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790 records · Page 44
All sourcesNASA NTRSDOE OSTI
NASA NTRS2000

A calmodulin binding protein from Arabidopsis is induced by ethylene and contains a DNA-binding motif

Calmodulin (CaM), a key calcium sensor in all eukaryotes, regulates diverse cellular processes by interacting with other proteins. To isolate CaM binding proteins involved in ethylene signal transduction, we screened an expression library prepared from ethylene-treated Arabidopsis seedlings with 35S-labeled CaM. A cDNA clone, EICBP (Ethylene-Induced CaM Binding Protein), encoding a protein that interacts with activated CaM was isolated in this screening. The CaM binding domain in EICBP was mapped to the C-terminus of the protein. These results indicate that calcium, through CaM, could regulate the activity of EICBP. The EICBP is expressed in different tissues and its expression in seedlings is induced by ethylene. The EICBP contains, in addition to a CaM binding domain, several features that are typical of transcription factors. These include a DNA-binding domain at the N terminus, an acidic region at the C terminus, and nuclear localization signals. In database searches a partial cDNA (CG-1) encoding a DNA-binding motif from parsley and an ethylene up-regulated partial cDNA from tomato (ER66) showed significant similarity to EICBP. In addition, five hypothetical proteins in the Arabidopsis genome also showed a very high sequence similarity with EICBP, indicating that there are several EICBP-related proteins in Arabidopsis. The structural features of EICBP are conserved in all EICBP-related proteins in Arabidopsis, suggesting that they may constitute a new family of DNA binding proteins and are likely to be involved in modulating gene expression in the presence of ethylene.

Non-NASA Center↗
DOE OSTI2023

Identification of 2-Hydroxyacyl-CoA Synthases with High Acyloin Condensation Activity for Orthogonal One-Carbon Bioconversion

One-carbon (C1) compounds are emerging as cost-effective and potentially carbon-negative feedstocks for biomanufacturing, which require efficient, versatile metabolic platforms for the synthesis of value-added products. Synthetic formyl-CoA elongation (FORCE) pathways allow diverse product synthesis from C1 compounds via iterative C1 elongation, operating independently from the host metabolism with reduced engineering complexity and improved theoretical yields. However, a major bottleneck was identified as the suboptimal kinetics of the core C1–C1 condensation enzyme, 2-hydroxyacyl-CoA synthase (HACS), catalyzing the acyloin condensation reaction between formaldehyde and formyl-CoA. Furthermore, we used a combinatorial approach of bioprospecting and rational protein engineering to identify multiple HACS variants with significantly improved activities toward C1 substrates. Sequence and structure alignment of the active variants elucidated the key regions for the catalytic function, which were targeted for mutagenesis, leading to improved catalytic efficiency. In parallel, a consecutive round of bioprospecting for homologs with high similarity with active variants revealed a highly active HACS variant exhibiting up to 7-fold improvement in catalytic efficiency (k cat /K M ) and 14-fold improvement in the FORCE pathway flux in vivo compared to the previous reports. Upon further optimization of the downstream pathway, the orthogonal C1-to-product bioconversion system showed a metabolic flux of up to 700 μM glycolate OD –1 h –1 (2.1 mmol gDCW –1 h –1 ) and an industrially relevant glycolate titer, rate, and yield of 5.2 g L –1 (67.8 mM), 0.22 g L –1 h –1 , and 94% carbon yield, respectively.

2-hydroxyacyl-CoA synthase↗
DOE OSTI2026

Gene and genome duplications have contrasting impacts on biosynthetic and flower developmental pathways in California poppy

Benzylisoquinoline alkaloids (BIAs) represent a vast group of specialized plant metabolites with diverse pharmaceutical applications, synthesized by a variety of gene families. Among the multiple plant lineages that produce BIAs, the most notable is the poppy family (Papaveraceae), with California poppy (Eschscholzia californica) emerging as a model organism. Here, we report a haplotype-resolved genome assembly, in combination with a high-density expression atlas, for California poppy. Genome analyses reveal recent diversification of BIA biosynthesis genes in poppy through localized duplications. Furthermore, we demonstrate that the degree of phylogenetic relatedness among paralogs within BIA biosynthesis-associated gene families correlates with similarities in gene expression. In contrast, gene families involved in carotenoid biosynthesis, which contributes to the intense orange petal pigmentation, are not phylogenetically clustered, and floral developmental regulators exhibit a high degree of retention of gene duplicates associated with ancient polyploidy events. These findings illustrate alternative roles for gene and genome duplications as drivers of trait evolution. Given the position of California poppy in the angiosperm phylogeny, the high-quality genomic resources generated for this work constitute a valuable resource for comparative genomic and transcriptomic analyses for poppies and flowering plants more generally.

Rössner, Le-Han [Justus-Liebig University, Giessen↗
NASA NTRS2003

Non-Genomic Origins of Proteins and Metabolism

It is proposed that evolution of inanimate matter to cells endowed with a nucleic acid- based coding of genetic information was preceded by an evolutionary phase, in which peptides not coded by nucleic acids were able to self-organize into networks capable of evolution towards increasing metabolic complexity. Recent findings that truly different, simple peptides (Keefe and Szostak, 2001) can perform the same function (such as ATP binding) provide experimental support for this mechanism of early protobiological evolution. The central concept underlying this mechanism is that the reproduction of cellular functions alone was sufficient for self-maintenance of protocells, and that self- replication of macromolecules was not required at this stage of evolution. The precise transfer of information between successive generations of the earliest protocells was unnecessary and, possibly, undesirable. The key requirement in the initial stage of protocellular evolution was an ability to rapidly explore a large number of protein sequences in order to discover a set of molecules capable of supporting self- maintenance and growth of protocells. Undoubtedly, the essential protocellular functions were carried out by molecules not nearly as efficient or as specific as contemporary proteins. Many, potentially unrelated sequences could have performed each of these functions at an evolutionarily acceptable level. As evolution progressed, however proteins must have performed their functions with increasing efficiency and specificity. This, in turn, put additional constraints on protein sequences and the fraction of proteins capable of performing their functions at the required level decreased. At some point, the likelihood of generating a sufficiently efficient set of proteins through a non-coded synthesis was so small that further evolution was not possible without storing information about the sequences of these proteins. Beyond this point, further evolution required coupling between proteins and informational polymers that is characteristic to all known forms of life. The emergence of such coupling must be postulated in any scenario of the origin of life, no matter whether it starts with RNA or proteins. To examine the evolutionary potential of non-genomic systems, a simple, computationally tractable model, which is still capable of capturing the essential features of the real system, has been studied computationally. Both constructive and destructive processes have been introduced into the model in a stochastic manner. Instead of assuming random reaction sets, only a suite of protobiologically plausible reactions has been considered. Peptides have been explicitly considered as protoenzymes and their catalytic efficiencies have been assigned on the basis of biochemical principles and experimental estimates. Simulations have been carried out using a novel approach (The Next Reaction Method) that is appropriate even for very low concentrations of reactants. Studies have focused on global autocatalytic processes and their diversity.

Pohorille, Andrew↗
NASA NTRS1993

Calcium and signal transduction in plants

Environmental and hormonal signals control diverse physiological processes in plants. The mechanisms by which plant cells perceive and transduce these signals are poorly understood. Understanding biochemical and molecular events involved in signal transduction pathways has become one of the most active areas of plant research. Research during the last 15 years has established that Ca2+ acts as a messenger in transducing external signals. The evidence in support of Ca2+ as a messenger is unequivocal and fulfills all the requirements of a messenger. The role of Ca2+ becomes even more important because it is the only messenger known so far in plants. Since our last review on the Ca2+ messenger system in 1987, there has been tremendous progress in elucidating various aspects of Ca(2+) -signaling pathways in plants. These include demonstration of signal-induced changes in cytosolic Ca2+, calmodulin and calmodulin-like proteins, identification of different Ca2+ channels, characterization of Ca(2+) -dependent protein kinases (CDPKs) both at the biochemical and molecular levels, evidence for the presence of calmodulin-dependent protein kinases, and increased evidence in support of the role of inositol phospholipids in the Ca(2+) -signaling system. Despite the progress in Ca2+ research in plants, it is still in its infancy and much more needs to be done to understand the precise mechanisms by which Ca2+ regulates a wide variety of physiological processes. The purpose of this review is to summarize some of these recent developments in Ca2+ research as it relates to signal transduction in plants.

NASA Program Space Biology↗
DOE OSTI2025

A distinct subpopulation of membrane vesicles in Pseudomonas putida is enriched in enzymes for lignin catabolism

Bacterial membrane vesicles (MVs) mediate diverse microbial processes and are emerging as powerful biomedical tools, but MV population heterogeneity remains an open question. Here, we separate, enumerate, and characterize two MV populations from the soil bacterium Pseudomonas putida during growth with or without lignin-derived carbon, a major carbon source from plant cells in the rhizosphere. Small MVs (MV-S, diameter ~100 nm) were produced from all cultures, whereas large MVs (MV-L, diameter ~300 nm) were observed during the late stationary phase of lignin cultivations. MV-S contained selectively packaged proteins with diverse physiological functions, whereas the MV-L proteome was smaller and largely enriched in outer membrane proteins. Interestingly, enzymes known to mediate the catabolism of lignin-derived aromatic compounds were enriched in MV-S. Overall, this study highlights the need for careful consideration of MV populations in microbial systems.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Rapid Cis–Trans Coevolution Driven by a Novel Gene Retroposed from a Eukaryotic Conserved CCR4–NOT Component in Drosophila

Young, or newly evolved, genes arise ubiquitously across the tree of life, and they can rapidly acquire novel functions that influence a diverse array of biological processes. Previous work identified a young regulatory duplicate gene in Drosophila, Zeus that unexpectedly diverged rapidly from its parent, Caf40, an extremely conserved component in the CCR4–NOT machinery in post-transcriptional and post-translational regulation of eukaryotic cells, and took on roles in the male reproductive system. This neofunctionalization was accompanied by differential binding of the Zeus protein to loci throughout the Drosophila melanogaster genome. However, the way in which new DNA-binding proteins acquire and coevolve with their targets in the genome is not understood. Here, by comparing Zeus ChIP-Seq data from D. melanogaster and D. simulans to the ancestral Caf40 binding events from D. yakuba, a species that diverged before the duplication event, we found a dynamic pattern in which Zeus binding rapidly coevolved with a previously unknown DNA motif, which we term Caf40 and Zeus-Associated Motif (CAZAM), under the influence of positive selection. Interestingly, while both copies of Zeus acquired targets at male-biased and testis-specific genes, D. melanogaster and D. simulans proteins have specialized binding on different chromosomes, a pattern echoed in the evolution of the associated motif. Using CRISPR-Cas9-mediated gene knockout of Zeus and RNA-Seq, we found that Zeus regulated the expression of 661 differentially expressed genes (DEGs). Our results suggest that the evolution of young regulatory genes can be coupled to substantial rewiring of the transcriptional networks into which they integrate, even over short evolutionary timescales. Our results thus uncover dynamic genome-wide evolutionary processes associated with new genes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

The future of fungi: threats and opportunities

The fungal kingdom represents an extraordinary diversity of organisms with profound impacts across animal, plant, and ecosystem health. Fungi simultaneously support life, by forming beneficial symbioses with plants and producing life-saving medicines, and bring death, by causing devastating diseases in humans, plants, and animals. With climate change, increased antimicrobial resistance, global trade, environmental degradation, and novel viruses altering the impact of fungi on health and disease, developing new approaches is now more crucial than ever to combat the threats posed by fungi and to harness their extraordinary potential for applications in human health, food supply, and environmental remediation. To address this aim, the Canadian Institute for Advanced Research (CIFAR) and the Burroughs Wellcome Fund convened a workshop to unite leading experts on fungal biology from academia and industry to strategize innovative solutions to global challenges and fungal threats. This report provides recommendations to accelerate fungal research and highlights the major research advances and ideas discussed at the meeting pertaining to 5 major topics: (1) Connections between fungi and climate change and ways to avert climate catastrophe; (2) Fungal threats to humans and ways to mitigate them; (3) Fungal threats to agriculture and food security and approaches to ensure a robust global food supply; (4) Fungal threats to animals and approaches to avoid species collapse and extinction; and (5) Opportunities presented by the fungal kingdom, including novel medicines and enzymes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Novosphingobium aromaticivorans LigR coordinates transcription of genes involved in metabolism of multiple types of aromatics

Aromatic compounds are a ubiquitous and diverse family of chemicals with functions as biomolecules, natural products, industrial chemicals, and pollutants. Novosphingobium aromaticivorans DSM 12444 uses multiple inducible pathways to catabolize H-, G-, and S-type aromatics that contain zero, one, or two methoxy groups, respectively. Here, we obtain a systems-level view of the transcriptional control of its aromatic metabolic pathways. Several in vitro analyses found that a N. aromaticivorans homolog of the Sphingobium lignivorans SYK-6 transcription factor LigR bound genomic DNA upstream of genes involved in metabolism of multiple aromatic types. We found that a ΔLigR mutant had growth defects on all three types of aromatics as sole carbon sources. Transcriptomic analysis revealed that LigR was required to increase expression of gene products that function in metabolism of all three aromatic types. We also found that, in media containing both glucose and an aromatic carbon source, the ΔLigR mutant directed intermediates through alternative aromatic metabolic pathways. Protein-DNA binding assays showed that N. aromaticivorans LigR binds immediately upstream of promoters of genes involved in aromatic metabolism. We found that N. aromaticivorans LigR coordinates the expression of enzymes that function in the catabolism of H-, G-, and S-type aromatics, and that there are differences in the role of LigR in N. aromaticivorans and S. lignivorans. A comparative genomic analysis predicted that LigR homologs and the aromatic-metabolizing genes that it directly regulates are often co-localized in the genomes of Sphingomonadales, but often not found in this arrangement in many other known aromatic metabolizing bacteria.

Aromatic Compound Degradation↗
DOE OSTI2025

Rewiring Aromatic Compound Consumption: Chromosomal Amplification and Evolution of a Foreign Pathway in Acinetobacter baylyi ADP1

Rational engineering strategies that seek to harness the remarkable diversity of microbial metabolism can be limited by incomplete biological knowledge. As described here, a novel approach to address this challenge involved replacing a native pathway for degrading lignin-derived aromatic compounds via ortho cleavage of protocatechuate in Acinetobacter baylyi ADP1 with a foreign meta-cleavage pathway that uses different enzymes, metabolites, and redox carriers. This alteration may improve lignin valorization and coordinate catabolism with bioproduction strategies. When a 14-kbp region of foreign DNA was inserted in the chromosome, the heterologous genes failed to confer growth on target substrates. Regional gene dosage was increased using a synthetic DNA fragment to promote recombination, and higher copy number enabled growth. During adaptive laboratory evolution, compensatory mutations arose that permit growth with one copy of the foreign genes. This complex metabolic remodeling was accomplished without assumptions about the impediments that initially prevented growth. To understand the changes that emerged, a novel transformation assay identified a combination of mutations sufficient for the new phenotype. Three unexpected changes were revealed: loss of one foreign enzyme, loss of one native enzyme, and loss of a two-component transcriptional regulatory system. This study establishes that large multicopy tandem arrays of poorly adapted pathway genes can confer new functions and improve understanding of metabolism.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

Aeromonas in South Asia: genomic insights into an environmental pathogen and reservoir of antimicrobial resistance

Aeromonads are an ecologically versatile group of bacteria that cause infections in aquatic animals and are recognised as emerging human pathogens. Despite this, our understanding of Aeromonas diversity, especially the relationship between clinical and environmental strains, remains limited. Here, we present a genomic analysis of the Aeromonas genus, comprising 1853 genomes, and a detailed comparison of clinical and environmental strains from South Asia, including 996 newly sequenced genomes from Bangladesh and India. Phylogenetic analyses revealed that Aeromonas is a highly diverse genus, with no distinct clade separating clinical and environmental isolates. We identified 28 Aeromonas species and 905 novel sequence types, comprising 72.5% of the genomes. Notably, we show a high incidence of antimicrobial resistance (AMR) genes across all isolates, including against front and last-line antibiotics. Finally, we highlight frequent misidentification of Aeromonas as Vibrio cholerae, which is relevant to cholera-endemic regions where both genera co-exist and are associated with diarrhoeal disease. Our study underscores Aeromonas as an important environmental AMR reservoir and emerging multi-species pathogen capable of spilling over into human populations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Spatio-temporal dynamics of Hendra virus in Australia reveal stable maintenance of diverse viral clades among Pteropus bats

Hendra virus (HeV) was discovered in 1994 in Australia. Limited genomic data have hindered comprehensive understanding of HeV’s evolutionary dynamics. Here, in this work, we recovered 48 HeV genomes from bats and 9 from horses from Australia between 2016 and 2020, revealing four distinct clades. Each clade was distributed over a large spatial area with multiple clades co-circulating within a single bat roost on the same day and over consecutive years. The diversity and temporal stability of co-circulating clades suggest that viral dynamics are driven by episodic shedding of existing lineages maintained at the population level, rather than immune-driven strain-replacement dynamics. HeV isolates of different clades displayed variation in phenotypic properties but minimal antigenic differences. We provide an overview of evolutionary dynamics, phenotypic properties and assessment of countermeasures for HeV, and provide insights into the processes that maintain virus diversity in bats and influence the potential for viral emergence.

genetic variation↗
DOE OSTI2025

Genomic and transcriptomic characterization of carbohydrate-active enzymes in the anaerobic fungus Neocallimastix cameroonii var. constans

Anaerobic gut fungi effectively degrade lignocellulose in the guts of large herbivores, but there remain a limited number of isolated, publicly available, and sequenced strains that impede our understanding of the role of anaerobic fungi within microbial communities. We isolated and characterized a new fungal isolate, Neocallimastix cameroonii var. constans, providing a transcriptomic and genomic understanding of its ability to degrade diverse carbohydrates. This anaerobic fungal strain was stably cultivated for multiple years in vitro among members of an initial enrichment microbial community derived from goat feces, and it demonstrated the ability to pair with other microbial members, namely, archaeal methanogens to produce methane from lignocellulose. Genomic analysis revealed a higher number of predicted carbohydrate-active enzymes encoded in the N. cameroonii var. constans genome compared to most other sequenced anaerobic fungi. The carbohydrate-active enzyme profile for this isolate contained 660 glycoside hydrolases, 160 carbohydrate esterases, 194 glycosyltransferases, and 85 polysaccharide lyases. Differential gene expression analysis showed the upregulation of thousands of genes (including predicted carbohydrate-active enzymes) when N. cameroonii var. constans was grown on lignocellulose (reed canary grass) compared to less complex substrates, such as cellulose (filter paper), cellobiose, and glucose. AlphaFold was used to predict functions of transcriptionally active yet poorly annotated genes, revealing feruloyl esterases that likely play an important role in lignocellulose degradation by anaerobic fungi. The combination of this strain's genomic and transcriptomic characterization, omics-informed structural prediction, and robustness in microbial co-culture make it a well-suited platform to conduct future investigations into bioprocessing and enzyme discovery.

CAZymes↗
DOE OSTI2024

Advanced Laboratory and Field Arrays (ALFA)/Lab Collaboration Project (LCP) for Marine Energy (Final Scientific/Technical Report)

The objective of the Advanced Laboratory and Field Arrays (ALFA) project was to reduce the Levelized Cost of Energy (LCOE) of Marine and Hydrokinetic (MHK) energy by leveraging research, development, and testing capabilities at Oregon State University, University of Washington, and the University of Alaska, Fairbanks. ALFA is a project within the Pacific Marine Energy Center (PMEC; formerly NNMREC), a multi-institution entity with a diverse funding base that focuses on research and development for marine renewables. The ALFA project aimed to accelerate the development of next-generation arrays of wave energy conversion (WEC) and tidal energy conversion (TEC) devices through a suite of field-focused R&D activities spanning a broad range of strategic opportunity areas identified in the Funding Opportunity Announcement: • Device and/or array operation and maintenance (O&M) logistics development; • High-fidelity resource characterization and/or modeling technique development and validation; • Array-specific component technology development (e.g. moorings and foundations, transmission, and other offshore grid components); • Array performance testing and evaluation; and • Novel cost-effective environmental monitoring techniques and instrumentation testing and evaluation. The objective of the Lab Collaboration Project (LCP) was to accelerate the development of next-generation marine energy conversion systems. The LCP aimed to achieve these project objectives in collaboration with the national laboratories by: • Developing concept generation and assessment tools; • Improving access to existing testing resources; • Validating collision risk models between fish and turbines; and • Advancing analysis and simulation capabilities for wave-WEC interactions and PTO analysis in nonlinear ocean waves. The ALFA portion of the project was comprised of six overarching technical tasks: • Task 1: Debris Modeling, Detection and Mitigation; • Task 2: Autonomous Monitoring & Intervention; • Task 3: Resource Characterization for Extreme Conditions; • Task 4: Robust Models for Design of Offshore Anchoring and Mooring Systems; • Task 5: Performance Enhancement for Marine Energy Converter (MEC) Arrays; and • Task 6: Evaluating Sampling Techniques for MHK Biological Monitoring. The LCP was divided into four overarching technical tasks: • Task 7: Project Management and Reporting • Task 8: Novel Design and Assessment Methodologies for Wave Energy Converter Design (Wave- SPARC) • Task 9: Testing Access for Commercial Marine Renewable Energy Technology Developers • Task 10: Quantifying Collision Risk for Fish and Turbines • Task 11: Nonlinear Ocean Waves and PTO Control Strategy Each ALFA/LCP task listed above functioned as a separate and discreet project. A final Technical Report was written for each individual task and these reports were uploaded to OSTI, after receiving DOE approval. The following document is a compilation of each of these final, approved reports arranged as individual chapters.

13 HYDRO ENERGY↗
DOE OSTI2026

Engineering and Application of a Thermostable MHETase for PET Depolymerization

Enzymatic hydrolysis of poly(ethylene terephthalate) (PET) releases mono(2-hydroxyethyl) terephthalate (MHET) as a major product, the accumulation of which can prolong reactor residence times and complicate downstream monomer separations. The use of a MHETase enzyme can enable MHET hydrolysis to the monomers, terephthalic acid and ethylene glycol, but industrial PETases typically operate at thermophilic temperatures and the well-known MHETase from Ideonella sakaiensis is a mesophilic enzyme, thus warranting the development of thermophilic MHETases. Here, we characterize thermostable MHET-active enzymes from a natural diversity screen by applying a hidden Markov model based on the previously reported, archaeal ferulic acid esterase, PET46. We identified enzymes with higher thermostability than PET46 and quantified their MHETase activity in reactions at 70 °C. The crystal structure of MHT077, the homologue with the highest MHETase activity and an apparent melting temperature (T m,app ) of 94.6 °C, informed site saturation mutagenesis in the active site and lid-domain interface. MHT077 exhibited a ∼100-fold slower unfolding rate at 65 °C than PET46, indicating substantially greater kinetic stability. In parallel, we applied evolution-informed design, a probabilistic model that leverages coevolutionary patterns in large multiple sequence alignments, to improve the activity and thermostability of five ferulic acid esterases. One design, EV-MHT043–5 was identified with a comparable thermostability (T m,app = 96.1 °C) and a 3-fold improvement in its MHETase activity relative to the wildtype enzyme, MHT043. Combination variants of beneficial mutations were screened and afforded a variant, MHT077 LFK , which reduced MHET accumulation in bioreactor experiments with postconsumer PET waste. Overall, this study expands the known MHET-hydrolyzing protein scaffolds available for enzymatic PET recycling.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

60 APPLIED LIFE SCIENCES↗