CRISPR/Cas9-mediated gene-editing tool for efficient genetic engineering of Yarrowia lipolytica.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Divergent selection and climate adaptation fuel genomic differentiation between sister species of Sphagnum (peat moss)

Abstract Background and Aims New plant species can evolve through the reinforcement of reproductive isolation via local adaptation along habitat gradients. Peat mosses (Sphagnaceae) are an emerging model system for the study of evolutionary genomics and have well-documented niche differentiation among species. Recent molecular studies have demonstrated that the globally distributed species Sphagnum magellanicum is a complex of morphologically cryptic lineages that are phylogenetically and ecologically distinct. Here, we describe the architecture of genomic differentiation between two sister species in this complex known from eastern North America: the northern S. diabolicum and the largely southern S. magniae. Methods We sampled plant populations from across a latitudinal gradient in eastern North America and performed whole genome and restriction-site associated DNA sequencing. These sequencing data were then analyzed computationally. Key Results Using sliding-window population genetic analyses we find that differentiation is concentrated within ‘islands’ of the genome spanning up to 400 kb that are characterized by elevated genetic divergence, suppressed recombination, reduced nucleotide diversity and increased rates of non-synonymous substitution. Sequence variants that are significantly associated with genetic structure and bioclimatic variables occur within genes that have functional enrichment for biological processes including abiotic stress response, photoperiodism and hormone-mediated signalling. Demographic modelling demonstrates that these two species diverged no more than 225 000 generations ago with secondary contact occurring where their ranges overlap. Conclusions We suggest that this heterogeneity of genomic differentiation is a result of linked selection and reflects the role of local adaptation to contrasting climatic zones in driving speciation. This research provides insight into the process of speciation in a group of ecologically important plants and strengthens our predictive understanding of how plant populations will respond as Earth’s climate rapidly changes.

58 GEOSCIENCES↗
DOE OSTI2022

An optimized ChIP-Seq framework for profiling histone modifications in Chromochloris zofingiensis

The eukaryotic green alga Chromochloris zofingiensis is a reference organism for studying carbon partitioning and a promising candidate for the production of biofuel precursors. Recent transcriptome profiling transformed our understanding of its biology and generally algal biology, but epigenetic regulation remains understudied and represents a fundamental gap in our understanding of algal gene expression. Chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) is a powerful tool for the discovery of such mechanisms, by identifying genome-wide histone modification patterns and transcription factor-binding sites alike. Here, we established a ChIP-Seq framework for Chr. zofingiensis yielding over 20 million high-quality reads per sample. The most critical steps in a ChIP experiment were optimized, including DNA shearing to obtain an average DNA fragment size of 250 bp and assessment of the recommended formaldehyde concentration for optimal DNA-protein cross-linking. We used this ChIP-Seq framework to generate a genome-wide map of the H3K4me3 distribution pattern and to integrate these data with matching RNA-Seq data. In line with observations from other organisms, H3K4me3 marks predominantly transcription start sites of genes. Our H3K4me3 ChIP-Seq data will pave the way for improved genome structural annotation in the emerging reference alga Chr. zofingiensis.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2011

Carbonaceous Meteorites Contain a Wide Range of Extraterrestrial Nucleobases

All terrestrial organisms depend on nucleic acids (RNA and DNA), which use pyrimidine and purine nucleobases to encode genetic information. Carbon-rich meteorites may have been important sources of organic compounds required for the emergence of life on the early Earth; however, the origin and formation of nuc1eobases in meteorites has been debated for over 50 y. So far, the few nuc1eobases reported in meteorites are biologically common and lacked the structural diversity typical of other indigenous meteoritic organics. Here, we investigated the abundance and distribution of nucleobases and nucleobase analogs in formic acid extracts of 12 different meteorites by liquid chromatography-mass spectrometry. The Murchison and Lonewolf Nunataks 94102 meteorites contained a diverse suite of nucleobases, which included three unusual and terrestrially rare nucleobase analogs; purine, 2,6-diminopurine, and 6,8-diaminopurine. In a parallel experiment, we found an identical suite of nucleobases and nucleobase analogs generated in reactions of ammonium cyanide. Additionally, these nucleobase analoge were not detected above our parts-per-billion detection limits in any of the procedural blanks, control samples, a terrestrial soil sample, and an Antarctic ice sample. Our results demonstrate that the purines detected in meteorites are consistent with products of ammonium cyanide chemistry, which provides a plausible mechanism for their synthesis in the asteroid parent bodies, and strongly supports an extraterrestrial origin. The discovery of new nucleobase analogs in meteorites also expands the prebiotic molecular inventory available for constructing the first genetic molecules.

Callahan, Michael P.↗
DOE OSTI2021

Contribution of advanced fluorescence nano microscopy towards revealing mitotic chromosome structure

The organization of chromatin into higherorder structures and its condensation process represent one of the key challenges in structural biology. This is important for elucidating several disease states. To address this long-standing problem, development of advanced imaging methods has played an essential role in providing understanding into mitotic chromosome structure and compaction. Amongst these are two fast evolving fluorescence imaging technologies, specifically fluorescence lifetime imaging (FLIM) and superresolution microscopy (SRM). FLIM in particular has been lacking in the application of chromosome research while SRM has been successfully applied although not widely. Furthermore, both these techniques are capable of providing fluorescence imaging with nanometer information. SRM or "nanoscopy" is capable of generating images of DNA with less than 50 nm resolution while FLIM when coupled with energy transfer may provide less than 20 nm information. Here, we discuss the advantages and limitations of both methods followed by their contribution to mitotic chromosome studies. Furthermore, we highlight the future prospects of how advancements in new technologies can contribute in the field of chromosome science.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2002

The Arabidopsis SKU5 gene encodes an extracellular glycosyl phosphatidylinositol-anchored glycoprotein involved in directional root growth

To investigate how roots respond to directional cues, we characterized a T-DNA-tagged Arabidopsis mutant named sku5 in which the roots skewed and looped away from the normal downward direction of growth on inclined agar surfaces. sku5 roots and etiolated hypocotyls were slightly shorter than normal and exhibited a counterclockwise (left-handed) axial rotation bias. The surface-dependent skewing phenotype disappeared when the roots penetrated the agar surface, but the axial rotation defect persisted, revealing that these two directional growth processes are separable. The SKU5 gene belongs to a 19-member gene family designated SKS (SKU5 Similar) that is related structurally to the multiple-copper oxidases ascorbate oxidase and laccase. However, the SKS proteins lack several of the conserved copper binding motifs characteristic of copper oxidases, and no enzymatic function could be assigned to the SKU5 protein. Analysis of plants expressing SKU5 reporter constructs and protein gel blot analysis showed that SKU5 was expressed most strongly in expanding tissues. SKU5 was glycosylated and modified by glycosyl phosphatidylinositol and localized to both the plasma membrane and the cell wall. Our observations suggest that SKU5 affects two directional growth processes, possibly by participating in cell wall expansion.

NASA Discipline Plant Biology↗
DOE OSTI2021

Designed and biologically active protein lattices

Versatile methods to organize proteins in space are required to enable complex biomaterials, engineered biomolecular scaffolds, cell-free biology, and hybrid nanoscale systems. Here, we demonstrate how the tailored encapsulation of proteins in DNA-based voxels can be combined with programmable assembly that directs these voxels into biologically functional protein arrays with prescribed and ordered two-dimensional (2D) and three-dimensional (3D) organizations. We apply the presented concept to ferritin, an iron storage protein, and its iron-free analog, apoferritin, in order to form single-layers, double-layers, as well as several types of 3D protein lattices. Our study demonstrates that internal voxel design and inter-voxel encoding can be effectively employed to create protein lattices with designed organization, as confirmed by in situ X-ray scattering and cryo-electron microscopy 3D imaging. The assembled protein arrays maintain structural stability and biological activity in environments relevant for protein functionality. The framework design of the arrays then allows small molecules to access the ferritins and their iron cores and convert them into apoferritin arrays through the release of iron ions. The presented study introduces a platform approach for creating bio-active protein-containing ordered nanomaterials with desired 2D and 3D organizations.

77 NANOSCIENCE AND NANOTECHNOLOGY↗
DOE OSTI2021

Decoding Cancer Variants of Unknown Significance for Helicase–Nuclease–RPA Complexes Orchestrating DNA Repair During Transcription and Replication

All tumors have DNA mutations, and a predictive understanding of those mutations could inform clinical treatments. However, 40% of the mutations are variants of unknown significance (VUS), with the challenge being to objectively predict whether a VUS is pathogenic and supports the tumor or whether it is benign. To objectively decode VUS, we mapped cancer sequence data and evolutionary trace (ET) scores onto crystallography and cryo-electron microscopy structures with variant impacts quantitated by evolutionary action (EA) measures. As tumors depend on helicases and nucleases to deal with transcription/replication stress, we targeted helicase–nuclease–RPA complexes: (1) XPB-XPD (within TFIIH), XPF-ERCC1, XPG, and RPA for transcription and nucleotide excision repair pathways and (2) BLM, EXO5, and RPA plus DNA2 for stalled replication fork restart. As validation, EA scoring predicts severe effects for most disease mutations, but disease mutants with low ET scores not only are likely destabilizing but also disrupt sophisticated allosteric mechanisms. For sites of disease mutations and VUS predicted to be severe, we found strong co-localization to ordered regions. Rare discrepancies highlighted the different survival requirements between disease and tumor mutations, as well as the value of examining proteins within complexes. In a genome-wide analysis of 33 cancer types, we found correlation between the number of mutations in each tumor and which pathways or functional processes in which the mutations occur, revealing different mutagenic routes to tumorigenesis. We also found upregulation of ancient genes including BLM, which supports a non-random and concerted cancer process: reversion to a unicellular, proliferation-uncontrolled, status by breaking multicellular constraints on cell division. Together, these genes and global analyses challenge the binary “driver” and “passenger” mutation paradigm, support a gradient impact as revealed by EA scoring from moderate to severe at a single gene level, and indicate reduced regulation as well as activity. The objective quantitative assessment of VUS scoring and gene overexpression in the context of functional interactions and pathways provides insights for biology, oncology, and precision medicine.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Microbial metabolic dependency and its impacts on the soil carbon cycle (Final Technical Report, DE-SC0016364)

The terrestrial biosphere contains a large fraction of global carbon (C) and nearly 70% of the organic C in terrestrial systems is found in soils. Global changes in atmospheric CO 2 , temperature, precipitation, and ecosystem N inputs, will impact primary production and carbon inputs to soils, but it remains difficult to predict soil responses to these environmental conditions. Our ability to predict C-cycle responses to global change remains limited by unexplained variability within the terrestrial C-cycle. Our difficulty in predicting responses of the soil C-cycle to environmental change suggests a need for a greater understanding of the biotic mechanisms that govern soil C-transformations. Changes in microbial community structure and function have been proposed to impact soil processes, but mechanistic connections between microbial activity and C-cycle transformations remain poorly described. We assembled an interdisciplinary team to conduct cross-scale examination of microbial contributions to C-cycle dynamics and C-fate in soils. We investigated microbial contributions to soil C-transformations using a suite of complementary isotopic techniques including DNA-Stable Isotope Probing (DNA-SIP), metagenomic-SIP, metabolomic-SIP, proteomic-SIP, and microspatial analysis of soil organic C. These techniques were deployed in experiments that tested fundamental assumptions that underlie terrestrial C-cycle models. We characterized the functional characteristics of soil microorganisms responsible for major C-transformations in soil, evaluated the metabolic and ecological interactions that underlie soil C-cycle dynamics, and evaluated the degree to which these interactions impact rates of C mineralization and stabilization in soils.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2025

Phosphorus Recycling from Ribonucleotide Structures by Iron Oxide Minerals

In this research, we combined experimental and molecular modeling to obtain a fundamental understanding required to evaluate and predict the role of three natural iron oxides minerals (ferrihydrite, goethite, and hematite) in recycling phosphorus from organic matter, particularly ribonucleotides.

58 GEOSCIENCES↗
NASA NTRS2003

Microbial characterization of the Mars Odyssey spacecraft and its encapsulation facility

Microbial characterization of the Mars Odyssey spacecraft and the Kennedy Space Center Spacecraft Assembly and Encapsulation Facility II (SAEF-II) was carried out by both culture-based and molecular methods. The most dominant cultivable microbes were species of Bacillus, with comamonads, microbacteria and actinomycetales also represented. Several spore-forming isolates were resistant to gamma-radiation, UV, H2O2 and desiccation, and one Acinetobacter radioresistens isolate and several Aureobasidium, isolated directly from the spacecraft, survived various conditions. Sequences arising in clone libraries were fairly consistent between the spacecraft and facility; predominant genera included Variovorax, Ralstonia and Aquaspirillum. This study improves our understanding of the microbial community structure, diversity and survival capabilities of microbes in an encapsulation facility and physically associated with colocated spacecraft.

Spacecraft↗
DOE OSTI2021

The Enterprise , a massive transposon carrying Spok meiotic drive genes

The genomes of eukaryotes are full of parasitic sequences known as transposable elements (TEs). Here, we report the discovery of a putative giant tyrosine-recombinase-mobilized DNA transposon, Enterprise, from the model fungus Podospora anserina. Previously, we described a large genomic feature called the Spok block which is notable due to the presence of meiotic drive genes of the Spok gene family. The Spok block ranges from 110 kb to 247 kb and can be present in at least four different genomic locations within P. anserina, despite what is an otherwise highly conserved genome structure. We propose that the reason for its varying positions is that the Spok block is not only capable of meiotic drive but is also capable of transposition. More precisely, the Spok block represents a unique case where the Enterprise has captured the Spoks, thereby parasitizing a resident genomic parasite to become a genomic hyperparasite. Furthermore, we demonstrate that Enterprise (without the Spoks) is found in other fungal lineages, where it can be as large as 70 kb. Lastly, we provide experimental evidence that the Spok block is deleterious, with detrimental effects on spore production in strains which carry it. This union of meiotic drivers and a transposon has created a selfish element of impressive size in Podospora, challenging our perception of how TEs influence genome evolution and broadening the horizons in terms of what the upper limit of transposition may be.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2006

Development of the Gecko (Pachydactylus turneri) Animal Model during Foton M-2 to Study Comparative Effects of Microgravity in Terrestrial and Aquatic Organisms

Terrestrial organisms exposed to microgravity during spaceflight experience degeneration in bone, muscle, and possibly other tissues that require gravity-mediated mechanical stimulation for normal regenerative growth. In the Gecko experiment aboard Foton M-2, we flew for the first time, five terrestrial Pachydactylus turneri specimens to develop a model of microgravity effects comparable to the newt Pleurodeles waltl, a well-established model organism for spaceflight. These lower vertebrate species have similar body plans and size, are poikilothermic, have tissue regenerative ability, and are adapted to moderate periods of fasting. Furthermore the gecko (Pachydactylus) can also survive prolonged periods without water. In pre-flight control experiments and after a 16-day Foton M-2 spaceflight without food or water, the geckos were recovered and showed no apparent negative health effects. However, detailed analysis of bone mass and architecture by micro Computed Tomography { pCT), showed that both synchronous control and spaceflight animals lost significant amounts of cancellous bone in the distal femur and humerus relative to basal controls. In addition, cell cycle analysis of 30h post-flight liver tissue reveals a shift of DNA content from G2 and S to G1, both in spaceflight and synchronous controls. Together, these results suggest that housing conditions alone induce rapid catabolism of cancellous bone and reduced normal tissue regeneration. Further use of the gecko Puchydactylus turneri as a spaceflight model requires modification of housing conditions, possibly by including water and food, or changing other factors such as eliminating housing stresses to obtain stable bone structure and tissue regeneration during spaceflight experiments.

Almeida, E. A.↗
DOE OSTI2020

A robust benchmark for detection of germline large deletions and insertions

New technologies and analysis methods are enabling genomic structural variants (SVs) to be detected with ever-increasing accuracy, resolution and comprehensiveness. To help translate these methods to routine research and clinical practice, we developed a sequence-resolved benchmark set for identification of both false-negative and false-positive germline large insertions and deletions. To create this benchmark for a broadly consented son in a Personal Genome Project trio with broadly available cells and DNA, the Genome in a Bottle Consortium integrated 19 sequence-resolved variant calling methods from diverse technologies. The final benchmark set contains 12,745 isolated, sequence-resolved insertion (7,281) and deletion (5,464) calls ≥50 base pairs (bp). The Tier 1 benchmark regions, for which any extra calls are putative false positives, cover 2.51 Gbp and 5,262 insertions and 4,095 deletions supported by ≥1 diploid assembly. We demonstrate that the benchmark set reliably identifies false negatives and false positives in high-quality SV callsets from short-, linked- and long-read sequencing and optical mapping.

59 BASIC BIOLOGICAL SCIENCES↗