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DOE OSTI2022

Genetic algorithm-based optimisation of the few-group structure for lead fast reactors analysis

The optimal choice of the few-group structure for full-core transient analyses is still an open issue in reactor physics, especially for fast system like the lead fast reactor. One possible approach to select the group boundaries is represented by heuristic search algorithms, such as evolutionary ones. In this paper, a genetic algorithm coupled with the SIMMER code is employed to determine optimized six-group boundaries for the analysis of the ALFRED reactor. The Serpent Monte Carlo code is adopted to produce both the fine-group cross section library and the fine-group flux, used as a figure of merit to drive the genetic optimisation. The results show that the algorithm is indeed able to find satisfactory solutions that comply with the set objectives and can be reasonably interpreted in light of the underlying physics of the considered core. (authors)

21 SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLANTS↗

DOE OSTI2022

A sensitive and specific genetically-encoded potassium ion biosensor for in vivo applications across the tree of life

Potassium ion (K + ) plays a critical role as an essential electrolyte in all biological systems. Genetically-encoded fluorescent K + biosensors are promising tools to further improve our understanding of K + -dependent processes under normal and pathological conditions. Here, we report the crystal structure of a previously reported genetically-encoded fluorescent K + biosensor, GINKO1, in the K + -bound state. Using structure-guided optimization and directed evolution, we have engineered an improved K + biosensor, designated GINKO2, with higher sensitivity and specificity. We have demonstrated the utility of GINKO2 for in vivo detection and imaging of K + dynamics in multiple model organisms, including bacteria, plants, and mice.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2016

A Multi-scale Computational Platform to Mechanistically Assess the Effect of Genetic Variation on Drug Responses in Human Erythrocyte Metabolism

Progress in systems medicine brings promise to addressing patient heterogeneity and individualized therapies. Recently, genome-scale models of metabolism have been shown to provide insight into the mechanistic link between drug therapies and systems-level off-target effects while being expanded to explicitly include the three-dimensional structure of proteins. The integration of these molecular-level details, such as the physical, structural, and dynamical properties of proteins, notably expands the computational description of biochemical network-level properties and the possibility of understanding and predicting whole cell phenotypes. In this study, we present a multi-scale modeling framework that describes biological processes which range in scale from atomistic details to an entire metabolic network. Using this approach, we can understand how genetic variation, which impacts the structure and reactivity of a protein, influences both native and drug-induced metabolic states. As a proof-of-concept, we study three enzymes (catechol-O-methyltransferase, glucose-6-phosphate dehydrogenase, and glyceraldehyde-3-phosphate dehydrogenase) and their respective genetic variants which have clinically relevant associations. Using all-atom molecular dynamic simulations enables the sampling of long timescale conformational dynamics of the proteins (and their mutant variants) in complex with their respective native metabolites or drug molecules. We find that changes in a protein’s structure due to a mutation influences protein binding affinity to metabolites and/or drug molecules, and inflicts large-scale changes in metabolism

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Filling gaps in bacterial catabolic pathways with computation and high-throughput genetics

To discover novel catabolic enzymes and transporters, we combined high-throughput genetic data from 29 bacteria with an automated tool to find gaps in their catabolic pathways. GapMind for carbon sources automatically annotates the uptake and catabolism of 62 compounds in bacterial and archaeal genomes. For the compounds that are utilized by the 29 bacteria, we systematically examined the gaps in GapMind’s predicted pathways, and we used the mutant fitness data to find additional genes that were involved in their utilization. We identified novel pathways or enzymes for the utilization of glucosamine, citrulline, myo-inositol, lactose, and phenylacetate, and we annotated 299 diverged enzymes and transporters. We also curated 125 proteins from published reports. For the 29 bacteria with genetic data, GapMind finds high-confidence paths for 85% of utilized carbon sources. In diverse bacteria and archaea, 38% of utilized carbon sources have high-confidence paths, which was improved from 27% by incorporating the fitness-based annotations and our curation. GapMind for carbon sources is available as a web server ( http://papers.genomics.lbl.gov/carbon ) and takes just 30 seconds for the typical genome.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2015

Scanning the landscape of genome architecture of non-O1 and non-O139 Vibrio cholerae by whole genome mapping reveals extensive population genetic diversity

Historically, cholera outbreaks have been linked to V. cholerae O1 serogroup strains or its derivatives of the O37 and O139 serogroups. A genomic study on the 2010 Haiti cholera outbreak strains highlighted the putative role of non O1/non-O139 V. cholerae in causing cholera and the lack of genomic sequences of such strains from around the world. Here we address these gaps by scanning a global collection of V. cholerae strains as a first step towards understanding the population genetic diversity and epidemic potential of non O1/non-O139 strains. Whole Genome Mapping (Optical Mapping) based bar coding produces a high resolution, ordered restriction map, depicting a complete view of the unique chromosomal architecture of an organism. To assess the genomic diversity of non-O1/non-O139 V. cholerae , we applied a Whole Genome Mapping strategy on a well-defined and geographically and temporally diverse strain collection, the Sakazaki serogroup type strains. Whole Genome Map data on 91 of the 206 serogroup type strains support the hypothesis that V. cholerae has an unprecedented genetic and genomic structural diversity. Interestingly, we discovered chromosomal fusions in two unusual strains that possess a single chromosome instead of the two chromosomes usually found in V. cholerae . We also found pervasive chromosomal rearrangements such as duplications and indels in many strains. The majority of Vibrio genome sequences currently in public databases are unfinished draft sequences. The Whole Genome Mapping approach presented here enables rapid screening of large strain collections to capture genomic complexities that would not have been otherwise revealed by unfinished draft genome sequencing and thus aids in assembling and finishing draft sequences of complex genomes. Furthermore, Whole Genome Mapping allows for prediction of novel V. cholerae non-O1/non-O139 strains that may have the potential to cause future cholera outbreaks.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2016

Real-Time Pathogen Detection in the Era of Whole-Genome Sequencing and Big Data: Comparison of k-mer and Site-Based Methods for Inferring the Genetic Distances among Tens of Thousands of Salmonella Samples

The adoption of whole-genome sequencing within the public health realm for molecular characterization of bacterial pathogens has been followed by an increased emphasis on real-time detection of emerging outbreaks (e.g., food-borne Salmonellosis). In turn, large databases of whole-genome sequence data are being populated. These databases currently contain tens of thousands of samples and are expected to grow to hundreds of thousands within a few years. For these databases to be of optimal use one must be able to quickly interrogate them to accurately determine the genetic distances among a set of samples. Being able to do so is challenging due to both biological (evolutionary diverse samples) and computational (petabytes of sequence data) issues. We evaluated seven measures of genetic distance, which were estimated from either k-mer profiles (Jaccard, Euclidean, Manhattan, Mash Jaccard, and Mash distances) or nucleotide sites (NUCmer and an extended multi-locus sequence typing (MLST) scheme). Finally, when analyzing empirical data (wholegenome sequence data from 18,997 Salmonella isolates) there are features (e.g., genomic, assembly, and contamination) that cause distances inferred from k-mer profiles, which treat absent data as informative, to fail to accurately capture the distance between samples when compared to distances inferred from differences in nucleotide sites. Thus, site-based distances, like NUCmer and extended MLST, are superior in performance, but accessing the computing resources necessary to perform them may be challenging when analyzing large databases.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2018

Genetic stability of foot-and-mouth disease virus during long-term infections in natural hosts

Foot-and-mouth disease (FMD) is a severe infection caused by a picornavirus that affects livestock and wildlife. Persistence in ruminants is a well-documented feature of Foot-andmouth disease virus (FMDV) pathogenesis and a major concern for disease control. Persistently infected animals harbor virus for extended periods, providing a unique opportunity to study within-host virus evolution. This study investigated the genetic dynamics of FMDV during persistent infections of naturally infected Asian buffalo. Using next-generation sequencing (NGS) we obtained 21 near complete FMDV genome sequences from 12 sub-clinically infected buffalo over a period of one year. Four animals yielded only one virus isolate and one yielded two isolates of different serotype suggesting a serial infection. Seven persistently infected animals yielded more than one virus of the same serotype showing a longterm intra-host viral genetic divergence at the consensus level of less than 2.5%. Quasi-species analysis showed few nucleotide variants and non-synonymous substitutions of progeny virus despite intra-host persistence of up to 152 days. Phylogenetic analyses of serotype Asia-1 VP1 sequences clustered all viruses from persistent animals with Group VII viruses circulating in Pakistan in 2011, but distinct from those circulating on 2008–2009. Furthermore, signature amino acid (aa) substitutions were found in the antigenically relevant VP1 of persistent viruses compared with viruses from 2008–2009. Intra-host purifying selective pressure was observed, with few codons in structural proteins undergoing positive selection. However, FMD persistent viruses did not show a clear pattern of antigenic selection. Our findings provide insight into the evolutionary dynamics of FMDV populations within naturally occurring subclinical and persistent infections that may have implications to vaccination strategies in the region.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2020

Fungal Pretreatment and Enzymatic Hydrolysis of Genetically-Modified Populus trichocarpa

Fungal pretreatment of Populus trichocarpa wood genetically modified to reduce lignin and alter lignin chemistry is investigated for its effectiveness as an alternative to common pretreatment methods. The goal of this work is to improve biomass utilization for biofuel and biochemical applications by increasing sugar release. Sugar release after enzymatic hydrolysis was measured after various biomass pretreatments (including wood-rot fungus, hot water, and dilute acid). In the wildtype, and in constructs downregulated in PAL, 4CL, and C3H, the fungal pretreatment resulted in substantial improvements in sugar yields, up to 2.4-fold increase in glucose yield and 6-fold increase in xylose yield after enzymatic hydrolysis compared to the unpretreated control. However, the effects of fungal pretreatment were inconsistent, and in genetic lines down-regulated in 4CL, CCoAOMT, CAld5H, and C3H, fungal pretreatment yielded similar or decreased sugar release after enzymatic hydrolysis.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2014

Programmed Nanomaterial Assemblies in Large Scales: Applications of Synthetic and Genetically- Engineered Peptides to Bridge Nano-Assemblies and Macro-Assemblies

Work is reported in these areas: Large-scale & reconfigurable 3D structures of precise nanoparticle assemblies in self-assembled collagen peptide grids; Binary QD-Au NP 3D superlattices assembled with collagen-like peptides and energy transfer between QD and Au NP in 3D peptide frameworks; Catalytic peptides discovered by new hydrogel-based combinatorial phage display approach and their enzyme-mimicking 2D assembly; New autonomous motors of metal-organic frameworks (MOFs) powered by reorganization of self-assembled peptides at interfaces; Biomimetic assembly of proteins into microcapsules on oil-in-water droplets with structural reinforcement via biomolecular recognition-based cross-linking of surface peptides; and Biomimetic fabrication of strong freestanding genetically-engineered collagen peptide films reinforced by quantum dot joints. We gained the broad knowledge about biomimetic material assembly from nanoscale to microscale ranges by coassembling peptides and NPs via biomolecular recognition. We discovered: Genetically-engineered collagen-like peptides can be self-assembled with Au NPs to generate 3D superlattices in large volumes (> μm{sup 3}); The assembly of the 3D peptide-Au NP superstructures is dynamic and the interparticle distance changes with assembly time as the reconfiguration of structure is triggered by pH change; QDs/NPs can be assembled with the peptide frameworks to generate 3D superlattices and these QDs/NPs can be electronically coupled for the efficient energy transfer; The controlled assembly of catalytic peptides mimicking the catalytic pocket of enzymes can catalyze chemical reactions with high selectivity; and, For the bacteria-mimicking swimmer fabrication, peptide-MOF superlattices can power translational and propellant motions by the reconfiguration of peptide assembly at the MOF-liquid interface.

36 MATERIALS SCIENCE↗

DOE OSTI2015

Ternary alloy material prediction using genetic algorithm and cluster expansion

This thesis summarizes our study on the crystal structures prediction of Fe-V-Si system using genetic algorithm and cluster expansion. Our goal is to explore and look for new stable compounds. We started from the current ten known experimental phases, and calculated formation energies of those compounds using density functional theory (DFT) package, namely, VASP. The convex hull was generated based on the DFT calculations of the experimental known phases. Then we did random search on some metal rich (Fe and V) compositions and found that the lowest energy structures were body centered cube (bcc) underlying lattice, under which we did our computational systematic searches using genetic algorithm and cluster expansion. Among hundreds of the searched compositions, thirteen were selected and DFT formation energies were obtained by VASP. The stability checking of those thirteen compounds was done in reference to the experimental convex hull. We found that the composition, 24-8-16, i.e., Fe 3 VSi 2 is a new stable phase and it can be very inspiring to the future experiments.

36 MATERIALS SCIENCE↗

DOE OSTI2020

Biologically Diverse Genetic Engineering Platform

This project focused on methods to genetically edit arbitrary prokaryotes to convert non-agricultural biomass to industrially relevant chemicals at scale and at a price point that would be competitive with petroleum. Our target chemical for this demonstration was succinic acid, a polymer precursor that could theoretically be produced at scale from biomass. We demonstrated genetic control over a selected bacterial type strain: we can make permanent and directed changes to its genome. After thoroughly characterizing its behavior, and the circumstances under which it produced the most succinic acid, the researchers found a wild-type isolate that produces at least eight times more succinic acid than the type strain.

09 BIOMASS FUELS↗

DOE OSTI2024

Conserved genetic mechanisms for biotic stress in sorghum (Final report)

Developing durable disease resistance for biofuel crops is crucial, particularly as the range of biofuel crop production expands and pathogens of other plant species evolve to cause diseases of bioenergy feedstocks. Setosphaeria species are significant pathogens of the Andropogonae, and S. turcica can infect both maize and sorghum. Sorghum leaf blight (SLB), caused by S. turcica, is widespread and can decrease grain yields up to 50%, reduce forage quantity and quality, and predispose plants to other diseases, such as anthracnose. Our overall objective was to gain a systems-level understanding of the pathosystem by leveraging natural genetic variation, host specificity of the pathogen, and transcriptome analysis to improve biotic stress resistance in sorghum. We proposed three specific goals: 1) Identify sorghum alleles conferring resistance to S. turcica using natural genetic variation. 2) Characterize genes associated with biotic stress response in sorghum. 3) Identify fungal genes responsible for host specificity.

09 BIOMASS FUELS↗

DOE OSTI2024

Conserved genetic mechanisms for biotic stress in sorghum (Final Report)

09 BIOMASS FUELS↗

DOE OSTI2023

Selecting Minimal Motion Primitive Libraries with Genetic Algorithms

Motion primitives allow for application of discrete search algorithms to rapidly produce trajectories in complex continuous space. The maneuver automaton (MA) provides an elegant formulation for creating a primitive library based on trims and maneuvers. However, performance is fundamentally limited by the contents of the primitive library. If the library is too sparse, performance can be poor in terms of path cost, whereas a library that is too large can increase run time. This work outlines new methods for using genetic algorithms to prune a primitive library. The proposed methods balance the path cost and planning time while maintaining the reachability of the MA. The genetic algorithm in this paper evaluates and mutates populations of motion primitive libraries to optimize both objectives. Here, we illustrate the performance of these methods with a simulated study using a nonlinear medium-fidelity F-16 model. We optimize a library with the presented algorithm for obstacle-free navigation and a nap-of-the-Earth navigation task. In the obstacle-free navigation task, we show a tradeoff of a 10.16% higher planning cost for a 96.63% improvement in run time. In the nap-of-the-Earth task, we show a tradeoff of a 9.712% higher planning cost for a 92.06% improvement in run time.

42 ENGINEERING↗

DOE OSTI2014

The genetic basis of energy conservation in the sulfate-reducing bacterium Desulfovibrio alaskensis G20

Sulfate-reducing bacteria play major roles in the global carbon and sulfur cycles, but it remains unclear how reducing sulfate yields energy. To determine the genetic basis of energy conservation, we measured the fitness of thousands of pooled mutants of Desulfovibrio alaskensis G20 during growth in 12 different combinations of electron donors and acceptors. We show that ion pumping by the ferredoxin:NADH oxidoreductase Rnf is required whenever substrate-level phosphorylation is not possible. The uncharacterized complex Hdr/flox-1 (Dde_1207:13) is sometimes important alongside Rnf and may perform an electron bifurcation to generate more reduced ferredoxin from NADH to allow further ion pumping. Similarly, during the oxidation of malate or fumarate, the electron-bifurcating transhydrogenase NfnAB-2 (Dde_1250:1) is important and may generate reduced ferredoxin to allow additional ion pumping by Rnf. During formate oxidation, the periplasmic [NiFeSe] hydrogenase HysAB is required, which suggests that hydrogen forms in the periplasm, diffuses to the cytoplasm, and is used to reduce ferredoxin, thus providing a substrate for Rnf. We found that during hydrogen utilization, the transmembrane electron transport complex Tmc is important and may move electrons from the periplasm into the cytoplasmic sulfite reduction pathway. Finally, mutants of many other putative electron carriers have no clear phenotype, which suggests that they are not important under our growth conditions, although we cannot rule out genetic redundancy.

58 GEOSCIENCES↗

DOE OSTI2021

The Distinctive Evolution of orfX Clostridium parabotulinum Strains and Their Botulinum Neurotoxin Type A and F Gene Clusters Is Influenced by Environmental Factors and Gene Interactions via Mobile Genetic Elements

Of the seven currently known botulinum neurotoxin-producing species of Clostridium, C. parabotulinum, or C. botulinum Group I, is the species associated with the majority of human botulism cases worldwide. Phylogenetic analysis of these bacteria reveals a diverse species with multiple genomic clades. The neurotoxins they produce are also diverse, with over 20 subtypes currently represented. The existence of different bont genes within very similar genomes and of the same bont genes/gene clusters within different bacterial variants/species indicates that they have evolved independently. The neurotoxin genes are associated with one of two toxin gene cluster types containing either hemagglutinin (ha) genes or orfX genes. These genes may be located within the chromosome or extrachromosomal elements such as large plasmids. Although BoNT-producing C parabotulinum bacteria are distributed globally, they are more ubiquitous in certain specific geographic regions. Notably, northern hemisphere strains primarily contain ha gene clusters while southern hemisphere strains have a preponderance of orfX gene clusters. OrfX C. parabotulinum strains constitute a subset of this species that contain highly conserved bont gene clusters having a diverse range of bont genes. While much has been written about strains with ha gene clusters, less attention has been devoted to those with orfX gene clusters. The recent sequencing of 28 orfX C. parabotulinum strains and the availability of an additional 91 strains for analysis provides an opportunity to compare genomic relationships and identify unique toxin gene cluster characteristics and locations within this species subset in depth. The mechanisms behind the independent processes of bacteria evolution and generation of toxin diversity are explored through the examination of bacterial relationships relating to source locations and evidence of horizontal transfer of genetic material among different bacterial variants, particularly concerning bont gene clusters. Analysis of the content and locations of the bont gene clusters offers insights into common mechanisms of genetic transfer, chromosomal integration, and development of diversity among these genes.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2018

Genome-Wide Association Study in Pseudo-F 2 Populations of Switchgrass Identifies Genetic Loci Affecting Heading and Anthesis Dates

Switchgrass ( Panicum virgatum ) is a native prairie grass and valuable bio-energy crop. The physiological change from juvenile to reproductive adult can draw important resources away from growth into producing reproductive structures, thereby limiting the growth potential of early flowering plants. Delaying the flowering of switchgrass is one approach by which to increase total biomass. The objective of this research was to identify genetic variants and candidate genes for controlling heading and anthesis in segregating switchgrass populations. Four pseudo-F 2 populations (two pairs of reciprocal crosses) were developed from lowland (late flowering) and upland (early flowering) ecotypes, and heading and anthesis dates of these populations were collected in Lafayette, IN and DeKalb, IL in 2015 and 2016. Across 2 years, there was a 34- and 73-day difference in heading and a 52- and 75-day difference in anthesis at the Lafayette and DeKalb locations, respectively. A total of 37,901 single nucleotide polymorphisms obtained by exome capture sequencing of the populations were used in a genome-wide association study (GWAS) that identified five significant signals at three loci for heading and two loci for anthesis. Among them, a homolog of FLOWERING LOCUS T on chromosome 5b associated with heading date was identified at the Lafayette location across 2 years. A homolog of ARABIDOPSIS PSEUDO-RESPONSE REGULATOR 5, a light modulator in the circadian clock associated with heading date was detected on chromosome 8a across locations and years. These results demonstrate that genetic variants related to floral development could lend themselves to a long-term goal of developing late flowering varieties of switchgrass with high biomass yield.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

A genetic screen for dominant chloroplast reactive oxygen species signaling mutants reveals life stage-specific singlet oxygen signaling networks

Plants employ intricate molecular mechanisms to respond to abiotic stresses, which often lead to the accumulation of reactive oxygen species (ROS) within organelles such as chloroplasts. Such ROS can produce stress signals that regulate cellular response mechanisms. One ROS, singlet oxygen ( 1 O 2 ), is predominantly produced in the chloroplast during photosynthesis and can trigger chloroplast degradation, programmed cell death (PCD), and retrograde (organelle-to-nucleus) signaling. However, little is known about the molecular mechanisms involved in these signaling pathways or how many different signaling 1 O 2 pathways may exist. The Arabidopsis thaliana plastid ferrochelatase two (fc2) mutant conditionally accumulates chloroplast 1 O 2 , making fc2 a valuable genetic system for studying chloroplast 1 O 2 -initiated signaling. Here, we have used activation tagging in a new forward genetic screen to identify eight dominant fc2 activation-tagged (fas) mutations that suppress chloroplast 1 O 2 -initiated PCD. While 1 O 2 -triggered PCD is blocked in all fc2 fas mutants in the adult stage, such cellular degradation in the seedling stage is blocked in only two mutants. This differential blocking of PCD suggests that life-stage-specific 1 O 2 -response pathways exist. In addition to PCD, fas mutations generally reduce 1 O 2 -induced retrograde signals. Furthermore, fas mutants have enhanced tolerance to excess light, a natural mechanism to produce chloroplast 1 O 2 . However, general abiotic stress tolerance was only observed in one fc2 fas mutant (fc2 fas2). Together, this suggests that plants can employ general stress tolerance mechanisms to overcome 1 O 2 production but that this screen was mostly specific to 1 O 2 signaling. We also observed that salicylic acid (SA) and jasmonate (JA) stress hormone response marker genes were induced in 1 O 2 -stressed fc2 and generally reduced by fas mutations, suggesting that SA and JA signaling is correlated with active 1 O 2 signaling and PCD. Together, this work highlights the complexity of 1 O 2 signaling by demonstrating that multiple pathways may exist and introduces a suite of new 1 O 2 signaling mutants to investigate the mechanisms controlling chloroplast-initiated degradation, PCD, and retrograde signaling.

59 BASIC BIOLOGICAL SCIENCES↗