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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
DOE OSTI2022

Functional characterization of diverse type I-F CRISPR-associated transposons

CRISPR-Cas systems generally provide adaptive immunity in prokaryotes through RNA-guided degradation of foreign genetic elements like bacteriophages and plasmids. Recently, however, transposon-encoded and nuclease-deficient CRISPR-Cas systems were characterized and shown to be co-opted by Tn7-like transposons for CRISPR RNA-guided DNA transposition. As a genome engineering tool, these CRISPR-Cas systems and their associated transposon proteins can be deployed for programmable, site-specific integration of sizable cargo DNA, circumventing the need for DNA cleavage and homology-directed repair involving endogenous repair machinery. Here, we selected a diverse set of type I-F3 CRISPR-associated transposon systems derived from Gammaproteobacteria, predicted all components essential for transposition activity, and deployed them for functionality testing within Escherichia coli. Our results demonstrate that these systems possess a significant range of integration efficiencies with regards to temperature, transposon size, and flexible PAM requirements. Additionally, our findings support the categorization of these systems into functional compatibility groups for efficient and orthogonal RNA-guided DNA integration. This work expands the CRISPR-based toolbox with new CRISPR RNA-guided DNA integrases that can be applied to complex and extensive genome engineering efforts.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Data for "Evaluating the industrial potential of emerging biomass pretreatment technologies in bioethanol production and lipid recovery from transgenic sugarcane"

The selection of pretreatment methods is critical to achieving high product yields during bioconversion of lignocellulosic biomass. Hydrothermal, soaking-in-aqueous ammonia, and ionic liquid pretreatment methods are viable candidates for minimizing sugar decomposition, permitting the effective hydrolysis of structural carbohydrates, and producing a fermentable substrate suitable for achieving industrial ethanol titers and yields. In this study, the effect of these three pretreatment methods on non-modified sugarcane cultivar CP88-1762 and two transgenic lipid-accumulating sugarcane lines, oilcane 1565 and oilcane 1566, were investigated and compared in terms of lipid recovery, sugar yield, and ethanol yields within the lignocellulosic biomass conversion pipeline. Fed-batch enzymatic hydrolysis at high solid loading yielded hydrolysates capable of supporting industrial bioethanol titers across all conditions. The highest sugar yields were obtained on ammonia-pretreated biomass hydrolysate (253.73 g L−1), followed by hydrothermally pretreated hydrolysate (213.10 g L−1) and ionic liquid-pretreated hydrolysate (154.20 g L−1). Commercially viable ethanol titers of 100.62 g L−1, 64.47 g L−1, and 52.95 g L−1 were achieved from ammonia, hydrothermal, and ionic liquid pretreated hydrolysate with the corresponding ethanol productivities of 2.08 g L−1 h−1, 0.53 g L−1 h−1, and 0.36 g L−1 h−1. The lower acetic acid concentration in ammonia-pretreated hydrolysate may have enhanced its fermentability relative to the hydrothermal pretreatment condition, as indicated by the differences in ethanol titer and productivity. Lower sugar yields and ethanol productivities under the ionic liquid conditions likely resulted from the inhibitory effect of cholinium lysinate. Oilcane 1565 and oilcane 1566 bagasse accumulated over 16- and 3 times higher lipids than the non-modified sugarcane CP88-1762. The total fatty acid content in the oilcane samples was reduced in ammonia and ionic liquid-pretreated bagasse relative to the hydrothermal pretreatment condition. While all pretreatment techniques tested are industrially viable, the observed differences in titer, productivity, and lipid content indicate that careful selection and validation of upstream processing methods can contribute to improved economic and environmental outcomes.

biomass analytics↗
DOE OSTI2026

Origin of replication discovery for environmentally isolated Pantoea strain enables expression of heterologous proteins, pathways and products

Leveraging predicted origin sequences from a previously characterized groundwater plasmidome, we constructed a barcoded plasmid library to screen for previously unknown origins. Testing this library against a panel of representative bacterial strains led to the identification of 3 previously unknown origins that replicate in gram-negative bacteria not previously associated with these origin sequences. Experimental validation confirmed that a plasmid bearing origin 6911 as the sole origin could replicate with a copy number of 9 (±2) in Pantoea sp. MT58, a fast growing and metal tolerant, environmentally important bacterium. Plasmids based on this new origin were used to express the reporter protein GFP, and non-native metabolite pathways for the natural product indigoidine and the terpenoid compound isoprenol. Functional previously unknown origins of replication in such non-model organisms can expand the toolkit for genetic manipulations of both model and less-studied bacteria.

molecular biology↗
DOE OSTI2022

Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression

The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA’s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dysfunctional under-responsive CD8+ T cells, reveal a potential role of 3-IPA in these responses. T-cell exhaustion was examined via infection of two genetically related mouse strains, DBA/1J and DBA/2J, with lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl13). The different mouse strains produced disparate outcomes driven by their T-cell responses. Infected DBA/2J presented with exhausted T cells and persistent infection, and DBA/1J mice died one week after infection from cytotoxic T lymphocytes (CTLs)-mediated pulmonary failure. Metabolomics revealed over 70 metabolites were altered between the DBA/1J and DBA/2J models over the course of the infection, most of them in mice with a fatal outcome. Cognitive-driven prioritization combined with statistical significance and fold change were used to prioritize the metabolites. 3-IPA, a tryptophan-derived metabolite, was identified as a high-priority candidate for testing. To test its activity 3-IPA was added to the drinking water of the mouse models during LCMV Cl13 infection, with the results showing that 3-IPA allowed the mice to survive longer. This negative immune-modulation effect might be of interest for the modulation of CTL responses in events such as autoimmune diseases, type I diabetes or even COVID-19. Moreover, 3-IPA’s bacterial origin raises the possibility of targeting the microbiome to enhance CTL responses in diseases such as cancer and chronic infection.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Assessment of Demographic, Genetic, and Imaging Variables Associated With Brain Resilience and Cognitive Resilience to Pathological Tau in Patients With Alzheimer Disease

Importance: Better understanding is needed of the degree to which individuals tolerate Alzheimer disease (AD)-like pathological tau with respect to brain structure (brain resilience) and cognition (cognitive resilience). Objective: To examine the demographic (age, sex, and educational level), genetic (APOE-ε4 status), and neuroimaging (white matter hyperintensities and cortical thickness) factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography (PET) load and to changes in global cognition over time. Design, setting, an participants: In this cross-sectional, longitudinal study, tau PET was performed from June 1, 2014, to November 30, 2017, and global cognition monitored for a mean [SD] interval of 2.0 [1.8] years at 3 dementia centers in South Korea, Sweden, and the United States. The study included amyloid-β-positive participants with mild cognitive impairment or AD dementia. Data analysis was performed from October 26, 2018, to December 11, 2019. Exposures: Standard dementia screening, cognitive testing, brain magnetic resonance imaging, amyloid-β PET and cerebrospinal fluid analysis, and flortaucipir (tau) labeled with fluor-18 (18F) PET. Main outcomes and measures: Separate linear regression models were performed between whole cortex [18F]flortaucipir uptake and cortical thickness, and standardized residuals were used to obtain a measure of brain resilience. The same procedure was performed for whole cortex [18F]flortaucipir uptake vs Mini-Mental State Examination (MMSE) as a measure of cognitive resilience. Bivariate and multivariable linear regression models were conducted with age, sex, educational level, APOE-ε4 status, white matter hyperintensity volumes, and cortical thickness as independent variables and brain and cognitive resilience measures as dependent variables. Linear mixed models were performed to examine whether changes in MMSE scores over time differed as a function of a combined brain and cognitive resilience variable. Results: A total of 260 participants (145 [55.8%] female; mean [SD] age, 69.2 [9.5] years; mean [SD] MMSE score, 21.9 [5.5]) were included in the study. In multivariable models, women (standardized β = -0.15, P = .02) and young patients (standardized β = -0.20, P = .006) had greater brain resilience to pathological tau. Higher educational level (standardized β = 0.23, P < .001) and global cortical thickness (standardized β = 0.23, P < .001) were associated with greater cognitive resilience to pathological tau. Linear mixed models indicated a significant interaction of brain resilience × cognitive resilience × time on MMSE (β [SE] = -0.235 [0.111], P = .03), with steepest slopes for individuals with both low brain and cognitive resilience. Conclusions and relevance: Results of this study suggest that women and young patients with AD have relative preservation of brain structure when exposed to neocortical pathological tau. Interindividual differences in resilience to pathological tau may be important to disease progression because participants with both low brain and cognitive resilience had the most rapid cognitive decline over time.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Advances in genetic tools for metabolic engineering of non-conventional yeasts

Non-conventional yeasts are emerging as powerful alternatives to Saccharomyces cerevisiae for metabolic engineering, owing to their innate stress tolerance, broad substrate utilization, and distinctive metabolic capabilities. These attributes position them as promising chassis for producing biofuels, pharmaceuticals, and specialty chemicals. This review synthesizes recent advances in genetic toolkits for four such species—Pichia kudriavzevii (Issatchenkia orientalis), Starmerella bombicola, Debaryomyces hansenii, and Pachysolen tannophilus—highlighting progress across plasmid architectures (episomal and integrative), identification of autonomously replicating sequences and centromeric elements, and the development of safe-harbor genomic loci. We summarize promoter and terminator libraries enabling tunable expression, the expansion of auxotrophic and antifungal selection markers with recycling strategies, and the rapid adaptation of CRISPR-based systems (Cas9 and Cas12a) with optimized guide RNA expression, multiplex editing, and approaches that enhance homologous recombination (e.g., KU70/80 disruption). We also review landing-pad platforms for modular, repeated integrations and transposon-based tools (e.g., piggyBac) that facilitate multigene pathway assembly. Collectively, these innovations are accelerating design-build-test-learn cycles and enabling precise, scalable engineering of non-conventional yeasts. Remaining challenges—including limited species-specific episomal systems, variable transformation efficiencies, genome-stability concerns, and alternative codon usage—define clear priorities for future toolkit development. Together, these advances and open needs chart a path toward robust, sustainable biomanufacturing using diverse non-conventional yeast chassis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Isochronic development of cortical synapses in primates and mice

Abstract The neotenous, or delayed, development of primate neurons, particularly human ones, is thought to underlie primate-specific abilities like cognition. We tested whether synaptic development follows suit—would synapses, in absolute time, develop slower in longer-lived, highly cognitive species like non-human primates than in shorter-lived species with less human-like cognitive abilities, e.g., the mouse? Instead, we find that excitatory and inhibitory synapses in the maleMus musculus(mouse) andRhesus macaque(primate) cortex form at similar rates, at similar times after birth. Primate excitatory and inhibitory synapses and mouse excitatory synapses also prune in such an isochronic fashion. Mouse inhibitory synapses are the lone exception, which are not pruned and instead continuously added throughout life. The monotony of synaptic development clocks across species with disparate lifespans, experiences, and cognitive abilities argues that such programs are likely orchestrated by genetic events rather than experience.

Science & Technology - Other Topics↗
DOE OSTI2023

A genomic region associated with iteroparous spawning phenology is linked with age‐at‐maturity in female steelhead trout

Abstract Age‐at‐maturity and iteroparity are two life history variations of steelhead trout ( Oncorhynchus mykiss ) that are believed to increase population resilience and stability. While repeat‐spawning individuals are thought to have historically made up a substantial portion of the reproductive population in the Columbia River and the majority of females still attempt outmigration as kelts, return rates of repeat‐spawner are low throughout the basin and below 1% for the furthest migrating stocks. Notably, outmigrating adults exhibit variation in rematuration phenology, displaying either “consecutive” (reproduce immediately the following season) or “skip” (delay spawning for future seasons) spawning patterns. Here, we use low coverage whole genome sequencing of consecutive versus skip spawning female Columbia River steelhead from two populations to test for genomic differences between these two iteroparous phenotypes. We identified genomic regions on several chromosomes which were associated with the phenology of iteroparity, including a region on chromosome 25 containing two genes, estradiol receptor beta ( ER β) and glycoprotein hormone beta‐5 ( GPHB5 ), which, in mammals, are estrogen‐sensitive and expressed in reproductive tissues. Allele frequencies in this ER β/ GPHB5 region differed among female steelhead of different age at maturity, but not males. These genes also shared an island of linkage disequilibrium with the SIX6 gene, 600Kbp away on the same chromosome, a region of known association with age‐at‐maturity. These observations contribute to growing evidence that age‐at‐maturity and the phenology of iteroparity are determined by overlapping physiological processes and genetic pathways.

Willis, Stuart↗
DOE OSTI2021

Mitochondrial Genomes of the United States Distribution of Gray Fox (Urocyon cinereoargenteus) Reveal a Major Phylogeographic Break at the Great Plains Suture Zone

We examined phylogeographic structure in gray fox (Urocyon cinereoargenteus) across the United States to identify the location of secondary contact zone(s) between eastern and western lineages and investigate the possibility of additional cryptic intraspecific divergences. We generated and analyzed complete mitochondrial genome sequence data from 75 samples and partial control region mitochondrial DNA sequences from 378 samples to investigate levels of genetic diversity and structure through population- and individual-based analyses including estimates of divergence (FST and SAMOVA), median joining networks, and phylogenies. We used complete mitochondrial genomes to infer phylogenetic relationships and date divergence times of major lineages of Urocyon in the United States. Despite broad-scale sampling, we did not recover additional major lineages of Urocyon within the United States, but identified a deep east-west split (~0.8 million years) with secondary contact at the Great Plains Suture Zone and confirmed the Channel Island fox (Urocyon littoralis) is nested within U. cinereoargenteus. Genetic diversity declined at northern latitudes in the eastern United States, a pattern concordant with post-glacial recolonization and range expansion. Beyond the east-west divergence, morphologically-based subspecies did not form monophyletic groups, though unique haplotypes were often geographically limited. Gray foxes in the United States displayed a deep, cryptic divergence suggesting taxonomic revision is needed. Secondary contact at a common phylogeographic break, the Great Plains Suture Zone, where environmental variables show a sharp cline, suggests ongoing evolutionary processes may reinforce this divergence. Follow-up study with nuclear markers should investigate whether hybridization is occurring along the suture zone and characterize contemporary population structure to help identify conservation units. Comparative work on other wide-ranging carnivores in the region should test whether similar evolutionary patterns and processes are occurring.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2020

Innovations in optimization and control of accelerators using methods of differential geometry and genetic algorithms (Final Report)

Online tuning of particle accelerators is necessary in order to achieve optimal machine performance. However, it is also a major challenge due to the large parameter space which must be searched and the fact that many of the desir- able objectives compete with one another, and so will not reach their optimal values simultaneously. In order to mitigate these issues, we have explored using dimension-reduction techniques to reduce the size of the parameter space which must be searched and multi-objective genetic algorithms to obtain the sets of tuning parameters which provide pareto-optimal values for the objectives. These methods have enabled us to obtain improved values of the vertical emittance at the Cornell Electron Storage Ring (CESR), and to do so with greater control of orbit errors. Algorithmic tuning is a multidisciplinary endeavour, requiring expertise in beam dynamics, diagnostics, control systems and computer science, and thus a key practical problem is to formulate a common language in which experts with different specialties can communicate. We developed a solution to this problem in the form of a generic accelerator software interface that allows for rapid prototyping of optimization and control algorithms. Our interface is built on the Experimental Physics and Industrial Control Systems (EPICS) and makes possible testing control code in simulation before deployment on real accelerators, as well as deployment of third-party optimization code.

43 PARTICLE ACCELERATORS↗
DOE OSTI2022

“Multiagent” Screening Improves Directed Enzyme Evolution by Identifying Epistatic Mutations

Enzyme evolution has enabled numerous advances in biotechnology and synthetic biology, yet still requires many iterative rounds of screening to identify optimal mutant sequences. This is due to the sparsity of the fitness landscape, which is caused by epistatic mutations that only offer improvements when combined with other mutations. We report an approach that incorporates diverse substrate analogues in the screening process, where multiple substrates act like multiple agents navigating the fitness landscape, identifying epistatic mutant residues without a need for testing the entire combinatorial search space. We initially validate this approach by engineering a malonyl-CoA synthetase and identify numerous epistatic mutations improving activity for several diverse substrates. The majority of these mutations would have been missed upon screening for a single substrate alone. We expect that this approach can accelerate a wide array of enzyme engineering programs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

An accurate and interpretable model for antimicrobial resistance in pathogenic Escherichia coli from livestock and companion animal species

Understanding the microbial genomic contributors to antimicrobial resistance (AMR) is essential for early detection of emerging AMR infections, a pressing global health threat in human and veterinary medicine. Here we used whole genome sequencing and antibiotic susceptibility test data from 980 disease causing Escherichia coli isolated from companion and farm animals to model AMR genotypes and phenotypes for 24 antibiotics. We determined the strength of genotype-to-phenotype relationships for 197 AMR genes with elastic net logistic regression. Model predictors were designed to evaluate different potential modes of AMR genotype translation into resistance phenotypes. Our results show a model that considers the presence of individual AMR genes and total number of AMR genes present from a set of genes known to confer resistance was able to accurately predict isolate resistance on average (mean F 1 score = 98.0%, SD = 2.3%, mean accuracy = 98.2%, SD = 2.7%). However, fitted models sometimes varied for antibiotics in the same class and for the same antibiotic across animal hosts, suggesting heterogeneity in the genetic determinants of AMR resistance. We conclude that an interpretable AMR prediction model can be used to accurately predict resistance phenotypes across multiple host species and reveal testable hypotheses about how the mechanism of resistance may vary across antibiotics within the same class and across animal hosts for the same antibiotic.

Chung, Henri C.↗
DOE OSTI2021

Accelerating Biological Insight for Understudied Genes

Synopsis The rapid expansion of genome sequence data is increasing the discovery of protein-coding genes across all domains of life. Annotating these genes with reliable functional information is necessary to understand evolution, to define the full biochemical space accessed by nature, and to identify target genes for biotechnology improvements. The majority of proteins are annotated based on sequence conservation with no specific biological, biochemical, genetic, or cellular function identified. Recent technical advances throughout the biological sciences enable experimental research on these understudied protein-coding genes in a broader collection of species. However, scientists have incentives and biases to continue focusing on well documented genes within their preferred model organism. This perspective suggests a research model that seeks to break historic silos of research bias by enabling interdisciplinary teams to accelerate biological functional annotation. We propose an initiative to develop coordinated projects of collaborating evolutionary biologists, cell biologists, geneticists, and biochemists that will focus on subsets of target genes in multiple model organisms. Concurrent analysis in multiple organisms takes advantage of evolutionary divergence and selection, which causes individual species to be better suited as experimental models for specific genes. Most importantly, multisystem approaches would encourage transdisciplinary critical thinking and hypothesis testing that is inherently slow in current biological research.

Zoology↗
DOE OSTI2025

Consistent performance of large language models in rare disease diagnosis across ten languages and 4917 cases

Background Large language models (LLMs) are increasingly used medicine for diverse applications including differential diagnostic support. The training data used to create LLMs such as the Generative Pretrained Transformer (GPT) predominantly consist of English-language texts, but LLMs could be used across the globe to support diagnostics if language barriers could be overcome. Initial pilot studies on the utility of LLMs for differential diagnosis in languages other than English have shown promise, but a large-scale assessment on the relative performance of these models in a variety of European and non-European languages on a comprehensive corpus of challenging rare-disease cases is lacking. Methods We created 4917 clinical vignettes using structured data captured with Human Phenotype Ontology (HPO) terms with the Global Alliance for Genomics and Health (GA4GH) Phenopacket Schema. These clinical vignettes span a total of 360 distinct genetic diseases with 2525 associated phenotypic features. We used translations of the Human Phenotype Ontology together with language-specific templates to generate prompts in English, Chinese, Czech, Dutch, French, German, Italian, Japanese, Spanish, and Turkish. We applied GPT-4o, version gpt-4o-2024-08-06, and the medically fine-tuned Meditron3-70B to the task of delivering a ranked differential diagnosis using a zero-shot prompt. An ontology-based approach with the Mondo disease ontology was used to map synonyms and to map disease subtypes to clinical diagnoses in order to automate evaluation of LLM responses. Findings For English, GPT-4o placed the correct diagnosis at the first rank 19.9% and within the top-3 ranks 27.0% of the time. In comparison, for the nine non-English languages tested here the correct diagnosis was placed at rank 1 between 16.9% and 20.6%, within top-3 between 25.4% and 28.6% of cases. The Meditron3 model placed the correct diagnosis within the first 3 ranks for 20.9% of cases in English and between 19.9% and 24.0% for the other nine languages. Interpretation The differential diagnostic performance of LLMs across a comprehensive corpus of rare-disease cases was largely consistent across the ten languages tested. This suggests that the utility of LLMs in clinical settings may extend to non-English clinical settings.

Artificial intelligence↗
DOE OSTI2024

Quantifying leaf symptoms of sorghum charcoal rot in images of field‐grown plants using deep neural networks

Abstract Charcoal rot of sorghum (CRS) is a significant disease affecting sorghum crops, with limited genetic resistance available. The causative agent, Macrophomina phaseolina (Tassi) Goid, is a highly destructive fungal pathogen that targets over 500 plant species globally, including essential staple crops. Utilizing field image data for precise detection and quantification of CRS could greatly assist in the prompt identification and management of affected fields and thereby reduce yield losses. The objective of this work was to implement various machine learning algorithms to evaluate their ability to accurately detect and quantify CRS in red‐green‐blue images of sorghum plants exhibiting symptoms of infection. EfficientNet‐B3 and a fully convolutional network emerged as the top‐performing models for image classification and segmentation tasks, respectively. Among the classification models evaluated, EfficientNet‐B3 demonstrated superior performance, achieving an accuracy of 86.97%, a recall rate of 0.71, and an F1 score of 0.73. Of the segmentation models tested, FCN proved to be the most effective, exhibiting a validation accuracy of 97.76%, a recall rate of 0.68, and an F1 score of 0.66. As the size of the image patches increased, both models’ validation scores increased linearly, and their inference time decreased exponentially. This trend could be attributed to larger patches containing more information, improving model performance, and fewer patches reducing the computational load, thus decreasing inference time. The models, in addition to being immediately useful for breeders and growers of sorghum, advance the domain of automated plant phenotyping and may serve as a foundation for drone‐based or other automated field phenotyping efforts. Additionally, the models presented herein can be accessed through a web‐based application where users can easily analyze their own images.

Gonzalez, Emmanuel M.↗
DOE OSTI2020

In vitro prototyping and rapid optimization of biosynthetic enzymes for cell design

The design and optimization of biosynthetic pathways for industrially relevant, non-model organisms is challenging due to transformation idiosyncrasies, reduced numbers of validated genetic parts and a lack of high-throughput workflows. Here we describe a platform for in vitro prototyping and rapid optimization of biosynthetic enzymes (iPROBE) to accelerate this process. In iPROBE, cell lysates are enriched with biosynthetic enzymes by cell-free protein synthesis and then metabolic pathways are assembled in a mix-and-match fashion to assess pathway performance. We demonstrate iPROBE by screening 54 different cell-free pathways for 3-hydroxybutyrate production and optimizing a six-step butanol pathway across 205 permutations using data-driven design. Observing a strong correlation (r = 0.79) between cell-free and cellular performance, we then scaled up our highest-performing pathway, which improved in vivo 3-HB production in Clostridium by 20-fold to 14.63 ± 0.48 g l -1 . Finally, we expect iPROBE to accelerate design–build–test cycles for industrial biotechnology.

36 MATERIALS SCIENCE↗
DOE OSTI2023

Evolutionary consequences of nascent multicellular life cycles

A key step in the evolutionary transition to multicellularity is the origin of multicellular groups as biological individuals capable of adaptation. Comparative work, supported by theory, suggests clonal development should facilitate this transition, although this hypothesis has never been tested in a single model system. We evolved 20 replicate populations of otherwise isogenic clonally reproducing ‘snowflake’ yeast (Δace2/∆ace2) and aggregative ‘floc’ yeast (GAL1p::FLO1 /GAL1p::FLO1) with daily selection for rapid growth in liquid media, which favors faster cell division, followed by selection for rapid sedimentation, which favors larger multicellular groups. While both genotypes adapted to this regime, growing faster and having higher survival during the group-selection phase, there was a stark difference in evolutionary dynamics. Aggregative floc yeast obtained nearly all their increased fitness from faster growth, not improved group survival; indicating that selection acted primarily at the level of cells. In contrast, clonal snowflake yeast mainly benefited from higher group-dependent fitness, indicating a shift in the level of Darwinian individuality from cells to groups. Through genome sequencing and mathematical modeling, we show that the genetic bottlenecks in a clonal life cycle also drive much higher rates of genetic drift—a result with complex implications for this evolutionary transition. Our results highlight the central role that early multicellular life cycles play in the process of multicellular adaptation.

Life Sciences & Biomedicine - Other Topics↗
DOE OSTI2021

Novel compound heterozygous CPLANE1 variants identified in a Chinese family with Joubert syndrome

Abstract Joubert syndrome (JS) and JS‐related disorders (JSRD) are a group of neurodevelopmental diseases that share the “molar tooth sign” on axial brain magnetic resonance imaging (MRI), accompanied by cerebellar vermis hypoplasia, ataxia, hypotonia, and developmental delay. To identify variants responsible for the clinical symptoms of a Chinese family with JS and to explore the genotype–phenotype associations, we conducted a series of clinical examinations, including blood tests, brain MRI scans, ultrasound imaging, and ophthalmologic examination. Genomic DNA was extracted from the peripheral blood of the six‐person family, and the pathogenic variants were detected by whole‐exome sequencing (WES) and verified by Sanger sequencing. WES revealed two novel compound heterozygous variants in CPLANE1 : c.1270C>T (p.Arg424*) in exon 10 and c.8901C>A (p.Tyr2967*) in exon 48 of one child, inherited from each parent. Both variants were absent in ethnically matched Chinese control individuals and were either absent or present at very low frequencies in public databases, suggesting that these variants could be the pathogenic triggers of the JS phenotype. Notably, these CPLANE1 sequence variants were related to the pathogenesis of autosomal recessive JS in this study. The newly discovered variants expand the mutation spectrum of CPLANE1 , which assists in understanding the molecular mechanism underlying JS and improving the recognition of genetic counseling, particularly for families with a history of autosomal recessive JS.

Zhang, Cheng↗