The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing.
Ontology highlight
ABSTRACT:
SUBMITTER: Rodin RE
PROVIDER: S-EPMC7983596 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Persons with and without autism process sensory information differently. Differences in sensory processing are directly relevant to social functioning and communicative abilities, which are known to be hampered in persons with autism. We collected functional magnetic resonance imaging data from 25 autistic individuals and 25 neurotypical individuals while they performed a silent gesture recognition task. We exploited brain network topology, a holistic quantification of how networks within the brain are organized to provide new insights into how visual communicative signals are processed in autistic and neurotypical individuals. Performing graph theoretical analysis, we calculated two network properties of the action observation network: 'local efficiency', as a measure of network segregation, and 'global efficiency', as a measure of network integration. We found that persons with autism and neurotypical persons differ in how the action observation network is organized. Persons with autism utilize a more clustered, local-processing-oriented network configuration (i.e. higher local efficiency) rather than the more integrative network organization seen in neurotypicals (i.e. higher global efficiency). These results shed new light on the complex interplay between social and sensory processing in autism.
| S-EPMC9629468 | biostudies-literature
Project description:Autistic individuals exhibit significant sensorimotor differences. Postural stability and control are foundational motor skills for successfully performing many activities of daily living. In neurotypical development, postural stability and control develop throughout childhood and adolescence. In autistic development, previous studies have focused primarily on individual age groups (e.g., childhood, adolescence, adulthood) or only controlled for age using age-matching. Here, we examined the age trajectories of postural stability and control in autism from childhood through adolescents using standardized clinical assessments. In study 1, we tested the postural stability of autistic (n = 27) and neurotypical (n = 41) children, adolescents, and young adults aged 7-20 years during quiet standing on a force plate in three visual conditions: eyes open (EO), eyes closed (EC), and eyes open with the head in a translucent dome (Dome). Postural sway variability decreased as age increased for both groups, but autistic participants showed greater variability than neurotypical participants across age. In study 2, we tested autistic (n = 21) and neurotypical (n = 32) children and adolescents aged 7-16 years during a dynamic postural control task with nine targets. Postural control efficiency increased as age increased for both groups, but autistic participants were less efficient compared to neurotypical participants across age. Together, these results indicate that autistic individuals have a similar age trajectory for postural stability and control compared to neurotypical individuals, but have lower postural stability and control overall.
| S-EPMC10023334 | biostudies-literature
Project description:Adenosine-to-inosine (A-to-I) RNA editing is a neurodevelopmentally regulated epigenetic modification shown to modulate complex behavior in animals. Little is known about human A-to-I editing, but it is thought to constitute one of many molecular mechanisms connecting environmental stimuli and behavioral outputs. Thus, comprehensive exploration of A-to-I RNA editing in human brains may shed light on gene-environment interactions underlying complex behavior in health and disease. Synaptic function is a main target of A-to-I editing, which can selectively recode key amino acids in synaptic genes, directly altering synaptic strength and duration in response to environmental signals. Here, we performed a high-resolution survey of synaptic A-to-I RNA editing in a human population, and examined how it varies in autism, a neurodevelopmental disorder in which synaptic abnormalities are a common finding. Using ultra-deep (>1000 × ) sequencing, we quantified the levels of A-to-I editing of 10 synaptic genes in postmortem cerebella from 14 neurotypical and 11 autistic individuals. A high dynamic range of editing levels was detected across individuals and editing sites, from 99.6% to below detection limits. In most sites, the extreme ends of the population editing distributions were individuals with autism. Editing was correlated with isoform usage, clusters of correlated sites were identified, and differential editing patterns examined. Finally, a dysfunctional form of the editing enzyme adenosine deaminase acting on RNA B1 was found more commonly in postmortem cerebella from individuals with autism. These results provide a population-level, high-resolution view of A-to-I RNA editing in human cerebella and suggest that A-to-I editing of synaptic genes may be informative for assessing the epigenetic risk for autism.
| S-EPMC3494744 | biostudies-literature
Project description:BackgroundIncreased urinary concentrations of pentacarboxyl-, precopro- and copro-porphyrins have been associated with prolonged mercury (Hg) exposure in adults, and comparable increases have been attributed to Hg exposure in children with autism (AU).ObjectivesThis study was designed to measure and compare urinary porphyrin concentrations in neurotypical (NT) children and same-age children with autism, and to examine the association between porphyrin levels and past or current Hg exposure in children with autism.MethodsThis exploratory study enrolled 278 children 2-12 years of age. We evaluated three groups: AU, pervasive developmental disorder-not otherwise specified (PDD-NOS), and NT. Mothers/caregivers provided information at enrollment regarding medical, dental, and dietary exposures. Urine samples from all children were acquired for analyses of porphyrin, creatinine, and Hg. Differences between groups for mean porphyrin and Hg levels were evaluated. Logistic regression analysis was conducted to determine whether porphyrin levels were associated with increased risk of autism.ResultsMean urinary porphyrin concentrations are naturally high in young children and decline by as much as 2.5-fold between 2 and 12 years of age. Elevated copro- (p < 0.009), hexacarboxyl- (p < 0.01) and pentacarboxyl- (p < 0.001) porphyrin concentrations were significantly associated with AU but not with PDD-NOS. No differences were found between NT and AU in urinary Hg levels or in past Hg exposure as determined by fish consumption, number of dental amalgam fillings, or vaccines received.ConclusionsThese findings identify disordered porphyrin metabolism as a salient characteristic of autism. Hg exposures were comparable between diagnostic groups, and a porphyrin pattern consistent with that seen in Hg-exposed adults was not apparent.
| S-EPMC2957928 | biostudies-literature
Project description:Morality can help guide behavior and facilitate relationships. Although moral judgments by autistic people are similar to neurotypical individuals, many researchers argue that subtle differences signify deficits in autistic individuals. Moral foundation theory describes moral judgments in terms of differences rather than deficits. The current research, aimed at assessing autistic individuals' moral inclinations using Haidt's framework, was co-designed with autistic community members. Our aim was to describe autistic moral thinking from a strengths-based perspective while acknowledging differences that may pose interpersonal challenges among autistic youth. We assessed 25 autistic and 23 neurotypical children's moral judgments using the Moral Foundations Questionnaire for Kids. We used semi-structured interviews and qualitative analysis with a subset of participants to describe children's moral reasoning. Analyses suggested that autistic and neurotypical children make similar judgments about moral transgressions across all five moral foundations. General linear mixed modeling showed that the greatest predictor of recommending punishment was how bad children deemed moral transgressions to be. We also found a trend that autistic children were more likely to recommend punishment for harmless norms violations than were neurotypical children. Future research could use longitudinal methods to understand the development of moral judgments among autistic and neurotypical children.
| S-EPMC8795511 | biostudies-literature
Project description:Lay abstractPeople with autism spectrum conditions (ASC) have difficulties imagining events, which might result from difficulty mentally generating and maintaining a coherent spatial scene. This study compared this scene construction ability between autistic (N = 55) and neurotypical (N = 63) adults. Results showed that scene construction was diminished in autistic compared to neurotypical participants, and participants with fewer autistic traits had better scene construction ability. ASC diagnosis did not influence the frequency of mentions of the self or of sensory experiences. Exploratory analysis suggests that scene construction ability is associated with the ability to understand our own and other people's mental states, and that these individual-level preferences/cognitive styles can overrule typical group-level characteristics.
| S-EPMC11301963 | biostudies-literature
Project description:Neurotypical (NT) individuals and individuals with autism spectrum disorder (ASD) make different judgments of social traits from others' faces; they also exhibit different social emotional responses in social interactions. A common hypothesis is that the differences in face perception in ASD compared with NT is related to distinct social behaviors. To test this hypothesis, we combined a face trait judgment task with a novel interpersonal transgression task that induces measures social emotions and behaviors. ASD and neurotypical participants viewed a large set of naturalistic facial stimuli while judging them on a comprehensive set of social traits (e.g., warm, charismatic, critical). They also completed an interpersonal transgression task where their responsibility in causing an unpleasant outcome to a social partner was manipulated. The purpose of the latter task was to measure participants' emotional (e.g., guilt) and behavioral (e.g., compensation) responses to interpersonal transgression. We found that, compared with neurotypical participants, ASD participants' self-reported guilt and compensation tendency was less sensitive to our responsibility manipulation. Importantly, ASD participants and neurotypical participants showed distinct associations between self-reported guilt and judgments of criticalness from others' faces. These findings reveal a novel link between perception of social traits and social emotional responses in ASD.
| S-EPMC10915137 | biostudies-literature
Project description:Human noroviruses (NoVs) are a major cause of gastroenteritis worldwide. It is thought that, similar to other RNA viruses, high mutation rates allow NoVs to evolve fast and to undergo rapid immune escape at the population level. However, the rate and spectrum of spontaneous mutations of human NoVs have not been quantified previously. Here, we analyzed the intra-patient diversity of the NoV capsid by carrying out RT-PCR and ultra-deep sequencing with 100,000-fold coverage of 16 stool samples from symptomatic patients. This revealed the presence of low-frequency sequences carrying large numbers of U-to-C or A-to-G base transitions, suggesting a role for hyper-mutation in NoV diversity. To more directly test for hyper-mutation, we performed transfection assays in which the production of mutations was restricted to a single cell infection cycle. This confirmed the presence of sequences with multiple U-to-C/A-to-G transitions, and suggested that hyper-mutation contributed a large fraction of the total NoV spontaneous mutation rate. The type of changes produced and their sequence context are compatible with ADAR-mediated editing of the viral RNA.
| S-EPMC7172324 | biostudies-literature
Project description:The Social Responsiveness Scale-Adult Version (SRS-A) measures autistic traits that are continuously distributed in the general population. Based on increased recognition of the dimensional nature of autistic traits, the authors examined the neural correlates of these traits in neurotypical individuals using the SRS-A and established a novel approach to assessing the neural basis of autistic characteristics, attempting to directly relate SRS-A scores to patterns of functional connectivity observed in the pregenual anterior cingulate cortex, a region commonly implicated in social cognition.Resting state functional magnetic resonance imaging scans were collected for 25 neurotypical adults. All participants provided SRS-A ratings completed by an informant who had observed them in natural social settings. Whole brain-corrected connectivity analyses were then conducted using SRS-A scores as a covariate of interest.Across participants, a significant negative relationship between SRS-A scores and the functional connectivity of the pregenual anterior cingulate cortex with the anterior portion of the mid-insula was found. Specifically, low levels of autistic traits were observed when a substantial portion of the anterior mid-insula showed positive connectivity with the pregenual anterior cingulate cortex. In contrast, elevated levels of autistic traits were associated with negative connectivity between these two regions.Resting state functional connectivity of the pregenual anterior cingulate cortex-insula social network was related to autistic traits in neurotypical adults. Application of this approach in samples with autism spectrum disorders is needed to confirm whether this circuit is dimensionally related to the severity of autistic traits in clinical populations.
| S-EPMC3075727 | biostudies-literature
Project description:During the clonal expansion of cancer from an ancestral cell with an initiating oncogenic mutation to symptomatic neoplasm, the occurrence of somatic mutations (both driver and passenger) can be used to track the on-going evolution of the neoplasm. All subclones within a cancer are phylogenetically related, with the prevalence of each subclone determined by its evolutionary fitness and the timing of its origin relative to other subclones. Recently developed massively parallel sequencing platforms promise the ability to detect rare subclones of genetic variants without a priori knowledge of the mutations involved. We used ultra-deep pyrosequencing to investigate intraclonal diversification at the Ig heavy chain locus in 22 patients with B-cell chronic lymphocytic leukemia. Analysis of a non-polymorphic control locus revealed artifactual insertions and deletions resulting from sequencing errors and base substitutions caused by polymerase misincorporation during PCR amplification. We developed an algorithm to differentiate genuine haplotypes of somatic hypermutations from such artifacts. This proved capable of detecting multiple rare subclones with frequencies as low as 1 in 5000 copies and allowed the characterization of phylogenetic interrelationships among subclones within each patient. This study demonstrates the potential for ultra-deep resequencing to recapitulate the dynamics of clonal evolution in cancer cell populations.
| S-EPMC2529122 | biostudies-literature