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A Qualitative Study of the Roles and Responsibilities of Academic and Journalistic Publishing in Social and Behavioral Genomics.

The conduct and translation of scientific research is shaped by academic and journalistic publishing. Academic journals issue editorial guidelines and policies that inform how researchers shape and present their studies. Journalists select and report on academic studies for public audiences. Despite the potential importance of journal editors and journalists in the scientific process, little has been done to examine how these groups think about their roles and responsibilities-especially when it comes to ethically sensitive scientific domains like social and behavioral genomics (SBG): the study of whether and how genetic differences between individuals correlate with differences in behaviors such as aggression and outcomes such as educational attainment. To begin filling this gap, we conducted semi-structured interviews with editors working at academic journals that publish SBG research (n = 10) and journalists who have reported on SBG studies (n = 13). Journal editors largely saw themselves as mediators between authors and peer reviewers who help to shepherd along research. Journalists frequently described themselves as translators of science for wide audiences; at times they also saw themselves as interrogators of science. While both groups considered SBG especially ethically sensitive and prone to risks such as misinterpretation, many expressed that systematic ethical review processes and guidelines for SBG are lacking. Further, many deferred the ethical responsibility to minimize risks associated with SBG to others. Our findings highlight the need for more explicit frameworks in academic and journalistic publishing to support the ethically responsible conduct and communication of SBG.

ELSI

Genetic variation influences food-sharing sociability in honey bees.

Individual variation in sociability is a central feature of every society. This includes honey bees, with some individuals well connected and sociable, and others at the periphery of their colony's social network. However, the genetic and molecular bases of sociability are poorly understood. Trophallaxis-a behavior involving sharing liquid with nutritional and signaling properties-comprises a social interaction and a proxy for sociability in honey bee colonies: more sociable bees engage in more trophallaxis. Here, we identify genetic and molecular mechanisms of trophallaxis-based sociability by combining genome sequencing, brain transcriptomics, and automated behavioral tracking. A genome-wide association study (GWAS) identified 18 single nucleotide polymorphisms (SNPs) associated with variation in sociability. Several SNPs were localized to genes previously associated with sociability in other species, including in the context of human autism, suggesting shared molecular mechanisms of sociability. Variation in sociability also was linked to differential brain gene expression, particularly genes associated with neural signaling and development. Using comparative genomic and transcriptomic approaches, we also detected evidence for divergent mechanisms underpinning sociability across species, including those related to reward sensitivity and encounter probability. These results highlight both potential evolutionary conservation of the molecular roots of sociability and points of divergence.

Animals

Exploring the genetics of social behaviour in C. calcarata.

Studies investigating social evolution often focus on species that are obligately eusocial, where presumably all of the adaptive genetic changes associated with sociality have already been completed. To fully understand eusociality, we must study species with facultative social behaviour. The small carpenter bee Ceratina calcarata is an ideal model for studying the genetics and molecular biology of eusocial evolution as it can exhibit both subsocial behaviour with parental care and social behaviour facilitated by the altruistic dwarf eldest daughter. Here, we sequenced the genomes of subsocial and social C. calcarata to identify mutations and genes associated with social behaviour and used these data to test several hypotheses related to the evolution of eusociality. Many single nucleotide polymorphisms that had high levels of genetic differentiation (Fst) between social and subsocial C. calcarata were in or near genes or regions important for regulating gene expression. These results are consistent with the Genetic Toolkit Hypothesis of eusocial evolution. Our findings suggest that the low behavioural complexity observed in C. calcarata may involve modulation of existing regulatory genes and gene networks to generate phenotypes associated with social behaviour.

Animals

Social evolution and diminished olfactory function in larval honey bees.

Social evolution made larval honey bees dependent on adult colony members for feeding; they are confined to cells in waxen honeycombs and visited about 100 times per day by adult "nurse" bees. Based on organismal resource conservation theory, we predicted larvae have diminished olfactory capabilities at both the molecular and behavioral levels. Consistent with theory, larvae expressed very low levels of Orco, an essential gene for olfactory receptor (OR) function. By contrast, they showed higher expression of Ir25a, essential for other forms of sensory perception including gustation. Also consistent with theory, behavioral assays demonstrated that larvae cannot find food via olfaction, suggesting they use taste for feeding. By contrast, it is known that adult honey bees use OR-based olfaction extensively for a variety of behavioral functions, and the honey bee genome contains many OR-encoding genes. Comparative transcriptomic analyses of social and nonsocial insects suggest that this developmentally regulated suppression of olfactory function is related to social evolution, especially systems of offspring care.

Animals

Multi-trait GWAS identifies pleiotropic loci shared between early pregnancy bleeding and psychiatric traits.

INTRODUCTION: Early pregnancy bleeding is a common pregnancy complication, yet its genetic basis and potential links with psychiatric traits remain poorly understood. This study aimed to characterize the shared genetic architecture between early pregnancy bleeding and reproductive, psychiatric, and cardiometabolic traits. METHODS: We integrated linkage disequilibrium score regression (LDSC), local genetic correlation analysis (LAVA), and multi-trait genome-wide association analysis (MTAG). LDSC was used to estimate genome-wide genetic correlations, including sex-stratified analyses. LAVA was applied to identify genomic regions contributing to local genetic sharing. Guided by these correlation patterns, MTAG was performed to improve locus discovery, followed by cis-eQTL analysis using GTEx v8 to explore potential regulatory mechanisms. RESULTS: LDSC revealed significant positive genetic correlations between early pregnancy bleeding and reproductive traits, including endometriosis, miscarriage, and uterine fibroids. Strong positive correlations were also observed with several psychiatric disorders, including major depressive disorder, post-traumatic stress disorder, and attention deficit hyperactivity disorder. Sex-stratified analyses suggested stronger genetic correlations with emotional reactivity-related traits in females, whereas social and behavioral traits were more prominent in males. LAVA localized these shared signals to specific genomic regions and identified pleiotropic hotspots at 8q21 near RUNX1T1 and 9p21 near CDKN2A/B. MTAG identified two novel loci, 15q15.1 marked by rs45457497 and 11q13.1 marked by rs2452681. Cis-eQTL analysis showed that the lead variant at 15q15.1 regulates RMDN3 expression across multiple brain regions, while the 11q13.1 locus regulates PACS1, GAL3ST3, and SF3B2 expression in brain tissues and the pituitary. DISCUSSION: These findings position early pregnancy bleeding as a multifactorial trait shaped by shared reproductive, psychiatric, neuroendocrine, and stress-related biology. The implication of RMDN3, which encodes a mitochondrial outer membrane protein involved in ER-mitochondria tethering and calcium homeostasis, suggests a potential molecular link between neuroendocrine stress pathways, psychiatric susceptibility, and reproductive vulnerability.

RMDN3

The mouse gut microbiota responds to predator odor and predicts host behavior.

Chronic stressors can alter the mammalian gut microbiota in ways that mediate host stress responses, but the impacts of acute stressors on these interactions are less well understood. Here, we show that brief exposure of wild-derived mice to predator odor altered gut-microbiota composition, which in turn predicted host behavior. We investigated the individual and combined effects of 15-minute exposures to synthetic fox fecal odor and 30 days of chronic social isolation, an established chronic stressor. Using ethological assays, visceral adipose tissue transcriptomics, and genome-resolved metagenomics, we found that predator-odor exposure significantly affected mouse behavior, gene expression, and gut microbiota. Predator odor-responsive bacteria were associated with the expression of genes involved in anti-microbial defense, and host behavioral responses were predicted by random forest models trained on gut-microbiota profiles. These findings indicate interactions between the gut microbiota and wild-mouse responses to the threat of predation, an ecologically relevant acute stressor.

Journal Article

Genome-wide analysis of screen behaviors among adolescents identifies novel loci and overlap with educational attainment and mental disorders.

Technological devices play a central role in adolescents' life. Despite concerns about negative effects of excessive screen time, there is little knowledge of screen behaviors' genetic architecture. Using self-reports from adolescents in the Norwegian Mother, Father, and Child Cohort Study (n = 18,490), we performed genome-wide association analysis for four screen behaviors: time spent (1) watching television; (2) gaming; (3) sitting/lying down with a screen device; and (4) using social media. The resulting summary statistics were analysed using the conditional false discovery rate (condFDR) approach to increase genetic discovery. We also estimated SNP-heritabilities of the screen behaviors and genetic correlations with eight psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, anorexia nervosa, cannabis use disorder and alcohol use disorder), and educational attainment. Screen behaviors displayed significant SNP-heritabilities (0.048-0.12). We observed significant genetic correlations between screen behaviors and psychiatric disorders (rg range: 0.21-0.42). Educational attainment demonstrated negative genetic correlation with screen behaviors, most strongly with social media use (rg = - 0.69). CondFDR analysis identified three novel loci associated with social media use. Thus, we show that screen behaviors are heritable, polygenic traits that partly share genetic signal with mental disorders and educational attainment.

Humans

Education, socioeconomic status, leisure sedentary behaviors and female infertility: mendelian randomization study.

BACKGROUND: Previous studies have indicated that education, socioeconomic status, and leisure sedentary behavior may be associated with female infertility. However, it remains unclear whether these associations imply causal relationships. METHODS: Genetic variants from genome-wide association studies (GWAS) of education, socioeconomic status, and leisure sedentary behaviors were obtained from the UK Biobank and MRC-IEU database (Medical Research Council Integrative Epidemiology Unit), female infertility data was acquired from the FinnGen Biobank. Univariable and multivariable MR analyses were performed to explore the relationships between these traits and female infertility. RESULTS: The results of the univariate MR analysis indicated that age of full-time education had a protective effect on female infertility (odds ratio [OR] 0.471; 95% confidence interval [CI] 0.24 to 0.93; p = 0.03). Multivariable MR and reverse MR studies support the existence of a relationship between them. However, no causal correlation was found between other traits and female infertility. No significant heterogeneity or horizontal pleiotropy was detected, and the stability of the results was confirmed through sensitivity analysis and the leave-one-out test. CONCLUSIONS: A later age of completion of full-time education may be causally related to a reduced risk of female infertility, but no causality is established between other educational levels factors, socioeconomic status, or sedentary behaviors and infertility risk.

Humans

[Genomic evolution and epidemiological patterns of respiratory syncytial virus and their implications for surveillance and early warning].

Respiratory syncytial virus (RSV) is an important respiratory pathogen in infants, young children and older adults. Based on global RSV genomic surveillance data, this review systematically summarizes the geographic distribution, seasonal epidemic patterns, and long-term evolutionary trends of RSV, with particular emphasis on the sustained circulation and evolutionary mechanisms of dominant genotypes such as ON1 in RSV-A and BA9 in RSV-B. Current evidence indicates that RSV transmission dynamics are tightly coupled with viral evolution. The G gene evolves relatively rapidly and contains multiple positively selected sites, suggesting an important role in immune escape and population adaptation. In recent years, changes in social behavior patterns and population immunity have further disrupted the seasonal rhythm of RSV and may have influenced the spread of dominant genotypes. Under routine respiratory infectious disease surveillance, strengthened genomic monitoring and integration of multi-source data are needed to improve early warning of abnormal RSV epidemics and variant-associated risks, thereby providing prospective evidence for protecting high-risk populations and informing public health decision-making.

Humans

Sociality and kinship constrain the free-mixing of pathogens in a wild mammal host population.

Pathogens rarely mix freely throughout host populations, and the presence of barriers to transmission can be detected as patterns of increased genetic isolation among pathogen isolates. Despite the importance of transmission patterns in host societies, and the risk of epizootics from wildlife disease systems, barriers to open pathogen transmission are poorly understood in wild hosts. We tested the influence of host kinship and social structure on genetic divergence among strains of Mycobacterium bovis, the causative agent of bovine tuberculosis (bTB), in a wild badger population. We measured genetic distances between M. bovis isolates from badger hosts that varied in their own genetic similarity (a proxy for kinship) and in their social group affiliations. Using jack-knifing analyses to control for pseudoreplication, we found that genetic distances between pathogen isolates decreased with increasing kinship of host dyads, but only when hosts shared the same social group. Our findings suggest that the open transmission of bTB in wild hosts is constrained by a combination of social and kin structure, in particular the sharing of similar pathogen strains among kin within social groups. We discuss the implications of these transmission structures for the understanding and management of wildlife diseases.

Animals

Synaptic Proteome Divergence in the Prefrontal Cortex of Tame and Aggressive Red Foxes (Vulpes vulpes).

The biological mechanisms behind aggressive and affiliative behaviors are difficult to pinpoint. In the Farm-Fox Experiment, conventional foxes were selectively bred since 1959 in two different directions, one for tame and another for aggressive response to humans. The distinct differences in social behavior of tame, aggressive, and conventional populations are genetically based and the three populations live in conditions that control for factors that could impact social reactions, such as environment and social experiences. Genomic and transcriptomic studies of genetic differences among the fox populations have highlighted genes involved in synaptic processes in the prefrontal cortex. To investigate how the synaptic mechanisms differ between the three fox populations, synaptosomes were isolated from prefrontal and premotor cortex extracts of sixteen female foxes. Tandem mass tags with liquid chromatography tandem mass spectrometry (LC-MS) were used to identify and quantify the relative abundance of the proteins. The results were sorted into protein groups and compared between populations using a limma analysis to determine proteins with differential expression (DE). In the tame versus aggressive comparison, 174 protein groups were found to be DE, while only five were found in the conventional versus aggressive comparison. Most DE protein groups had lower fold expression in the aggressive population compared to tame and aggressive populations. ADGRB2 was found to be the most DE protein group, with 11-fold higher expression in aggressive foxes than in tame foxes. ADGRB2 was previously shown to affect depression-like behavior in mice and is involved in the vascular endothelial growth factor signaling pathway, that is known to influence neurogenesis. Enrichment analyses on the DE protein groups found gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that were enriched in the tame versus aggressive comparison, including multiple, highly enriched terms involving ribosome and translation. Local translation at synapses plays an important role in synaptic plasticity and, as a result, can profoundly influence behavior. This study highlighted potential mechanisms that could underly the behavioral differences between tame and aggressive foxes.

Journal Article

Excitation/inhibition balance subtypes in autism and their genetic, neural, and clinical profiles.

Excitation (E)/inhibition (I) imbalance is considered a key mechanism in Autism Spectrum Disorder (ASD). However, E/I imbalance can have different etiologies with increased E relative to I (E&#x2009;>&#x2009;I) and increased I relative to E (E&#x2009;<&#x2009;I). Both neural profiles can be associated with altered clinical phenotype, suggesting "bell"-shape brain-behavior relationships. We derived E/I balance measures from resting-state EEG in a large sex-balanced sample of youths with and without autism (N&#x2009;=&#x2009;310; 164 youths with ASD and 146 typically developing (TD) youths) to address group discriminative power of neural markers, their relation to social skills, and the potential to define different neural subtypes within the autistic group. We also conducted genome-wide copy number variant (CNV) and gene expression analyses to provide additional insight into distinct neural subtypes in autism. A high-density 128-channel electroencephalography (EEG) was used to register neural activity of participants, blood samples were collected from the ASD youths to obtain genomic DNA, and rich behavioral phenotyping was provided for each participant. The results revealed three subgroups within the autistic cohort with the presence of "typical" E/I, E&#x2009;>&#x2009;I, and E&#x2009;<&#x2009;I neural profiles. The two subgroups with E/I imbalance had altered clinical phenotypes. In addition, these subgroups had different genetic profiles, showing that genes within identified CNVs had distinct expression patterns with the evidence of more prenatal (E&#x2009;<&#x2009;I) vs. postnatal (E&#x2009;>&#x2009;I) gene expression. The study suggests that the proposed clustering approach has relevance for the identification of clinically meaningful neural and genetic subtypes within a heterogeneous autistic cohort.

Autism spectrum disorder

Personality Genomics.

Recent research advances have precipitated the era of personality genomics: the study of how variation in human DNA sequence predicts individual differences in characteristic patterns of thinking, feeling, and behaving. Here, we introduce personality and genomics, and we review key findings from recent genome-wide association studies of personality traits. These findings support five key observations: (a) sizable genetic effects on personality arise from a vast number of genetic variants with individually miniscule effects; (b) genetic variants associated with personality have widespread associations with other attributes, including social, economic, and medical outcomes; (c) genetic effects on personality generalize across groupings of people; (d) genetic effects on personality are minimally confounded by familial environmental effects; and (e) many recent genomic findings were anticipated by classic twin genetic research. For personality psychologists, embracing genomics provides unique and powerful inferential tools. For genomics researchers, incorporating unifying personality frameworks enables an integrative understanding of core behavioral dimensions.

Humans

Interaction of host gene-gut microbiota in male grading of Macrobrachium rosenbergii.

UNLABELLED: The giant freshwater prawn (GFP; Macrobrachium rosenbergii), a crustacean of high nutritional and economic value, is crucial for aquaculture. During the same growth cycle, male GFPs develop into three distinct forms: small males, orange claw males, and blue claw males. These morphotypes display varying social behaviors, which severely constrain their industrial development. To address this, this study collected male GFP samples at critical developmental time points (100, 110, and 120 days post-hatching) for phenotypic trait measurement and analysis to obtain external morphological data. Through gut microbiota diversity analysis, we identified key gut bacteria (Lactococcus garvieae and Lactobacillus taiwanensis) influencing male morphotype differentiation. Transcriptomic analysis revealed host Kyoto Encyclopedia of Gene and Genome pathways and key genes (Wnt-6, CTSB, CTSL, PPAE, and TP53) associated with morphotype differentiation. The interactions among phenotypic traits, gut microbiota, and key genes were systematically studied through association analysis. Weighted gene co-expression network analysis was employed to construct co-expression modules, from which critical gene modules influencing phenotypic variation were identified. Through association network analysis, we established an "Achromobacter-CD-TRINITY_DN93139_c0_g2 (calpain clp-1)" interaction model. Our findings provide novel insights into the genetic enhancement of GFPs and offer guidelines for future research regarding gut symbiotic bacteria and breeding initiatives. IMPORTANCE: Male Macrobrachium rosenbergii (giant freshwater prawn [GFP]) in the same growth cycle will develop into small males, orange claw males, and blue claw males. This individual heterogeneity in growth significantly impacts the benefits of aquaculture. However, the factors influencing the differentiation of male GFP morphotype remain unclear. This study analyzed the phenotypic data of various GFP levels, the structure of the intestinal microbiota, and the differential genes within the gonadal transcriptome at critical time points of male GFP-level type differentiation. The aim was to explore the potential role of intestinal microbiota and differential genes in this phenomenon. This study offers new insights into the research on the phenomenon of male GFP-level type differentiation.

Animals

Simulation of CRISPR/Cas9-mediated gene editing for the&#xa0;Vitellogenin gene in Apis mellifera.

CRISPR/Cas9 genome editing provides a powerful framework for interrogating gene function in Apis mellifera. Yet, empirical application remains challenging due to biological constraints, including haplodiploid genetics, narrow embryonic injection window, and the social rearing requirements that complicate functional validation. These constraints necessitate in silico pre-screening to maximize editing success before resource-intensive wet-lab implementation. Within the omnigenic framework, which distinguishes core regulatory genes from peripheral loci buffered by network effects, vitellogenin (Vg) represents an optimal target which is ancestrally dedicated to yolk provisioning; it has been co-opted to orchestrate diverse non-reproductive functions including longevity, stress resistance, immunity, and social behavior. We developed a computational pipeline to design a list of 57 and 56 candidate guide RNAs&#xa0;(gRNA) for targeted Vg knockout, evaluating candidate sites in both functional exons 2 and 3 based on structural accessibility and frameshift efficiency. Comparative analysis revealed complementary strengths in two top-best candidates from initial target pool of predicted gRNAs. The gRNA targeting exon 2 exhibits weaker secondary structure (&#x394;G&#x2009;=&#x2009;-0.25&#x202f;kcal/mol versus -2.10&#x202f;kcal/mol for exon 3), aligning with empirical evidence that sites with &#x394;G&#x2009;>&#x2009;-1.0&#x202f;kcal/mol achieve 2-5&#x2009;&#xd7;&#x2009;higher Cas9 binding efficiency. This site yielded moderate frameshift frequency (77.8%; 61.9 percentile). Conversely, the predicted editing outcome for the gRNA targeting exon 3, despite stronger structural constraints, demonstrated superior functional disruption metrics demonstrating very high frameshift frequency (88.3%; 95.2 percentile), high in silico editing precision, minimal microhomology-mediated repair bias, and reproducible outcomes wherein nearly all predicted indels disrupt the coding sequence. Protein structure and domain analyses further predict that frameshift edits will generate a truncated protein missing all downstream functional domains. We recommend parallel empirical validation of both exon 2 and exon 3 targets to resolve the trade-off between structural accessibility (favoring higher editing rates) and frameshift efficacy (favoring complete loss-of-function). This dual-target strategy accommodates uncertainty in in vivo performance while maximizing the probability of generating informative phenotypes. Our in silico framework enables rational CRISPR design in non-model organisms by computationally balancing biophysical accessibility with functional impact, accelerating functional genomics in species where empirical optimization faces substantial biological constraints.

Animals

The Role of Emergence in Genetically Informed Relationships Research: A Methodological Analysis.

This paper provides a critical analysis of genetically informed research on relationships, with an emphasis on relationships among unrelated individuals (e.g., spouses). To date, research in this area has used traditional behavioral genetic frameworks to either partition the variance in relationship-related outcomes into genetic and environmental components, or to examine gene-environment interplay between relationship factors and other outcomes. However, this conventional approach is at odds with the long-standing understanding from the field of relationship science that both partners' characteristics matter when predicting shared outcomes-that is, outcomes that are emergent. We examine briefly the philosophical concept of emergence, and discuss ways to model dyadic outcomes in genetically informed relationships research. We also review the related topic of social genetic effects, which refer to the influence of a social partner's genotype on a proband's phenotype. A genetically informed dyadic perspective has potentially important consequences for our understanding of the pathways from genotype&#x2192;shared or individual-level phenotypes, and more fully recognizes the complexity of how genetic and social/environmental factors come together to influence human behavior.

Genetics, Behavioral

Predicting the First Onset of Suicidal Thoughts and Behaviors in Adolescents Using Multimodal Risk Factors: A 4-Year Longitudinal Study.

OBJECTIVE: Suicide is one of the leading causes of death among youth worldwide, yet existing studies that aimed to predict the first onset of suicidal thoughts and behaviors (STB) included a limited number of data modalities and/or focused on adult populations. This study aimed to prospectively predict first-onset STB across 4-year follow-ups in adolescents using an existing STB history classification model that was previously applied to baseline data and a new machine learning model with 195 biopsychosocial features. METHOD: Participants were 7,503 unrelated adolescents (54.5% female, ages 9-11 years at baseline) from the multisite, longitudinal Adolescent Brain Cognitive Development (ABCD) Study. An existing baseline STB history classification model was applied to predict longitudinal first-onset STB in adolescents compared with healthy controls and clinical controls (individuals with a mental health disorder but no STB). A new elastic net logistic regression model with 195 features was trained on data from 14 sites (n = 5,220), and the resulting top 15 features were validated at 7 independent sites (n = 2,283). RESULTS: The previously developed model to classify STB lifetime history also prospectively predicted first-onset STB in adolescents with an area under the curve (AUC) [95% CI] of 0.73 [0.70, 0.75], p < .001, compared with healthy controls and AUC [95% CI] of 0.63 [0.60, 0.66], p < .001, compared with clinical controls. The newly trained model with top 15 features performed similarly with AUC [95% CI] of 0.73 [0.71, 0.76], p < .001, and AUC [95% CI] of 0.64 [0.60, 0.66], p < .001, for the same comparison groups. The most consistent predictors across models included female sex, sleep disturbances, and maladaptive home and school environments. CONCLUSION: The models predicted first-onset STB in adolescents with moderate accuracy. This study also confirmed the roles of well-established psychological risk factors for STB and identified several novel neurocognitive and brain imaging risk factors. Future studies should validate these models in large-scale diverse samples before clinical translation. PLAIN LANGUAGE SUMMARY: This study followed over 7,500 adolescents for 4 years and tested 2 machine learning models using psychological, social, and brain data to identify those at risk of experiencing suicidal thoughts or behaviors. Both models predicted first-time suicidal thoughts or behaviors with moderate accuracy. Key risk factors that were identified included being female, experiencing sleep problems, and negative home and school environments. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. Diverse cell lines and/or genomic datasets were not available. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Adolescent

Rare variation in noncoding regions with evolutionary signatures contributes to autism spectrum disorder risk.

Little is known about the role of noncoding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of noncoding regions: Human Accelerated Regions (HARs), which show signatures of positive selection in humans; experimentally validated neural Vista Enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole genome analysis of >16,600 samples and >4900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in a VE near SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved noncoding regions in ASD risk and suggest potential mechanisms of how changes in regulatory regions can modulate social behavior.

Human Accelerated Regions