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Decades of educational genetics research have highlighted that differences in academic achievement are partly explained by genetic variation between individuals. Consequently, there is ongoing discussion about whether genetic influences on educationally related traits should be more widely acknowledged in schools and communicated specifically to teachers. Nonetheless, there is little research on how teachers might interpret such information, and how it might alter their perceptions of the students they teach or their teaching practice. In this review, we draw on the mixed blessings model proposed by Haslam and Kvaale, "Current Directions in Psychological Science," 2015, 24, 399-404, as a framework for defining both positive and negative repercussions of disseminating the findings of educational genetic research to teachers. We discuss research examining teacher perceptions of student ability and behavior and findings outlining perceptions of psychological disorders when genetic explanations are invoked. We conclude by proposing new directions for research designed to better understand interpretations of genetic information in school contexts.

Classroom-level influences on literacy skills in kindergarten through Grade 2, and on literacy and numeracy skills in Grades 3, 5, 7, and 9, were examined by comparing the similarity of twins who shared or did not share classrooms with each other. We analyzed two samples using structural equation modeling adapted for twin data. The first, Study 1, was of Australia-wide tests of literacy and numeracy, with 1,098; 1,080; 790, and 812 complete twin pairs contributing data for Grades 3, 5, 7, and 9, respectively. The second, Study 2, was of literacy tests from 753 twin pairs from kindergarten through Grade 2, which included a sample of United States and Australian students and was a reanalysis and extension of Byrne et al. (2010). Classroom effects were mostly nonsignificant; they accounted for only 2-3% of variance in achievement when averaged over tests and grades. Although the averaged effects may represent a lower-bound figure for classroom effects, and the design cannot detect classroom influences limited to individual students, the results are at odds with claims in public discourse of substantial classroom-level influences, which are mostly portrayed as teacher effects.

Asbury and Wai ("Journal of School Choice," 2019) perform a valuable service by summarizing much available behavior--genetic research on academic achievement. However they consider that no specific policies stem from the research body at this time. Here we do propose a policy based on some of our research using twins, namely that available funding for students struggling with learning to read be targeted to them individually rather than allocated to schools per se. We briefly canvass some practical issues, such as the variety of funding mechanisms, best-practice intervention techniques, and identification of struggling readers. We also outline a general research strategy for uncovering factors contributing to educational attainment that takes behavior-genetic research as its starting point and drills down from there, and advocate including genetically-sensitive methods in a growing list of quantitative research techniques in education. [For Asbury and Wai's "Viewing Education Policy through a Genetic Lens," see EJ1259282.]

With memory encoding reliant on persistent changes in the properties of synapses, a key question is how can memories be maintained from days to months or a lifetime given molecular turnover? It is likely that positive feedback loops are necessary to persistently maintain the strength of synapses that participate in encoding. Such feedback may occur within signal-transduction cascades and/or the regulation of translation, and it may occur within specific subcellular compartments or within neuronal networks. Not surprisingly, numerous positive feedback loops have been proposed. Some posited loops operate at the level of biochemical signal-transduction cascades, such as persistent activation of Ca[superscript 2+]/calmodulin kinase II (CaMKII) or protein kinase M?. Another level consists of feedback loops involving transcriptional, epigenetic and translational pathways, and autocrine actions of growth factors such as BDNF. Finally, at the neuronal network level, recurrent reactivation of cell assemblies encoding memories is likely to be essential for late maintenance of memory. These levels are not isolated, but linked by shared components of feedback loops. Here, we review characteristics of some commonly discussed feedback loops proposed to underlie the maintenance of memory and long-term synaptic plasticity, assess evidence for and against their necessity, and suggest experiments that could further delineate the dynamics of these feedback loops. We also discuss crosstalk between proposed loops, and ways in which such interaction can facilitate the rapidity and robustness of memory formation and storage.

Each year, all Australian students in grades 3, 5, 7 and 9 sit nationwide large-scale tests in literacy and numeracy which have their validity frequently questioned. We compared the performance of grade 3 twins on these large-scale reading tests with their performance on three individually administered literacy tests in comprehension, word reading and vocabulary within a genetically sensitive design. Comprehension, word reading and vocabulary accounted for a substantial amount of the variance in school reading tests. Performance on large-scale reading tests and individually administered tests was moderately to substantially heritable and the same genes contributed to performance in both types of test. These results confirm that large-scale school reading tests measure, at least in part, the literacy skills assessed by individual tests that are frequently considered to be the 'gold-standard' in testing. Also, as could be expected, the individually administered literacy tests were more closely related to performance on large-scale reading tests than to performance on large-scale school numeracy tests.

The present study explored the environmental and genetic etiologies of the longitudinal relations between prereading skills and reading and spelling. Twin pairs (n = 489) were assessed before kindergarten (M = 4.9 years), post-first grade (M = 7.4 years), and post-fourth grade (M = 10.4 years). Genetic influences on five prereading skills (print knowledge, rapid naming, phonological awareness, vocabulary, and verbal memory) were primarily responsible for relations with word reading and spelling. However, relations with post-fourth-grade reading comprehension were due to both genetic and shared environmental influences. Genetic and shared environmental influences that were common among the prereading variables covaried with reading and spelling, as did genetic influences unique to verbal memory (only post-fourth-grade comprehension), print knowledge, and rapid naming.

Modern behavior-genetic studies of twins in the United States, Australia, Scandinavia, and the United Kingdom show that genes account for most of the variance in children's reading ability by the end of the 1st year of formal reading instruction. Strong genetic influence continues across the grades, though the relevant genes vary for reading words and comprehending text, and some of the genetic influence comes through a gene-environment correlation. Strong genetic influences do not diminish the importance of the environment for reading development in the population and for helping struggling readers, but they question setting the same minimal performance criterion for all children.

Abstract Background Drought adaptation is critical to many tree species persisting under climate change, however our knowledge of the genetic basis for trees to adapt to drought is limited. This knowledge gap impedes our fundamental understanding of drought response and application to forest production and conservation. To improve our understanding of the genomic determinants, architecture, and trait constraints, we assembled a reference genome and detected ~ 6.5 M variants in 432 phenotyped individuals for the foundational tree Corymbia calophylla. Results We found 273 genomic variants determining traits with moderate heritability (h 2 SNP = 0.26–0.64). Significant variants were predominantly in gene regulatory elements distributed among several haplotype blocks across all chromosomes. Furthermore, traits were constrained by frequent epistatic and pleiotropic interactions. Conclusions Our results on the genetic basis for drought traits in Corymbia calophylla have several implications for the ability to adapt to climate change: (1) drought related traits are controlled by complex genomic architectures with large haplotypes, epistatic, and pleiotropic interactions; (2) the most significant variants determining drought related traits occurred in regulatory regions; and (3) models incorporating epistatic interactions increase trait predictions. Our findings indicate that despite moderate heritability drought traits are likely constrained by complex genomic architecture potentially limiting trees response to climate change.

Abstract To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.

Purpose: The goal of this study was to investigate the etiologic basis for the association between deficits in phonological memory (PM) and vocabulary in school-age children. Method: Children with deficits in PM or vocabulary were identified within the International Longitudinal Twin Study (ILTS; Samuelsson et al., 2005). The ILTS includes 1,045 twin pairs (between the ages of 5 and 8 years) from the United States, Australia, and Scandinavia. The authors applied the DeFries-Fulker (DeFries & Fulker, 1985, 1988) regression method to determine whether problems in PM and vocabulary tend to co-occur because of overlapping genes, overlapping environmental risk factors, or both. Results: Among children with isolated PM deficits, the authors found significant bivariate heritability of PM and vocabulary weaknesses both within and across time. However, when probands were selected for a vocabulary deficit, there was no evidence for bivariate heritability. In this case, it appears that the PM--vocabulary relationship is caused by common shared environmental experiences. Conclusions: The findings are consistent with previous research on the heritability of specific language impairment and suggest that there are etiologic subgroups of children with low vocabulary for different reasons, 1 being more influenced by genes and another being more influenced by environment. (Contains 5 tables and 1 footnote.)

This first Japanese twin study of early literacy development investigated the extent to which genetic and environmental factors influence individual differences in prereading skills in 238 pairs of twins at 42 months of age. Twin pairs were individually tested on measures of phonological awareness, "kana" letter name/sound knowledge, receptive vocabulary, visual perception, nonword repetition, and digit span. Results obtained from univariate behavioral-genetic analyses yielded little evidence for genetic influences, but substantial shared-environmental influences, for all measures. Phenotypic confirmatory factor analysis suggested three correlated factors: phonological awareness, letter name/sound knowledge, and general prereading skills. Multivariate behavioral genetic analyses confirmed relatively small genetic and substantial shared environmental influences on the factors. The correlations among the three factors were mostly attributable to shared environment. Thus, shared environmental influences play an important role in the early reading development of Japanese children. (Contains 7 tables and 1 figure.)

Objective: The Strengths and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN) Rating Scale differs from previous parent reports of ADHD in that it was designed to also measure variability at the positive end of the symptom spectrum. Method: The psychometric properties of the SWAN were tested and compared with an established measure of ADHD, the Disruptive Behavior Rating Scale (DBRS). Results: The SWAN demonstrates comparable validity, reliability, and heritability to the DBRS. Furthermore, plots of the SWAN and DBRS reveal heteroscedasticity, which supports the SWAN as a preferred measure of positive attention and impulse regulation behaviors. Conclusion: The ability of the SWAN to measure additional variance at the adaptive end of the ADHD symptom dimensions makes it a promising tool for behavioral genetic studies of ADHD. (Contains 6 tables and 1 figure.)

The genetic factor structure of a range of learning measures was explored in twin children, recruited in preschool and followed to Grade 2 ("N"?=?2,084). Measures of orthographic learning and word reading were included in the analyses to determine how these patterned with the learning processes. An exploratory factor analysis of the genetic correlations among the variables indicated a three-factor model. Vocabulary tests loaded on the first factor, the Grade 2 measures of word reading and orthographic learning, plus preschool letter knowledge, loaded on the second, and the third was characterized by tests of verbal short-term memory. The three genetic factors correlated, with the second (print) factor showing the most specificity. We conclude that genetically influenced learning processes underlying print-speech integration, foreshadowed by preschool letter knowledge, have a degree of independence from genetic factors affecting spoken language. We also argue that the psychology and genetics of associative learning be afforded a more central place in studies of reading (dis)ability and suggest some links to molecular studies of the genetics of learning. (Contains 6 tables and 1 figure.)

Although previous research has identified contemporaneous associations between cognitive deficits and symptom phenotypes in Attention Deficit/Hyperactivity Disorder, no studies have as yet attempted to identify direction of effect. The present study used cross-lagged path modeling to examine competing hypotheses about longitudinal associations between rapid naming speed and symptoms of inattention in children. 1,506 school-age twins from Australia and the U.S. were tested for inattention, hyperactivity/impulsivity, and rapid naming speed at three and four time points, respectively. Symptom severity of inattention from Kindergarten to fourth grade is consistently predicted by previous rapid naming, over and above auto-regressive and correlational associations in the model. Likewise, inattention symptoms have a small but significant predictive effect on subsequent rapid naming. The findings support a reciprocal relationship between naming speed and ADHD inattentive symptoms.

We present one of the first behavior-genetic studies of individual differences in school students' levels of achievement in instructed second language acquisition (ISLA). We assessed these language abilities in Australian twin pairs (maximum N pairs = 251) by means of teacher ratings, class rankings, and self-ratings of proficiency, and used the classic twin design to estimate the relative influences of genes, shared (family/school) environment, and unique environment. Achievement in ISLA was more influenced by additive genetic effects (72%, 68%, and 38% for teacher ratings, class rankings, and twin self-ratings, respectively) than by shared environment effects, which were generally not substantial (20%, 07%, and 13%). Genetic effects distinct to speaking and listening, on the one hand, and reading and writing, on the other, were evident for the twin self-ratings. We discuss the limitations and implications of these findings and point to research questions that could profitably be addressed in future studies. (Contains 3 figures and 1 note.)

Genetic and environmental relations between vocabulary and reading skills were explored longitudinally from preschool through Grades 2 and 4. At preschool there were strong shared-environment and weak genetic influences on both vocabulary and print knowledge but substantial differences in their source. Separation of etiology for vocabulary and reading continued for word recognition and decoding through Grade 4, but genetic and environmental correlations between vocabulary and reading comprehension approached unity by Grade 4, when vocabulary and word recognition accounted for all of the genetic and shared environment influences on reading comprehension. (Contains 7 tables.)

The genetic and environmental overlap between static and dynamic measures of preschool phonological awareness (PA) and their relation to preschool letter knowledge (LK) and kindergarten reading were examined using monozygotic and dizygotic twin children (maximum N = 1,988). The static tests were those typically used to assess a child's current level of PA such as blending and elision, and the dynamic test included instruction in phoneme identity to assess the child's ability to respond to this instruction. Both forms were influenced by genes and by shared and nonshared environment. The static and dynamic versions were influenced by the same genes, and part of the total genetic influence was shared with LK. They were subject to both overlapping and independent shared environment influences, with the component in common also affecting LK. Nonshared environment influences were mostly independent. Scores from dynamic assessment added only minimally to variance explained in kindergarten reading after LK and static assessment had been factored in. Although one of the genetic factors that influenced both forms of PA also affected kindergarten reading, it was only the one shared with LK. The authors conclude that dynamic assessment of PA in preschool offers little advantage over the more commonly used static forms, especially if LK scores are available, although they acknowledge its potential in cases of preschool educational disadvantage. (Contains 4 tables.)

Objective: Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of DSM-IV-TR ADHD. Method: Families were ascertained at Massachusetts General Hospital (MGH; N = 309 trios), Washington University at St. Louis (WASH-U; N = 272 trios), and University of California at Los Angeles (UCLA; N = 156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families. Results: Our smallest p value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08), but one of the 20 most significant associations was located in a candidate gene of interest for ADHD (SLC9A9, rs9810857, p = 6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9. Conclusions: We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders. (Contains 3 figures and 5 tables.)

It is often assumed that differences in teacher characteristics are a major source of variability in children's educational achievements. We examine this assumption for early literacy achievement by calculating the correlations between pairs of twin children who either shared or did not share a teacher in kindergarten, Grade 1, and Grade 2. Teacher effects--or, more strictly, classroom effects--would show up as higher correlations for same-class than for different-class twin pairs. Same-class correlations were generally higher than different-class correlations, though not significantly so on most occasions. On the basis of the results, we estimate that the maximum variance accounted for by being assigned to the same or different classrooms is 8%. This is an upper-bound figure for a teacher effect because factors other than teachers may contribute to variation attributable to classroom assignment. We discuss the limitations of the study and draw out some of its educational implications. (Contains 3 tables. )

As part of a longitudinal twin study of literacy and language, we conducted a behaviour-genetic analysis of orthographic learning, spelling and decoding in Grade 2 children (225 identical and 214 fraternal twin pairs) in the United States and Australia. Each variable showed significant genetic and unique environment influences. Multivariate analyses revealed very high genetic correlations among the variables, indicating that the same genes are involved in their aetiology. These genes are partly independent of those contributing to intelligence. A further analysis indicated that the covariation between decoding and orthographic learning is mediated by shared genes rather than by a direct causal path. The authors argue that a learning parameter, most directly assessed by orthographic learning in this study, underlies all three literacy variables. The results are also discussed in relation to Share's self-teaching hypothesis, which may require modification.

Genetic and environmental influences on early reading and spelling at the end of kindergarten and Grade 1 were compared across three twin samples tested in the United States, Australia, and Scandinavia. Proportions of variance due to genetic influences on kindergarten reading were estimated at 0.84 in Australia, 0.68 in the U.S., and 0.33 in Scandinavia. The effects of shared environment on kindergarten reading were estimated at 0.09 in Australia, 0.25 in the U.S., and 0.52 in Scandinavia. A similar pattern of genetic and environmental influences was obtained for kindergarten spelling. One year later when twins in all three samples had received formal literacy instruction for at least one full school year, heritability was similarly high across country, with estimated genetic influences varying between 0.79 and 0.83 for reading and between 0.62 and 0.79 for spelling. These findings indicate that the pattern of genetic and environmental influences on early reading and spelling development varies according to educational context, with genetic influence increasing as a function of increasing intensity of early instruction. Longitudinal analyses revealed genetic continuity for both reading and spelling between kindergarten and Grade 1 across country. However, a new genetic factor comes into play accounting for independent variance in reading at Grade 1 in the U.S. and Scandinavia, suggesting a change in genetic influences on reading. Implications for response-to-instruction are discussed. (Contains 7 tables.)

Grade 1 literacy skills of twin children in Australia (New South Wales) and the United States (Colorado) were explored in a genetically sensitive design (N = 319 pairs). Analyses indicated strong genetic influence on word and nonword identification, reading comprehension, and spelling. Rapid naming showed more modest, though reliable, genetic influence. Phonological awareness was subject to high nonshared environment and no reliable genetic effects, and individual measures of memory and learning were also less affected by genes than nonshared environment. Multivariate analyses showed that the same genes affected word identification, reading comprehension, and spelling. Country comparisons indicated that the patterns of genetic influence on reading and spelling in Grade 1 were similar, though for the U.S. but not the Australian children new genes came on stream in the move from kindergarten to Grade 1. We suggest that this is because the more intensive kindergarten literacy curriculum in New South Wales compared with Colorado, consistent with the mean differences between the two countries, means that more of the genes are "online" sooner in Australia because of accelerated overall reading development.

Genetic and environmental influences on prereading skills in preschool and on early reading and spelling development at the end of kindergarten were compared among samples of identical and fraternal twins from the U.S. (Colorado), Australia, and Scandinavia. Mean comparisons revealed significantly lower preschool print knowledge in Scandinavia, consistent with the relatively lower amount of shared book reading and letter-based activities with parents, and lack of emphasis on print knowledge in Scandinavian preschools. The patterns of correlations between all preschool environment measures and prereading skills within the samples were remarkably similar, as were the patterns of genetic, shared environment, and non-shared environment estimates: in all samples, genetic influence was substantial and shared environment influence was relatively weak for phonological awareness, rapid naming, and verbal memory; genetic influence was weak, and shared environment influence was relatively strong for vocabulary and print knowledge. In contrast, for reading and spelling assessed at the end of kindergarten in the Australian and U.S. samples, there was some preliminary evidence for country differences in the magnitude of genetic and environmental influences. We argue that the apparently higher genetic and lower shared environment influence in the Australian sample was related to a greater emphasis on formal reading instruction, resulting in more advanced reading and spelling skills at the end of kindergarten, and thus there was greater opportunity to observe genetic influences on response to systematic reading instruction among the Australian twins.

Prereading and early reading skills of preschool twin children in Australia, Scandinavia and the United States were explored in a genetically sensitive design (max. N=627 preschool pairs and 422 kindergarten pairs). Analyses indicated a strong genetic influence on preschool phonological awareness, rapid naming and verbal memory. Print awareness, vocabulary and grammarmorphology were subject primarily to shared environment effects. There were significant genetic and shared environment correlations among the preschool traits. Kindergarten reading, phonological awareness and rapid naming were primarily affected by genes, and spelling was equally affected by genes and shared environment. Multivariate analyses revealed genetic and environmental overlap and independence among kindergarten variables. Longitudinal analyses showed genetic continuity as well as change in phonological awareness and rapid naming across the 2 years. Relations among the preschool variables of print awareness, phonological awareness and rapid naming and kindergarten reading were also explored in longitudinal analyses. Educational implications are discussed.

Individual differences in measures of prereading skills and in questionnaire measures of 4-5-year-old twins' print environments in Australia, Scandinavia, and the United States were explored with a behavioral-genetic design. Modest phenotypic correlations were found between environmental measures and the twins' print knowledge, general verbal ability, and phoneme awareness. Lower print knowledge in Scandinavian twins was related to country differences in preschool print environment. Latent-trait behavioral-genetic analyses indicated very strong shared-environment influences on individual differences in Print Knowledge. Genetic influence was also significant. Several other prereading skills varied in their environmental and genetic influence, including a significant contrast between Phonological Awareness and Print Knowledge. Rapid Naming also revealed very strong genetic influence, as did Verbal Memory. Stronger shared-environment influences were found for Vocabulary and Grammar/Morphology. Genetic and environmental correlations among latent traits for General Verbal Ability, Phonological Awareness, and Print Knowledge were high, but there were also significant independent genetic and environmental contributions to each skill. Practical implications include the need for substantial and sustained instructional support for children hampered by genetic constraints on early literacy development.

Abstract Background In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA. Results In comparison to controls, we show that RA patients have multiple and strong differences in the B cell receptor repertoire including reduced diversity as well as altered isotype, chain, and segment frequencies. We demonstrate that therapeutic tumor necrosis factor inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific T cell receptor repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool. Conclusions Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases.

Consumer acceptance or rejection of biotechnology is often shaped by information prepared by communicators with varying levels of scientific knowledge, awareness, and acceptance. This study compared the prior, post-workshop, and sustained (1 year) biotechnology awareness, acceptance, and attitudes of professionals who communicate biotechnology to the public at an informational, day-long, university-sponsored workshop. Thirty-seven participants completed the three rounds of data collection. They consistently rated their scientific knowledge high. Throughout the three rounds, their primary media source of biotechnology information was newspapers, with the web being the second most frequently cited source. Participants were somewhat accepting of genetic modification of microorganisms, forests/landscape plants, and food crops, but were somewhat unaccepting of genetic modification of animals and humans. Fear of genes moving unchecked to other plants, insects, or microorganisms; fear of environmental harm; and fear of food safety consequences were identified as obstacles to their acceptance of food biotechnology. Participants were most confident with statements related to biotechnology from university scientists and health professionals and least confident with statements from celebrities. They saw their professional role in providing analysis and interpretation regarding desirable and undesirable consequences of biotechnology as important. Although the study participants were professionals, their awareness and attitudes toward biotechnology were similar to consumer awareness and attitudes measured in previous studies. It is important that university scientists provide unbiased, research-based biotechnology information to those who communicate biotechnology to the public (e.g., through workshops, websites, etc.) and accommodate learners with varying levels of scientific knowledge, because these communicators will affect consumer attitudes. (Contains 1 table.)

Preliminary results from data on 146 Australian, 284 American, and 70 Norwegian preschool twins indicate reliable genetic influences on phonological awareness and memory and learning. Vocabulary, grammar, and morphology showed significant shared environment and negligible genetic effects. A print knowledge composite showed genetic and shared environment influences. (Contains references.) (Author/CR)

Erysipelothrix spp., including E. rhusiopathiae, are zoonotic bacterial pathogens that can cause morbidity and mortality in mammals, fish, reptiles, birds, and humans. The southern sea otter (SSO; Enhydra lutris nereis) is a federally-listed threatened species for which infectious disease is a major cause of mortality. We estimated the frequency of detection of these opportunistic pathogens in dead SSOs, described pathology associated with Erysipelothrix infections in SSOs, characterized the genetic diversity and antimicrobial susceptibility of SSO isolates, and evaluated the virulence of two novel Erysipelothrix isolates from SSOs using an in vivo fish model. From 1998 to 2021 Erysipelothrix spp. were isolated from six of >500 necropsied SSOs. Erysipelothrix spp. were isolated in pure culture from three cases, while the other three were mixed cultures. Bacterial septicemia was a primary or contributing cause of death in five of the six cases. Other pathology observed included suppurative lymphadenopathy, fibrinosuppurative arteritis with thrombosis and infarction, bilateral uveitis and endophthalmitis, hypopyon, petechia and ecchymoses, mucosal infarction, and suppurative meningoencephalitis and ventriculitis. Short to long slender Gram-positive or Gram-variable bacterial rods were identified within lesions, alone or with other opportunistic bacteria. All six SSO isolates had the spaA genotype-four isolates clustered with spaA E. rhusiopathiae strains from various terrestrial and marine animal hosts. Two isolates did not cluster with any known Erysipelothrix spp.; whole genome sequencing revealed a novel Erysipelothrix species and a novel E. rhusiopathiae subspecies. We propose the names Erysipelothrix enhydrae sp. nov. and Erysipelothrix rhusiopathiae ohloneorum ssp. nov. respectively. The type strains are E. enhydrae UCD-4322-04 and E. rhusiopathiae ohloneorum UCD-4724-06, respectively. Experimental injection of tiger barbs (Puntigrus tetrazona) resulted in infection and mortality from the two novel Erysipelothrix spp. Antimicrobial susceptibility testing of Erysipelothrix isolates from SSOs shows similar susceptibility profiles to isolates from other terrestrial and aquatic animals. This is the first description of the pathology, microbial characteristics, and genetic diversity of Erysipelothrix isolates recovered from diseased SSOs. Methods presented here can facilitate case recognition, aid characterization of Erysipelothrix isolates, and illustrate assessment of virulence using fish models.

Spatial transcriptomics extends single-cell RNA sequencing (scRNA-seq) by providing spatial context for cell type identification and analysis. Imaging-based spatial technologies such as multiplexed error-robust fluorescence in situ hybridization (MERFISH) can achieve single-cell resolution, directly mapping single-cell identities to spatial positions. MERFISH produces a different data type than scRNA-seq, and a technical comparison between the two modalities is necessary to ascertain how to best integrate them. We performed MERFISH on the mouse liver and kidney and compared the resulting bulk and single-cell RNA statistics with those from the Tabula Muris Senis cell atlas and from two Visium datasets. MERFISH quantitatively reproduced the bulk RNA-seq and scRNA-seq results with improvements in overall dropout rates and sensitivity. Finally, we found that MERFISH independently resolved distinct cell types and spatial structure in both the liver and kidney. Computational integration with the Tabula Muris Senis atlas did not enhance these results. We conclude that MERFISH provides a quantitatively comparable method for single-cell gene expression and can identify cell types without the need for computational integration with scRNA-seq atlases.

The rising prevalence of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales is a significant threat to animal and human health. This study aims to describe the clinical features, antimicrobial susceptibility patterns, and genotypic features of infections associated with ESBL-producing Enterobacterales in dogs and cats seen at a tertiary referral veterinary teaching hospital. Enterobacterales isolated from dogs and cats that underwent ESBL testing during the study period were identified using a search of the hospital antimicrobial susceptibility test software database. Medical records of confirmed ESBL isolates were reviewed, and the source of infection, clinical findings, and antimicrobial susceptibility were recorded. Genomic DNA from bacterial isolates was evaluated for antimicrobial resistance genes with whole genome sequencing. Thirty ESBL-producing isolates were identified based on phenotypic testing (twenty-nine from dogs, one from a cat); twenty-six were Escherichia coli and the remainder were Klebsiella spp. Bacterial cystitis was the most commonly identified (8/30, 27%) clinical problem associated with infection. Resistance to three or more antimicrobial classes was identified in 90% (27/30) of isolates, and all isolates were susceptible to imipenem. Over 70% of isolates were susceptible to piperacillin-tazobactam, amikacin, and cefoxitin. BlaCTX-M-15 was the most common ESBL gene identified, present in 13/22 (59%) isolate genomes. A wide range of clinical infections were identified. Piperacillin-tazobactam and amikacin may be alternatives to carbapenem therapy. Further, larger-scale studies are needed.

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q

Women with maturity-onset diabetes of the young (MODY) need tailored antenatal care and monitoring of their offspring. Each MODY subtype has different implications for glycaemic targets, treatment choices and neonatal management. Hyperglycaemia of MODY is often first diagnosed in adolescence or early adulthood and therefore is clinically relevant to pregnant women. MODY remains an under-recognised and undiagnosed condition. Pregnancy represents an opportune time to make a genetic diagnosis of MODY and provide precision treatment. This review describes the nuance of antenatal care in women with MODY and the implications for pregnancies affected by a positive paternal genotype. Mutations in hepatic nuclear factor 1-alpha (HNF1A) and 4-alpha (HNF4A) genes are associated with progressive β-cell dysfunction resulting in early onset diabetes. Patients are largely managed with sulphonylureas outside of pregnancy. Macrosomia and persistent neonatal hypoglycaemia are reported in 54% and 15% of HNF4A genotype positive offspring respectively with a median increase in birthweight of 790 g. Close observation of foetal growth in utero allows optimal timing of delivery to minimise peri- and postpartum materno-foetal complications. Glucokinase (GCK)-MODY causes mild fasting hyperglycaemia which does not require treatment outside of pregnancy. Birthweight of offspring of maternal carriers is dependent on foetal genotype; heterozygous mutation carriers are usually normal weight while genotype negative offspring are large for gestational age (600 g heavier). Affected offspring of paternal carriers may be small for gestational age (500 g lighter). Serial growth scans with measurement of the abdominal circumference indirectly differentiate foetal genotype. Measurement of cell free foetal DNA in maternal blood from the late first trimester is superior to traditionally used ultrasound to distinguish foetal genotype. Cost and accessibility may limit its use.

Abstract Background Hoof structure and health are essential for the welfare and productivity of beef cattle. Therefore, we assessed the genetic and genomic background of foot score traits in American (US) and Australian (AU) Angus cattle and investigated the feasibility of performing genomic evaluations combining data for foot score traits recorded in US and AU Angus cattle. The traits evaluated were foot angle (FA) and claw set (CS). In total, 109,294 and ~ 1.12 million animals had phenotypic and genomic information, respectively. Four sets of analyses were performed: (1) genomic connectedness between US and AU Angus cattle populations and population structure, (2) estimation of genetic parameters, (3) single-step genomic prediction of breeding values, and (4) single-step genome-wide association studies for FA and CS. Results There was no clear genetic differentiation between US and AU Angus populations. Similar heritability estimates (FA: 0.22–0.24 and CS: 0.22–0.27) and moderate-to-high genetic correlations between US and AU foot scores (FA: 0.61 and CS: 0.76) were obtained. A joint-genomic prediction using data from both populations outperformed within-country genomic evaluations. A genomic prediction model considering US and AU datasets as a single population performed similarly to the scenario accounting for genotype-by-environment interactions (i.e., multiple-trait model considering US and AU records as different traits), even though the genetic correlations between countries were lower than 0.80. Common significant genomic regions were observed between US and AU for FA and CS. Significant single nucleotide polymorphisms were identified on the Bos taurus (BTA) chromosomes BTA1, BTA5, BTA11, BTA13, BTA19, BTA20, and BTA23. The candidate genes identified were primarily from growth factor gene families, including FGF12 and GDF5, which were previously associated with bone structure and repair. Conclusions This study presents comprehensive population structure and genetic and genomic analyses of foot scores in US and AU Angus cattle populations, which are essential for optimizing the implementation of genomic selection for improved foot scores in Angus cattle breeding programs. We have also identified candidate genes associated with foot scores in the largest Angus cattle populations in the world and made recommendations for genomic evaluations for improved foot score traits in the US and AU.

Abstract Background Understanding the mechanistic effects of novel immunotherapy agents is critical to improving their successful clinical translation. These effects need to be studied in preclinical models that maintain the heterogenous tumor microenvironment (TME) and dysfunctional cell states found in a patient’s tumor. We investigated immunotherapy perturbations targeting co-stimulatory molecule GITR and co-inhibitory immune checkpoint TIGIT in a patient-derived ex vivo system that maintains the TME in its near-native state. Leveraging single-cell genomics, we identified cell type-specific transcriptional reprogramming in response to immunotherapy perturbations. Methods We generated ex vivo tumor slice cultures from fresh surgical resections of gastric and colon cancer and treated them with GITR agonist or TIGIT antagonist antibodies. We applied paired single-cell RNA and TCR sequencing to the original surgical resections, control, and treated ex vivo tumor slice cultures. We additionally confirmed target expression using multiplex immunofluorescence and validated our findings with RNA in situ hybridization. Results We confirmed that tumor slice cultures maintained the cell types, transcriptional cell states and proportions of the original surgical resection. The GITR agonist was limited to increasing effector gene expression only in cytotoxic CD8 T cells. Dysfunctional exhausted CD8 T cells did not respond to GITR agonist. In contrast, the TIGIT antagonist increased TCR signaling and activated both cytotoxic and dysfunctional CD8 T cells. This included cells corresponding to TCR clonotypes with features indicative of potential tumor antigen reactivity. The TIGIT antagonist also activated T follicular helper-like cells and dendritic cells, and reduced markers of immunosuppression in regulatory T cells. Conclusions We identified novel cellular mechanisms of action of GITR and TIGIT immunotherapy in the patients’ TME. Unlike the GITR agonist that generated a limited transcriptional response, TIGIT antagonist orchestrated a multicellular response involving CD8 T cells, T follicular helper-like cells, dendritic cells, and regulatory T cells. Our experimental strategy combining single-cell genomics with preclinical models can successfully identify mechanisms of action of novel immunotherapy agents. Understanding the cellular and transcriptional mechanisms of response or resistance will aid in prioritization of targets and their clinical translation.

The role of microbes in insecticide resistance is an emerging question. Here, we describe six metagenome-assembled genomes (MAGs) associated with the glassy-winged sharpshooter (Homalodisca vitripennis [Germar, 1821]) (Hemiptera, Cicadellidae). MAGs representing the obligate symbionts Candidatus Sulcia muelleri and Candidatus Baumannia cicadellinicola and the facultative symbiont Wolbachia were obtained from imidacloprid-resistant and imidacloprid-susceptible sharpshooters.

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

Adeno-associated virus (AAV) vectors are used for correcting multiple genetic disorders. Although the goal is to achieve lifelong correction with a single vector administration, the ability to redose would enable the extension of therapy in cases in which initial gene transfer is insufficient to achieve a lasting cure, episomal vector forms are lost in growing organs of pediatric patients, or transgene expression is diminished over time. However, AAV typically induces potent and long-lasting neutralizing antibodies (NAbs) against capsid that prevents re-administration. To prevent NAb formation in hepatic AAV8 gene transfer, we developed a transient B cell-targeting protocol using a combination of monoclonal Ab therapy against CD20 (for B cell depletion) and BAFF (to slow B cell repopulation). Initiation of immunosuppression before (rather than at the time of) vector administration and prolonged anti-BAFF treatment prevented immune responses against the transgene product and abrogated prolonged IgM formation. As a result, vector re-administration after immune reconstitution was highly effective. Interestingly, re-administration before the immune system had fully recovered achieved further elevated levels of transgene expression. Finally, this immunosuppression protocol reduced Ig-mediated AAV uptake by immune cell types with implications to reduce the risk of immunotoxicities in human gene therapy with AAV.

Gene therapy is a potential treatment for Friedreich ataxia, with multiple programs on the horizon. The purpose of this study was to collect opinions about gene therapy from individuals 14 years or older with Friedreich ataxia or parents/caregivers of Friedreich ataxia patients who were diagnosed as children 17 or younger. Participants were asked to complete a survey after reading brief educational materials regarding gene therapy. Most of the patients captured in this survey have an early-onset (classical) presentation of the disease. Participants expressed urgency in participating in gene therapy clinical trials despite the associated risks. About half of the respondents believed that gene therapy would cease progression or minimize symptoms, whereas nearly one-fourth expected to be cured. The survey also revealed how participants perceive their symptom burden, because a substantial majority reported that balance/walking issues most interfere with their quality of life and would be the symptom they would prioritize treating. Although not statistically significant, more caregivers prioritized treating cardiomyopathy than patients. This study provides valuable information on priorities, beliefs, and expectations regarding gene therapy and serves to guide future gene therapy opinion studies and gene therapy trial design.

Erysipelothrix spp., including E. rhusiopathiae, are zoonotic bacterial pathogens that can cause morbidity and mortality in mammals, fish, reptiles, birds, and humans. The southern sea otter (SSO; Enhydra lutris nereis) is a federally-listed threatened species for which infectious disease is a major cause of mortality. We estimated the frequency of detection of these opportunistic pathogens in dead SSOs, described pathology associated with Erysipelothrix infections in SSOs, characterized the genetic diversity and antimicrobial susceptibility of SSO isolates, and evaluated the virulence of two novel Erysipelothrix isolates from SSOs using an in vivo fish model. From 1998 to 2021 Erysipelothrix spp. were isolated from six of >500 necropsied SSOs. Erysipelothrix spp. were isolated in pure culture from three cases, while the other three were mixed cultures. Bacterial septicemia was a primary or contributing cause of death in five of the six cases. Other pathology observed included suppurative lymphadenopathy, fibrinosuppurative arteritis with thrombosis and infarction, bilateral uveitis and endophthalmitis, hypopyon, petechia and ecchymoses, mucosal infarction, and suppurative meningoencephalitis and ventriculitis. Short to long slender Gram-positive or Gram-variable bacterial rods were identified within lesions, alone or with other opportunistic bacteria. All six SSO isolates had the spaA genotype–four isolates clustered with spaA E. rhusiopathiae strains from various terrestrial and marine animal hosts. Two isolates did not cluster with any known Erysipelothrix spp.; whole genome sequencing revealed a novel Erysipelothrix species and a novel E. rhusiopathiae subspecies. We propose the names Erysipelothrix enhydrae sp. nov. and Erysipelothrix rhusiopathiae ohloneorum ssp. nov. respectively. The type strains are E. enhydrae UCD-4322-04 and E. rhusiopathiae ohloneorum UCD-4724-06, respectively. Experimental injection of tiger barbs (Puntigrus tetrazona) resulted in infection and mortality from the two novel Erysipelothrix spp. Antimicrobial susceptibility testing of Erysipelothrix isolates from SSOs shows similar susceptibility profiles to isolates from other terrestrial and aquatic animals. This is the first description of the pathology, microbial characteristics, and genetic diversity of Erysipelothrix isolates recovered from diseased SSOs. Methods presented here can facilitate case recognition, aid characterization of Erysipelothrix isolates, and illustrate assessment of virulence using fish models.

Gene replacement therapy is a rational therapeutic strategy and clinical intervention for neurodegenerative disorders like Canavan disease, a leukodystrophy caused by biallelic mutations in the aspartoacylase (ASPA) gene. We aimed to investigate whether simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA provides a safe and effective therapeutic strategy in an open-label, individual-patient, expanded-access trial for Canavan disease. Immunomodulation was given prophylactically prior to adeno-associated virus (AAV) treatment to prevent an immune response to ASPA or the vector capsid. The patient served as his own control, and change from baseline was assessed by clinical pathology tests, vector genomes in the blood, antibodies against ASPA and AAV capsids, levels of cerebrospinal fluid (CSF) N-acetylaspartate (NAA), brain water content and morphology, clinical status, and motor function tests. Two years post treatment, the patient’s white matter myelination had increased, motor function was improved, and he remained free of typical severe epilepsy. NAA level was reduced at 3 months and remained stable up to 4 years post treatment. Immunomodulation prior to AAV exposure enables repeat dosing and has prevented an anti-transgene immune response. Dual-route administration of gene therapy may improve treatment outcomes.

Host-pathogen specificity can arise from certain selective environments mediated by both the host and pathogen. Therefore, understanding the degree to which host species identity is correlated with pathogen genotype can help reveal historical host-pathogen dynamics. One animal disease of particular concern is chytridiomycosis, typically caused by the global panzootic lineage of the amphibian chytrid fungus (Batrachochytrium dendrobatidis, Bd), termed Bd-GPL. This pathogen lineage has caused devastating declines in amphibian communities around the world. However, the site of origin for the common ancestor of modern Bd-GPL and the fine-scale transmission dynamics of this lineage have remained a mystery. This is especially the case in North America where Bd-GPL is widespread, but disease outbreaks occur sporadically. Herein, we use Bd genetic data collected throughout the United States from amphibian skin swabs and cultured isolate samples to investigate Bd genetic patterns. We highlight two case studies in Pennsylvania and Nevada where Bd-GPL genotypes are strongly correlated with host species identity. Specifically, in some localities bullfrogs (Rana catesbeiana) are infected with Bd-GPL lineages that are distinct from those infecting other sympatric amphibian species. Overall, we reveal a previously unknown association of Bd genotype with host species and identify the eastern United States as a Bd diversity hotspot and potential site of origin for Bd-GPL.

BackgroundHomalodisca vitripennis Germar, the glassy-winged sharpshooter, is an invasive insect in California and a critical threat to agriculture through its transmission of the plant pathogen, Xylella fastidiosa. Quarantine, broad-spectrum insecticides, and biological control have been used for population management of H. vitripennis since its invasion and subsequent proliferation throughout California. Recently wide-spread neonicotinoid resistance has been detected in populations of H. vitripennis in the southern portions of California's Central Valley. In order to better understand potential mechanisms of H. vitripennis neonicotinoid resistance, we performed RNA sequencing on wild-caught insecticide-resistant and relatively susceptible sharpshooters to profile their transcriptome and population structure.ResultsWe identified 81 differentially expressed genes with higher expression in resistant individuals. The significant largest differentially expressed candidate gene linked to resistance status was a cytochrome P450 gene with similarity to CYP6A9. Furthermore, we observed an over-enrichment of GO terms representing functions supportive of roles in resistance mechanisms (cytochrome P450s, M13 peptidases, and cuticle structural proteins). Finally, we saw no evidence of broad-scale population structure, perhaps due to H. vitripennis' relatively recent introduction to California or due to the relatively small geographic scale investigated here.ConclusionsIn this work, we characterized the transcriptome of insecticide-resistant and susceptible H. vitripennis and identified candidate genes that may be involved in resistance mechanisms for this species. Future work should seek to build on the transcriptome profiling performed here to confirm the role of the identified genes, particularly the cytochrome P450, in resistance in H. vitripennis. We hope this work helps aid future population management strategies for this and other species with growing insecticide resistance.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

Cytogenetic and molecular abnormalities are known to influence post-transplant outcomes in acute myeloid leukemia (AML) but data assessing the prognostic value of combined genetic models in the HCT setting are limited. We developed an adapted European LeukemiaNet (aELN) risk classification based on available genetic data reported to the Center for International Blood and Marrow Transplant Research, to predict post-transplant outcomes in 2289 adult AML patients transplanted in first remission, between 2013 and 2017. Patients were stratified according to aELN into three groups: favorable (Fav, N = 181), intermediate (IM, N = 1185), and adverse (Adv, N = 923). Univariate analysis demonstrated significant differences in 2-year overall survival (OS) (Fav: 67.7%, IM: 64.9% and Adv: 53.9%; p

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

Enhancers are cis-regulatory elements that play critical regulatory roles in modulating developmental transcription programs and driving cell-type-specific and context-dependent gene expression in the brain. The development of massively parallel reporter assays (MPRAs) has enabled high-throughput functional screening of candidate DNA sequences for enhancer activity. Tissue-specific screening of in vivo enhancer function at scale has the potential to greatly expand our understanding of the role of non-coding sequences in development, evolution, and disease. Here, we adapted a self-transcribing regulatory element MPRA strategy for delivery to early postnatal mouse brain via recombinant adeno-associated virus (rAAV). We identified and validated putative enhancers capable of driving reporter gene expression in mouse forebrain, including regulatory elements within an intronic CACNA1C linkage disequilibrium block associated with risk in neuropsychiatric disorder genetic studies. Paired screening and single enhancer in vivo functional testing, as we show here, represents a powerful approach towards characterizing regulatory activity of enhancers and understanding how enhancer sequences organize gene expression in the brain.

Homalodisca vitripennis (Hemiptera: Cicadellidae), known as the glassy-winged sharpshooter, is a xylem feeding leafhopper and an important agricultural pest as a vector of Xylella fastidiosa, which causes Pierce's disease in grapes and a variety of other scorch diseases. The current H. vitripennis reference genome from the Baylor College of Medicine's i5k pilot project is a 1.4-Gb assembly with 110,000 scaffolds, which still has significant gaps making identification of genes difficult. To improve on this effort, we used a combination of Oxford Nanopore long-read sequencing technology combined with Illumina sequencing reads to generate a better assembly and first-pass annotation of the whole genome sequence of a wild-caught Californian (Tulare County) individual of H. vitripennis. The improved reference genome assembly for H. vitripennis is 1.93-Gb in length (21,254 scaffolds, N50 = 650 Mb, BUSCO completeness = 94.3%), with 33.06% of the genome masked as repetitive. In total, 108,762 gene models were predicted including 98,296 protein-coding genes and 10,466 tRNA genes. As an additional community resource, we identified 27 orthologous candidate genes of interest for future experimental work including phenotypic marker genes like white. Furthermore, as part of the assembly process, we generated four endosymbiont metagenome-assembled genomes, including a high-quality near complete 1.7-Mb Wolbachia sp. genome (1 scaffold, CheckM completeness = 99.4%). The improved genome assembly and annotation for H. vitripennis, curated set of candidate genes, and endosymbiont MAGs will be invaluable resources for future research of H. vitripennis.