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年终盘点：2019年自闭症十大研究突破
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2019年自闭症十大研究突破
1. Nature—IL-17a可以改善自闭症谱系疾病的社会性行为
英文摘要：
A subsetof children with autism spectrum disorder appear to show an improvement in theirbehavioural symptoms during the course of a fever, a sign of systemicinflammation1,2. Here we elucidate the molecular and neuralmechanisms that underlie the beneficial effects of inflammation on socialbehaviour deficits in mice. We compared an environmental model ofneurodevelopmental disorders in which mice were exposed to maternal immuneactivation (MIA) during embryogenesis3,4 with mouse models that aregenetically deficient for contactin-associated protein-like 2(Cntnap2)5, fragile X mental retardation-1 (Fmr1)6or Sh3 and multiple ankyrin repeat domains 3 (Shank3)7.We establish that the social behaviour deficits in offspring exposed to MIA canbe temporarily rescued by the inflammatory response elicited by theadministration of lipopolysaccharide (LPS). This behavioural rescue wasaccompanied by a reduction in neuronal activity in the primary somatosensorycortex dysgranular zone (S1DZ), the hyperactivity of which was previouslyimplicated in the manifestation of behavioural phenotypes associated withoffspring exposed to MIA8. By contrast, we did not observe anLPS-induced rescue of social deficits in the monogenic models. We demonstratethat the differences in responsiveness to the LPS treatment between the MIA andthe monogenic models emerge from differences in the levels of cytokineproduction. LPS treatment in monogenic mutant mice did not induce amounts ofinterleukin-17a (IL-17a) comparable to those induced in MIA offspring;bypassing this difference by directly delivering IL-17a into S1DZ wassufficient to promote sociability in monogenic mutant mice as well as in MIAoffspring. Conversely, abrogating the expression of IL-17 receptor subunit a(IL-17Ra) in the neurons of the S1DZ eliminated the ability of LPS to reversethe sociability phenotypes in MIA offspring. Our data support a neuroimmunemechanism that underlies neurodevelopmental disorders in which the productionof IL-17a during inflammation can ameliorate the expression of social behaviourdeficits by directly affecting neuronal activity in the central nervous system.
参考文献：
Reedet al (2020). IL-17a promotes sociability in mouse models of neurodevelopmentaldisorders. Nature. 2020 Jan;577(7789):249-253.
2. Cell—靶向于外周体表感觉神经元可改善自闭症模型中触觉相关的表型
英文摘要：
Somatosensoryover-reactivity is common among patients with autismspectrum disorders (ASDs) and is hypothesized to contribute to core ASDbehaviors. However, effective treatments for sensory over-reactivity andASDs are lacking. We found distinct somatosensory neuronpathophysiological mechanisms underlie tactile abnormalities in different ASDmouse models and contribute to some ASD-related behaviors. Developmental lossof ASD-associated genes Shank3 or Mecp2 in peripheral mechanosensory neuronsleads to region-specific brain abnormalities, revealing links betweendevelopmental somatosensory over-reactivity and the genesis of aberrantbehaviors. Moreover, acute treatment with a peripherally restricted GABAAreceptor agonist that acts directly on mechanosensory neurons reduced tactileover-reactivity in six distinct ASD models. Chronic treatment of Mecp2 andShank3 mutant mice improved body condition, some brain abnormalities,anxiety-like behaviors, and some social impairments but not memory impairments,motor deficits, or overgrooming. Our findings reveal a potential therapeuticstrategy targeting peripheral mechanosensory neurons to treat tactileover-reactivity and select ASD-related behaviors.
参考文献：
Oreficeet al (2019). Targeting Peripheral Somatosensory Neurons to ImproveTactile-Related Phenotypes in ASD Models. Cell. 2019 Aug 8;178(4):867-886.e24.
3．Cell—自闭症中遗传和新发遗传变异影响相似的蛋白相互作用网络
英文摘要：
Weperformed a comprehensive assessment of rare inherited variation in autism spectrum disorder(ASD) by analyzing whole-genome sequences of 2,308 individuals from familieswith multiple affected children. We implicate 69 genes in ASD risk, including24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, mostsupported by rare inherited variants, a substantial extension ofprevious findings. Biological pathways enriched for genes harboringinherited variants represent cytoskeletal organization and ion transport, whichare distinct from pathways implicated in previous studies. Nevertheless, the denovo and inherited genes contribute to a common protein-protein interactionnetwork. We also identified structural variants (SVs) affecting non-codingregions, implicating recurrent deletions in the promoters of DLG2 and NR3C2.Loss of nr3c2 function in zebrafish disrupts sleep and social function,overlapping with human ASD-related phenotypes. These data support the utilityof studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.
参考文献：
Ruzzo et al (2019). Inherited and De Novo Genetic Riskfor Autism Impacts Shared Networks. Cell. 2019 Aug 8;178(4):850-866.e26.
4. Nat Genet—5%的自闭症中存在隐性突变
英文摘要：
Autism spectrum disorder(ASD) affects up to 1 in 59 individuals1. Genome-wide associationand large-scale sequencing studies strongly implicate both common variants2-4and rare de novo variants5-10 in ASD. Recessive mutations have alsobeen implicated11-14 but their contribution remains less welldefined. Here we demonstrate an excess of biallelic loss-of-function anddamaging missense mutations in a large ASD cohort, corresponding toapproximately 5% of total cases, including 10% of females, consistent with afemale protective effect. We document biallelic disruption of known or emergingrecessive neurodevelopmental genes (CA2, DDHD1, NSUN2, PAH, RARB, ROGDI,SLC1A1, USH2A) as well as other genes not previously implicated in ASDincluding FEV (FEV transcription factor, ETS family member), which encodes akey regulator of the serotonergic circuitry. Our data refine estimates of thecontribution of recessive mutation to ASD and suggest new paths forilluminating previously unknown biological pathways responsible for thiscondition.
参考文献：
Doanet al (2019). Recessive gene disruptions in autism spectrum disorder. NatGenet. 2019 Jul;51(7):1092-1098.
5.Nature—全球首个自闭症猴模型表现出类似于患者的异常行为和功能连接
英文摘要：
Mutationor disruption of the SH3 and ankyrin repeat domains 3 (SHANK3) gene representsa highly penetrant, monogenic risk factor for autismspectrum disorder, and is a cause ofPhelan-McDermid syndrome. Recent advances in gene editing have enabled thecreation of genetically engineered non-human-primate models, which might betterapproximate the behavioural and neural phenotypes of autismspectrum disorder than do rodent models, and maylead to more effective treatments. Here we report CRISPR-Cas9-mediatedgeneration of germline-transmissible mutations of SHANK3 in cynomolgus macaques(Macaca fascicularis) and their F1 offspring. Genotyping of somatic cells aswell as brain biopsies confirmed mutations in the SHANK3 gene and reducedlevels of SHANK3 protein in these macaques. Analysis of data from functionalmagnetic resonance imaging revealed altered local and global connectivitypatterns that were indicative of circuit abnormalities. The founder mutantsexhibited sleep disturbances, motor deficits and increased repetitivebehaviours, as well as social and learning impairments. Together, these resultsparallel some aspects of the dysfunctions in the SHANK3 gene and circuits, aswell as the behavioural phenotypes, that characterize autismspectrum disorder and Phelan-McDermid syndrome.
参考文献：
Zhou et al (2019). Atypical behaviour and connectivity inSHANK3-mutant macaques. Nature. 2019 Jun;570(7761):326-331.
6. Cell—自闭症患者的肠道微生物可诱导小鼠出现自闭症样表型，而肠道微生物代谢物可改善自闭症表型
英文摘要：
Autism spectrum disorder(ASD) manifests as alterations in complex human behaviors including socialcommunication and stereotypies. In addition to genetic risks, the gutmicrobiome differs between typically developing (TD) and ASD individuals,though it remains unclear whether the microbiome contributes to symptoms. Wetransplanted gut microbiota from human donors with ASD or TD controls intogerm-free mice and reveal that colonization with ASD microbiota is sufficientto induce hallmark autistic behaviors. The brainsof mice colonized with ASD microbiota display alternative splicing ofASD-relevant genes. Microbiome and metabolome profiles of mice harboring humanmicrobiota predict that specific bacterial taxa and their metabolites modulateASD behaviors. Indeed, treatment of an ASD mouse model with candidate microbialmetabolites improves behavioral abnormalities and modulates neuronalexcitability in the brain. We propose that the gut microbiota regulatesbehaviors in mice via production of neuroactive metabolites, suggesting thatgut-brain connections contribute to the pathophysiology of ASD.
参考文献：
Sharon et al (2019). Human Gut Microbiota from AutismSpectrum Disorder Promote Behavioral Symptoms in Mice. Cell. 2019 May30;177(6):1600-1618.e17.
7. Science—自闭症单细胞基因组学研究揭示细胞特异性的分子异常改变
英文摘要：
Despitethe clinical and genetic heterogeneity of autism,bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways.However, direct assessment of specific cell types in the brain affected by autism has not been feasible until recently. We usedsingle-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associatedtranscriptomic changes in specific cell types. We found that synaptic signalingof upper-layer excitatory neurons and the molecular state of microglia arepreferentially affected in autism. Moreover, ourresults show that dysregulation of specific groups of genes in cortico-corticalprojection neurons correlates with clinical severity of autism.These findings suggest that molecular changes in upper-layer cortical circuitsare linked to behavioral manifestations of autism.
参考文献：
Velmeshev et al (2019). Single-cell genomics identifiescell type-specific molecular changes in autism. Science. 2019 May17;364(6441):685-689.
8. Nat Genet—自闭症谱系疾病存在共有的遗传变异
英文摘要：
Autism spectrum disorder(ASD) is a highly heritable and heterogeneous group of neurodevelopmentalphenotypes diagnosed in more than 1% of children. Common genetic variantscontribute substantially to ASD susceptibility, but to date no individualvariants have been robustly associated with ASD. With a marked sample-sizeincrease from a unique Danish population resource, we report a genome-wideassociation meta-analysis of 18,381 individuals with ASD and 27,969 controlsthat identified five genome-wide-significant loci. Leveraging GWAS results fromthree phenotypes with significantly overlapping genetic architectures(schizophrenia, major depression, and educational attainment), we identifiedseven additional loci shared with other traits at equally strict significancelevels. Dissecting the polygenic architecture, we found both quantitative andqualitative polygenic heterogeneity across ASD subtypes. These resultshighlight biological insights, particularly relating to neuronal function andcorticogenesis, and establish that GWAS performed at scale will be much moreproductive in the near term in ASD.
参考文献：
Groveet al (2019). Identification of common genetic risk variants for autismspectrum disorder.
NatGenet. 2019 Mar;51(3):431-444.
9. Nat Genet—全基因组深度学习分析揭示了自闭症存在非编码区的遗传变异
英文摘要：
Weaddress the challenge of detecting the contribution of noncoding mutations todisease with a deep-learning-based framework that predicts the specificregulatory effects and the deleterious impact of genetic variants. Applyingthis framework to 1,790 autism spectrum disorder (ASD) simplex families reveals a role indisease for noncoding mutations-ASD probands harbor both transcriptional- andpost-transcriptional-regulation-disrupting de novo mutations of significantlyhigher functional impact than those in unaffected siblings. Further analysissuggests involvement of noncoding mutations in synaptic transmission andneuronal development and, taken together with previous studies, reveals aconvergent genetic landscape of coding and noncoding mutations in ASD. Wedemonstrate that sequences carrying prioritized mutations identified inprobands possess allele-specific regulatory activity, and we highlight a linkbetween noncoding mutations and heterogeneity in the IQ of ASD probands. Ourpredictive genomics framework illuminates the role of noncoding mutations inASD and prioritizes mutations with high impact for further study, and isbroadly applicable to complex human diseases.
参考文献：
Zhou et al (2019). Whole-genome deep-learning analysisidentifies contribution of noncoding mutations to autism risk. Nat Genet. 2019Jun;51(6):973-980.
10. Nat Med—通过计算父亲精子的嵌合变异可预测子女的自闭症风险
英文摘要：
Denovo mutations arising on the paternal chromosome make the largest knowncontribution to autism risk, and correlate withpaternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading manyfamilies to decline future pregnancies, but the potential impact of assessingparental gonadal mosaicism has not been considered. We measured sperm mosaicismusing deep-whole-genome sequencing, for variants both present in an offspringand evident only in father's sperm, and identified single-nucleotide,structural and short tandem-repeat variants. We found that mosaicismquantification can stratify autism spectrum disordersrecurrence risk due to de novo mutations into a vast majority with near 0%recurrence and a small fraction with a substantially higher and quantifiablerisk, and we identify novel mosaic variants at risk for transmission to afuture offspring. This suggests, therefore, that genetic counseling wouldbenefit from the addition of sperm mosaicism assessment.
参考文献：
Breuss et al (2019). Autism risk in offspring can beassessed through quantification of male sperm mosaicism. Nat Med. 2019 Dec 23.
2019年十大研究进展名录
6. 年终盘点：2019年抑郁症领域十大基础研究进展（一半来自中国）
11. 年终盘点：2019年医学和生物学领域深度学习和神经网络十大基础研究进展
15.年终盘点：2019年神经发育及成年神经再生十大研究突破
2018年十大研究进展名录
14. 2018年的十大睡眠研究突破
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