Biology subjects

Olson, A.

Publications and source records attributed to Olson, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Olfactory Deficits and Structural Anomalies of the Peripheral Olfactory System in 22q11.2 Deletion Syndrome

Background: Approximately 25% of individuals with 22q11.2 deletion syndrome (22q11DS) develop a psychotic disorder, and the syndrome shares key neurodevelopmental features with psychosis in the general population. The olfactory system develops early in utero, providing a window into gestational disruptions relevant to psychosis risk. We hypothesized that 22q11DS would show impairments in olfactory function and structural anomalies of the olfactory system relative to psychosis spectrum (PS) youth without a known genetic syndrome and typically developing controls (TD). Methods: Participants included individuals with 22q11DS (n=101), PS (n=56), and TD (n=52). Sinonasal symptoms, odor identification, and discrimination (Sniffin' Sticks) behaviorally. Structural 3T MRI measured olfactory bulb volume, sulcus depth, and sulcus length. Sample sizes vary per analysis. Results: Relative to TD, 22q11DS showed elevated sinonasal burden (p<.001), lower odor identification (p<.001), and lower odor discrimination (p<.001). PS showed elevated sinonasal burden (p<.001) and marginally lower odor identification (p=.06), but no discrimination deficit. Olfactory bulb volume was significantly smaller in 22q11DS versus TD (p=.007, r=.39); PS showed a non-significant trend (p=.07). Olfactory sulcus depth (p=.52) and length (p=.82) did not differ across groups. Conclusions: 22q11DS is associated with elevated sinonasal burden, robust olfactory identification and discrimination deficits exceeding those of PS and reduced olfactory bulb volume. The co-occurrence of functional deficits and reduced bulb volume without sulcal anomalies may distinguish the 22q11DS olfactory phenotype from that of PS. These hypothesis-generating findings are consistent with partially dissociable neurodevelopmental mechanisms and support the utility of 22q11DS as a genetic model for psychosis risk.

neuroscience↗

bioRxiv2026

Evolutionary-scale protein language models uncover beneficial variants in a Sorghum bicolor diversity panel

Quantitative genetic approaches such as genome-wide association studies and genomic prediction are widely used to identify favourable genetic variation, but they have limited resolution due to linkage disequilibrium. Comparative genomics approaches, especially Protein Language Models (PLMs), have emerged as powerful alternatives, by detecting phylogenetic residue conservation (PRC) across evolutionary time scales. However, the extent to which these tools can guide the detection of impactful variants for field agronomic traits is still unclear. In this study, we used the pre-trained PLM ESM2 to predict PRC scores of nonsynonymous mutations segregating within a diverse panel of 387 accessions in sorghum (SAP). The distribution of fitness effects (DFE) of the same set of nonsynonymous mutations was inferred using unfolded site frequency spectra to assess whether the DFE distribution covaried with PRC scores. Furthermore, we estimated the load of putatively nonneutral mutations of SAP accessions and evaluated associations between this mutation load and phenotypic performance across multiple agronomic traits. Our results show that ESM2 can detect mutations associated with fitness-enhancing effects in SAP, as indicated by enrichments in positive selection signatures among the variants with positive PRC scores. Significant associations were also detected between phenotypic performance and mutation load for several agronomic traits, indicating that PLMs can identify functionally important genetic variation. However, these signals were not consistent across all traits in the SAP population. Altogether, our findings suggest that large language models may support breeding efforts, as PLM predictions covaried with fitness effects and captured agronomic performance for some traits in plant populations.

genetics↗

bioRxiv2026

Membrane Tension Integrates Physical and Signaling Cues to Gate Cell Fate Transitions

Physical forces shape cell behavior, yet how they integrate with signaling to control fate and disease remains unclear. The alveolar epithelium is patterned by FGF signaling and mechanical stretch, but how these cues specify AT1 and AT2 cells is poorly understood. Here we show that cell membrane tension (CMT) is a conserved regulator of epithelial fate in mouse and human lungs. CMT drops before differentiation and is spatially patterned, defining where bipotent progenitors acquire AT1 or AT2 identity. Lower CMT enhances FGFR2 endocytosis and ERK signaling to drive AT2 differentiation and permits architectural remodeling that enables stretch-mediated YAP/TAZ nuclear entry for AT1 maturation. {beta}-catenin elevates CMT cell-intrinsically independent of its role in canonical WNT transcription, while embedding, osmotic compression, or fibroblast wrapping elevate CMT extrinsically. Combined intrinsic and extrinsic tension traps alveolar epithelial cells in a KRT8 transitional state seen in fibrotic lungs. Membrane tension thus integrates physical and molecular cues linking morphogenesis to fibrosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=160 HEIGHT=200 SRC="FIGDIR/small/708749v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1a9c04forg.highwire.dtl.DTLVardef@190bee2org.highwire.dtl.DTLVardef@1e41664org.highwire.dtl.DTLVardef@17a3ec7_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefWe identify a conserved drop in cell membrane tension (CMT) that gates epithelial fate transitions across mouse and human lungs. In bipotent progenitors, reduced CMT promotes Alveolar Type 2 (AT2) fate via FGFR2 endocytosis and ERK signaling, as well as Alveolar Type 1 (AT1) fate by enabling architectural remodeling required for YAP/TAZ nuclear entry. We further show that intrinsic {beta}-catenin and extrinsic confinement cues, including mesenchymal contact, converge to elevate CMT, restricting differentiation and--in adult AT2s--inducing a KRT8 transitional state associated with fibrosis. HighlightsO_LICell membrane tension drops before differentiation and is required for AT1 and AT2 fate acquisition. C_LIO_LIReduced tension enhances FGFR2 endocytosis and ERK signaling to drive AT2 specification. C_LIO_LIReduced tension permits architectural remodeling and YAP/TAZ nuclear entry required for AT1 maturation. C_LIO_LIIntrinsic {beta}-catenin and extrinsic confinement elevate CMT to restrict differentiation and together strongly induce a KRT8 transitional state associated with fibrosis. C_LI

cell biology↗

bioRxiv2026

Identification of low threshold off-target activation pathways during stimulation of carotid baroreceptor afferents in swine.

ObjectiveElectrical stimulation of the baroreceptors pathways at the carotid sinus bulb - known as baroreflex activation therapy (BAT) - is intended to change autonomic tone and ultimately reduce blood pressure and heart rate. BAT is pre-market approved by the United States Food and Drug Administration (FDA) for the treatment of heart failure and received an FDA humanitarian device exemption for drug resistant hypertension. However, responder rates are limited by side-effects including numbness in the head and neck, altered speech, respiratory constriction, dry cough, vomiting, and altered sensory and motor function of the tongue. We hypothesized that these side-effects are driven by activation of other nearby nerve fibers of similar or lower threshold than the carotid sinus nerve. In this study, we sought to identify the neural sources responsible for off-target muscle activation contributing to these side-effects. These sources would inform strategies mitigating off-target activation in BAT therapy. MethodsDomestic swine were used in this work as the diameter and thickness of the swine carotid artery are closer to human than those of canine models. A monopolar disk electrode mimicking the clinical CVRx(R) Neo electrode was surgically placed proximal to the carotid bifurcation with the position optimized for stimulation dose responsive changes in blood pressure. Evoked responses were recorded during dose response testing from multiple neck muscles, and the corresponding off-target nerve pathways were identified by sequential transection of nearby nerves. ResultsThe following activated off-target muscle groups and their corresponding nerve pathways were verified which included 1) the cricoarytenoid via recurrent laryngeal nerve, 2) cricothyroid via superior laryngeal nerve, 3) sternocleidomastoid via accessory nerve, and 4) the tongue via hypoglossal nerve. The constrictor muscle group was also activated through a more complex neural pathway. ConclusionWe identified multiple sources of therapy-limiting side-effects of BAT in the swine model. These results will help guide the design of improved stimulation electrodes, surgical placement, and parameter programming to reduce BAT-associated side-effects while increasing on-target activation in patients.

bioengineering↗

bioRxiv2025

Mating Type Gene Divergence is Associated with Life Cycle Differentiation in Scots Pine Blister Rust

Reproductive systems are central to the evolutionary and ecological processes shaping population structure and adaptability. Rust fungi are a large group of obligate plant pathogens with complex life cycles and diverse reproductive modes. In the rust fungus Cronartium pini, which exists in both macrocyclic heteroecious and microcyclic autoecious forms, transitions between reproductive modes can be studied within a single species. Here, we used comparative genomics to analyse the structure, diversity, and organization of mating-type (MAT) loci across both forms of C. pini. We identified a canonical tetrapolar system in the heteroecious form, characterized by unlinked, multiallelic homeodomain (HD) and pheromone/receptor (P/R) loci, consistent with obligate outcrossing. In contrast, the autoecious form displayed distinct reproductive signatures, including MAT gene homozygosity in some samples--indicative of clonal reproduction--and MAT gene duplications in others, suggesting self-fertility or altered mating pathways. Three HD loci were detected, but only one exhibited high allelic diversity and was consistently present, indicating functional divergence. Expanded allelic diversity at the STE3.2 pheromone receptor further suggests plasticity at the P/R locus. Although allele sharing between life cycle forms was rare, isolated cases of shared MAT alleles suggest limited historical connectivity and possible trans-specific polymorphism. Together, our findings reveal flexibility in the mating system architecture of C. pini and suggest that transitions between sexual and asexual reproduction may be facilitated by retained, functionally ambiguous MAT structures. This work highlights C. pini as a powerful model for studying life cycle evolution and mating system transitions in rust fungi.

evolutionary biology↗

bioRxiv2025

A molecular circuit regulates fate plasticity in emerging and adult AT2 cells

Alveolar AT1 and AT2 cells are vital for lung gas exchange and become compromised in several diseases. While key differentiation signals are known, their emergence and fate plasticity are unclear. Here we show in the embryonic lung that single AT2s emerge at intermediate zones, extrude, and connect with nearby epithelium via interlumenal junctioning. We observe that AT2s retain fate plasticity until the bZIP transcription factor C/EBP suppresses Notch signaling at a novel Dlk1 enhancer. Both Dlk1 and Cebpa are regulated by the polycomb repressive complex (PRC2), which together form a "pulse generator" circuit that times Dlk1 expression and thus Notch activation, resulting in a "salt and pepper" pattern of AT1 and AT2 fate. In injured adult lungs, C/EBP downregulation is required to re-access AT2 fate plasticity and is mediated by the dominant negative C/EBP family member CHOP. Finally, Cebpa loss also activates a "defender" AT2 state, distinct from its reparative state, and we propose AT2s toggle between either state following infection to protect and repair alveoli.

developmental biology↗

bioRxiv2025

A pan-gene catalogue of Asian cultivated rice

The rice genome underpins fundamental research and breeding, but the Nipponbare (japonica) reference does not fully encompass the genetic diversity of Asian rice. To address this gap, the Rice Population Reference Panel (RPRP) was developed, comprising high-quality assemblies of 16 rice cultivars to represent japonica, indica, aus, and aromatic varietal groups. The RPRP has been consistently annotated, supported by extensive experimental data and here we report the computational assignment, characterization and dissemination of stably identified pan-genes. We identified 25,178 core pan-genes shared across all cultivars, alongside cultivar-specific and family-enriched genes. Core genes exhibit higher gene expression and proteomic evidence, higher confidence protein domains and AlphaFold structures, while cultivar-specific genes were enriched for domains under selective breeding pressure, such as for disease resistance. This resource, integrated into public databases, enables researchers to explore genetic and functional diversity via a population-aware "reference guide" across rice genomes, advancing both basic and applied research.

genomics↗

bioRxiv2024

Macrophage-intrinsic MDA5-IRF5 axis drives HIV-1 icRNA-induced inflammatory responses

Despite effective antiretroviral therapy (ART), transcriptionally competent HIV-1 reservoirs persist and contribute to persistent immune activation in people living with HIV (PWH). HIV-1-infected macrophages are important mediators of chronic innate immune activation, though mechanisms remain unclear. We previously reported that nuclear export and cytoplasmic expression of HIV-1 intron-containing RNA (icRNA) activates mitochondrial antiviral signaling protein (MAVS)-mediated type I interferon (IFN) responses in macrophages. In this study, we demonstrate an essential role of melanoma differentiation-associated protein 5 (MDA5) in sensing HIV-1 icRNA and promoting MAVS-dependent IRF5 activation in macrophages. Suppression of MDA5, but not RIG-I expression nor disruption of endosomal TLR pathway, abrogated HIV-1 icRNA-induced type I IFN responses and IP-10 expression in macrophages. Furthermore, induction of IP-10 in macrophages upon HIV-1 icRNA sensing by MDA5 was uniquely dependent on IRF5. Additionally, monocytes and MDMs from older (>50 years) individuals exhibit constitutively higher levels of IRF5 expression compared to younger (<35 years) individuals, and HIV-1 icRNA induced IP-10 expression was significantly enhanced in older macrophages, which was attenuated upon ablation of IRF5 expression suggesting that IRF5 functions as a major mediator of pro-inflammatory response downstream of MDA5-dependent HIV-1 icRNA sensing, dysregulation of which might contribute to chronic inflammation in older PWH.

microbiology↗

bioRxiv2023

Enhlink infers distal and context-specific enhancer-promoter linkages

Enhancers play a crucial role in regulating gene expression and their functional status can be queried with cell type precision using using single-cell (sc)ATAC-seq. To facilitate analysis of such data, we developed Enhlink, a novel computational approach that leverages single -cell signals to infer linkages between regulatory DNA sequences, such as enhancers and promoters. Enhlink uses an ensemble strategy that integrates cell-level technical covariates to control for batch effects and biological covariates to infer robust condition-specific links and their associated p-values. It can integrate simultaneous gene expression and chromatin accessibility measurements of individual cells profiled by multi-omic experiments for increased specificity. We evaluated Enhlink using simulated and real scATAC-seq data, including those paired with physical enhancer-promoter links enumerated by promoter capture Hi-C and with multi-omic scATAC-/RNA-seq data we generated from the mouse striatum. These examples demonstrated that our method outperforms popular alternative strategies. In conjunction with eQTL analysis, Enhlink revealed a putative super-enhancer regulating key cell type-specific markers of striatal neurons. Taken together, our analyses demonstrate that Enhlink is accurate, powerful, and provides features that can lead to novel biological insights.

bioinformatics↗

bioRxiv2022

Ten new high-quality genome assemblies for diverse bioenergy sorghum genotypes

Sorghum (Sorghum bicolor (L.) Moench) is an agriculturally and economically important staple crop that has immense potential as a bioenergy feedstock due to its relatively high productivity on marginal lands. To capitalize on and further improve sorghum as a potential source of sustainable biofuel, it is essential to understand the genomic mechanisms underlying complex traits related to yield, composition, and environmental adaptations. Expanding on a recently developed mapping population, we generated de novo genome assemblies for 10 parental genotypes from this population and identified a comprehensive set of over 24 thousand large structural variants (SVs) and over 10.5 million single nucleotide polymorphisms (SNPs).These resources can be integrated into both ongoing and future mapping and trait discovery for sorghum and its myriad uses including food, feed, bioenergy, and increasingly as a carbon dioxide removal mechanism. We show that SVs and nonsynonymous SNPs are enriched in different gene categories, emphasizing the need for long read sequencing in crop species to identify novel variation. Furthermore, we highlight SVs and SNPs occurring in genes and pathways with known associations to critical bioenergy-related phenotypes and characterize the landscape of genetic differences between sweet and cellulosic genotypes.

genomics↗

bioRxiv2022

Metabolic Engineering of Oleaginous Yeast Rhodotorula toruloides for Overproduction of Triacetic Acid Lactone

The plant-sourced polyketide triacetic acid lactone (TAL) has been recognized as a promising platform chemical for the biorefinery industry. However, its practical application was rather limited due to low natural abundance and inefficient cell factories for biosynthesis. Here we report the metabolic engineering of oleaginous yeast Rhodotorula toruloides for TAL overproduction. We first introduced a 2-pyrone synthase gene from Gerbera hybrida (GhPS) into R. toruloides and investigated the effects of different carbon sources on TAL production. We then systematically employed a variety of metabolic engineering strategies to increase the flux of acetyl-CoA by enhancing its biosynthetic pathways and disrupting its competing pathways. We found that overexpression of citrate lyase (ACL1) improved TAL production by 45% compared to the GhPS overexpressing strain, and additional overexpression of acetyl-CoA carboxylase (ACC1) further increased TAL production by 29%. Finally, we characterized the resulting strain I12-ACL1-ACC1 using fed-batch bioreactor fermentation in glucose or oilcane juice medium with acetate supplementation and achieved a titer of 28 g/L or 23 g/L TAL, respectively. This study demonstrates that R. toruloides is a promising host for production of TAL and other acetyl-CoA-derived polyketides from low-cost carbon sources. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=57 SRC="FIGDIR/small/481788v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@32eb52org.highwire.dtl.DTLVardef@f786dborg.highwire.dtl.DTLVardef@b6d3f5org.highwire.dtl.DTLVardef@115aa67_HPS_FORMAT_FIGEXP M_FIG C_FIG Triacetic acid lactone (TAL) is a promising platform chemical. Cao et al. overexpressed 2-pyrone synthase in oleaginous yeast Rhodotorula toruloides to produce TAL. They systematically evaluated various metabolic gene targets to increase acetyl-CoA and malonyl-CoA levels for TAL production and found that overexpression of both ACL1 and ACC1 led to 28 g/L or 23 g/L of TAL from glucose or oilcane juice with acetate supplementation, respectively, in fed-batch fermentation.

synthetic biology↗

bioRxiv2022

First comprehensive identification of proteins with increased O-GlcNAc levels during pressure overload hypertrophy.

Protein posttranslational modifications (PTMs) by O-GlcNAc globally rise during pressure-overload hypertrophy (POH). However, only a few specific proteins with altered O-GlcNAc levels during POH are known primarily because this PTM is easily lost during standard mass spectrometry (MS) conditions used for protein identification. Methodologies have recently emerged to stabilize the O-GlcNAc moiety for MS analysis. Accordingly, our goal was to determine the proteins undergoing changes in O-GlcNAc levels during POH. We used C57/Bl6 mice subjected to Sham or transverse aortic constriction (TAC) to create POH. From the hearts, we stabilized and labelled the O-GlcNAc moiety with tetramethylrhodamine azide (TAMRA) before enriching by TAMRA immunoprecipitation (IP). We used LC-MS to identify the captured O-GlcNAcylated proteins. We identified a total of 707 O-GlcNAcylated proteins in Sham and POH. Two hundred thirty-three of these proteins were significantly increased in POH over Sham whereas no proteins were significantly decreased in POH. We examined two MS identified proteins, CPT1B and PDH, to validate the MS data by immunoprecipitation. We corroborated increased O-GlcNAc levels during POH for the metabolic enzymes CPT1B and PDH. Enzyme activity assays showed higher O-GlcNAcylation increased CPT1 activity and decreased PDH activity. In summary, we generated the first comprehensive list of proteins with changes in O-GlcNAc levels during POH and, to our knowledge, the largest list for any cardiac pathology. Our results demonstrate the large number of proteins and cellular processes affected by O-GlcNAc during POH and serve as a guide for testing specific O-GlcNAc-regulated mechanisms.

physiology↗

bioRxiv2022

The Collaborative Cross strains and their founders vary widely in cocaine-induced behavioral sensitization

Cocaine use and overdose deaths attributed to cocaine have increased significantly in the United States in the last 10 years. Despite the prevalence of cocaine use disorder (CUD) and the personal and societal problems it presents, there are currently no approved pharmaceutical treatments. The absence of treatment options is due, in part, to our lack of knowledge about the etiology of CUDs. There is ample evidence that genetics plays a role in increasing CUD risk but thus far, very few risk genes have been identified in human studies. Genetic studies in mice have been extremely useful for identifying genetic loci and genes, but have been limited to very few genetic backgrounds, leaving substantial phenotypic and genetic diversity unexplored. Herein we report the measurement of cocaine-induced behavioral sensitization using a 19-day protocol that captures baseline locomotor activity, acute locomotor response to cocaine and locomotor sensitization across 5 exposures to the drug. These behaviors were measured in 51 genetically diverse yet tractable Collaborative Cross (CC) strains along with their inbred founder strains. The CC was generated by crossing 8 genetically diverse inbred strains such that each inbred CC strain has genetic contributions from each of the founder strains. Inbred CC mice are infinitely reproducible and provide a stable, yet diverse genetic platform on which to study the genetic architecture and genetic correlations among phenotypes. We have identified significant differences in cocaine locomotor sensitivity and behavioral sensitization across the panel of CC strains and their founders. We have established relationships among cocaine sensitization behaviors and identified extreme responding strains that can be used in future studies aimed at understanding the genetic, biological and pharmacological mechanisms that drive addiction-related behaviors. Finally, we have determined that these behaviors exhibit relatively robust heritability making them amenable to future genetic mapping studies to identify addiction risk genes and genetic pathways that can be studied as potential targets for the development of novel therapeutics.

genetics↗

bioRxiv2021

Intragenic proviral elements support transcription of defective HIV-1 proviruses

HIV-establishes a persistent proviral reservoir by integrating into the genome of infected host cells. Current antiretroviral treatments do not target this persistent population of proviruses which include latently infected cells that upon treatment interruption can be reactivated to contribute to HIV-1 rebound. Deep sequencing of persistent HIV proviruses has revealed that greater than 90% of integrated HIV genomes are defective and unable to produce infectious virions. We hypothesized that intragenic elements in the HIV genome support transcription of aberrant HIV-1 RNAs from defective proviruses that lack long terminal repeats (LTRs). Using an intact provirus detection assay, we observed that resting CD4+ T cells and monocyte-derived macrophages (MDMs) are biased towards generating defective HIV-1 proviruses. Multiplex reverse transcription digital drop PCR identified Env and Nef transcripts which lacked 5 untranslated regions (UTR) in acutely infected CD4+ T cells and MDMs indicating transcripts are generated that do not utilize the promoter within the LTR. 5UTR-deficient Env transcripts were also identified in a cohort of people living with HIV (PLWH) on ART, suggesting that these aberrant RNAs are produced in vivo. Using 5 rapid amplification of cDNA ends (RACE), we mapped the start site of these transcripts within the Env gene. This region bound several cellular transcription factors and functioned as a transcriptional regulatory element that could support transcription and translation of downstream HIV-1 RNAs. These studies provide mechanistic insights into how defective HIV-1 proviruses are persistently expressed to potentially drive inflammation in PLWH. Author SummaryPeople living with HIV establish a persistent reservoir which includes latently infected cells that fuel viral rebound upon treatment interruption. However, the majority of HIV-1 genomes in these persistently infected cells are defective. Whether these defective HIV genomes are expressed and whether they contribute to HIV associated diseases including accelerated aging, neurodegenerative symptoms, and cardiovascular diseases are still outstanding questions. In this paper, we demonstrate that acute infection of macrophages and resting T cells is biased towards generating defective viruses which are expressed by DNA regulatory elements in the HIV genome. These studies describe an alternative mechanism for chronic expression of HIV genomes.

microbiology↗

bioRxiv2021

Heritable Variation in Locomotion, Reward Sensitivity, and Impulsive Action, Choice, and Waiting in a Genetically Diverse Inbred Mouse Panel

Drugs of abuse, including alcohol and stimulants like cocaine, produce effects that are subject to individual variability, and genetic variation accounts for at least a portion of those differences. Notably, research in both animal models and human subjects point towards reward sensitivity and impulsivity as being trait characteristics that predict relatively greater positive subjective responses to stimulant drugs. Here we describe use of the eight Collaborative Cross (CC) founder strains and multiple CC strains to examine the heritability of reward sensitivity and impulsivity traits, as well as genetic correlations between these measures and existing addiction-related phenotypes. Methods. Strains were all tested for activity in an open field and reward sensitivity (intake of chocolate BOOST(R)). Mice were then divided into two counterbalanced groups and underwent reversal learning (impulsive action and waiting impulsivity) or delay discounting (impulsive choice). Results. CC and founder mice demonstrate significant heritability for impulsive action, impulsive choice, waiting impulsivity, locomotor activity, and reward sensitivity, with each impulsive phenotype determined to be non-correlating, independent traits. This research was conducted within the broader, inter-laboratory effort of the Center for Systems Neurogenetics of Addiction (CSNA) to characterize CC and DO mice for multiple, cocaine abuse related traits. These data will facilitate the discovery of genetic correlations between predictive traits, which will then guide discovery of genes and genetic variants that contribute to addictive behaviors.

neuroscience↗

bioRxiv2021

A recombinant ACE2 Triple Decoy that traps and neutralizes SARS-CoV-2 shows enhanced affinity for highly transmissible SARS-CoV-2 variants

The highly-transmissible SARS-CoV-2 variants now replacing the first wave strain pose an increased threat to human health by their ability, in some instances, to escape existing humoral protection conferred by previous infection, neutralizing antibodies, and possibly vaccination. Thus, other therapeutic options are necessary. One such therapeutic option that leverages SARS-CoV-2 initiation of infection by binding of its spike receptor binding domain (S RBD) to surface-expressed host cell angiotensin-converting enzyme 2 (ACE2) is an ACE2 decoy that would trap the virus by competitive binding and thus inhibit propagation of infection. Here, we used Molecular Dynamic (MD) simulations to predict ACE2 mutations that might increase its affinity for S RBD and screened these candidates for binding affinity in vitro. A double mutant ACE2(T27Y/H34A)-IgG1FC fusion protein was found to have very high affinity for S RBD and to show greater neutralization of SARS-CoV-2 in a live virus assay as compared to wild type ACE2. We further modified the double mutant ACE2 decoy by addition of an H374N mutation to inhibit ACE2 enzymatic activity while maintaining high S RBD affinity. We then confirmed the potential efficacy of our ACE2(T27Y/H34A/H374N)-IgG1FC Triple Decoy against S RBD expressing variant-associated E484K, K417N, N501Y, and L452R mutations and found that our ACE2 Triple Decoy not only maintains its high affinity for S RBD expressing these mutations, but shows enhanced affinity for S RBD expressing the N501Y or L452R mutations and the highest affinity for S RBD expressing both the E484K and N501Y mutations. The ACE2 Triple Decoy also demonstrates the ability to compete with wild type ACE2 in the cPass surrogate virus neutralization in the presence of S RBD with these mutations. Additional MD simulation of ACE2 WT and decoy interactions with S RBD WT or B.1.351 variant sequence S RBD provides insight into the enhanced affinity of the ACE2 decoy for S RBD and reveals its potential as a tool to predict affinity and inform therapeutic design. The ACE2 Triple Decoy is now undergoing continued assessment, including expression by a human adenovirus serotype 5 (hAd5) construct to facilitate delivery in vivo. Summary sentenceAn ACE2(N27Y/H34A/H374N)-IgG1FC fusion protein decoy sustains high affinity to all SARS-CoV-2 spike receptor binding domain (RBD) protein variants tested, shows enhanced affinity for the N501Y and L452R variants, and the highest affinity for combined N501Y and E484K variants.

bioengineering↗

bioRxiv2021

De novo assembly, annotation, and comparative analysis of 26 diverse maize genomes

We report de novo genome assemblies, transcriptomes, annotations, and methylomes for the 26 inbreds that serve as the founders for the maize nested association mapping population. The data indicate that the number of pan-genes exceeds 103,000 and that the ancient tetraploid character of maize continues to degrade by fractionation to the present day. Excellent contiguity over repeat arrays and complete annotation of centromeres further reveal the locations and internal structures of major cytological landmarks. We show that combining structural variation with SNPs can improve the power of quantitative mapping studies. Finally, we document variation at the level of DNA methylation, and demonstrate that unmethylated regions are enriched for cis-regulatory elements that overlap QTL and contribute to changes in gene expression. One sentence summaryA multi-genome analysis of maize reveals previously unknown variation in gene content, genome structure, and methylation.

genomics↗

bioRxiv2021

Pan-genome Analysis in Sorghum Highlights the Extent of Genomic Variation and Sugarcane Aphid Resistance Genes

Sorghum bicolor, one of the most important grass crops around the world, harbors a high degree of genetic diversity. We constructed chromosome-level genome assemblies for two important sorghum inbred lines, Tx2783 and RTx436. The final high-quality reference assemblies consist of 19 and 18 scaffolds, respectively, with contig N50 values of 25.6 and 20.3 Mb. Genes were annotated using evidence-based and de novo gene predictors, and RAMPAGE data demonstrate that transcription start sites were effectively captured. Together with other public sorghum genomes, BTx623, RTx430, and Rio, extensive structural variations (SVs) of various sizes were characterized using Tx2783 as a reference. Genome-wide scanning for disease resistance (R) genes revealed high levels of diversity among these five sorghum accessions. To characterize sugarcane aphid (SCA) resistance in Tx2783, we mapped the resistance region on chromosome 6 using a recombinant inbred line (RIL) population and found a SV of 191 kb containing a cluster of R genes in Tx2783. Using Tx2783 as a backbone, along with the SVs, we constructed a pan-genome to support alignment of resequencing data from 62 sorghum accessions, and then identified core and dispensable genes using this population. This study provides the first overview of the extent of genomic structural variations and R genes in the sorghum population, and reveals potential targets for breeding of SCA resistance.

genomics↗