Synergistic interactions between Drosophila orthologues of genes spanned by de novo human CNVs support multiple-hit models of autism.
Synergistic interactions between Drosophila orthologues of genes spanned by de novo human CNVs support multiple-hit models of autism.
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DOI：
10.1371/journal.pgen.1004998
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发表时间：
2015-03
期刊：
影响因子：
4.5
通讯作者：
Webber C
中科院分区：
文献类型：
--
作者：
Grice SJ;Liu JL;Webber C
自闭症谱系障碍（ASD）具有高度遗传性，其特征是社交和沟通方面的缺陷，以及限制和重复行为。虽然已经确定了一些高度外显的ASD基因变异，但越来越多的证据支持多个基因座的贡献所产生的组合效应的因果作用。通过检查突触和昼夜神经表型的剂量变异的独特的人类：果蝇的直系同源物，我们观察到许多协同作用的候选基因对信息识别的直系同源物的共同影响的大从头拷贝数变异（CNVs）之间的相互作用。这些CNV是在自闭症患者的基因组中发现的，包括一名携带22q11.2缺失的患者。我们首先证明，剂量改变的独特果蝇直系同源候选基因从头CNVs，海港只有一个单一的候选基因显示神经系统的缺陷，类似于以前报道的ASD相关变异的果蝇模型。然后，我们考虑了受同一个人从头CNV影响的候选基因直系同源物组内的成对剂量变化。对于四个CNV中的三个具有完全的正向关系，我们观察到从单个CNV提取的基因对的同时剂量变化后的显著协同效应。从这些相互作用的遗传变异的结果在果蝇突触观察到的表型变异支持一个一致的表型结果在所有相互作用的基因对以下的方向人类基因拷贝数的变化。我们观察到特异性和传递性之间的相互作用，无论是在CNV候选基因集内和之间，支持共享和不同的遗传病因。然后，我们表明，不同的相互作用影响不同的突触过程，表现出不同的分子病因。我们的研究阐明了由大的结构变异引起的协同效应可能导致人类疾病的机制。自闭症谱系障碍（ASD）的特征是社会互动不良和重复行为，部分原因是遗传变异。已经鉴定出ASD患者中拷贝数不同的许多基因，其中许多已知在神经元突触处起作用。我们的理论是，在某些情况下，多个基因的剂量同时变化，而不是单独变化，可能导致神经元发育不良，并导致ASD。为了验证这一点，我们询问这些候选基因的改变是否会导致果蝇神经元突触和睡眠/休息的变化，并使用单基因模型验证了这个模型。我们考虑了同时变化的基因对，共同受到一个大的人类拷贝数变异（CNVs），这是基因组中的结构变化。在四个CNV中的三个中，基因子集中的突变协同相互作用，引起与单个候选基因相当的神经元变化。我们还观察到突触大小的变化遵循人类基因拷贝数变化的方向。最后，我们表明，不同的相互作用通过不同的机制影响突触的发育，使我们能够确定不同的分子改变，阐明ASD的病因异质性。
Autism spectrum disorders (ASDs) are highly heritable and characterised by deficits in social interaction and communication, as well as restricted and repetitive behaviours. Although a number of highly penetrant ASD gene variants have been identified, there is growing evidence to support a causal role for combinatorial effects arising from the contributions of multiple loci. By examining synaptic and circadian neurological phenotypes resulting from the dosage variants of unique human:fly orthologues in Drosophila, we observe numerous synergistic interactions between pairs of informatically-identified candidate genes whose orthologues are jointly affected by large de novo copy number variants (CNVs). These CNVs were found in the genomes of individuals with autism, including a patient carrying a 22q11.2 deletion. We first demonstrate that dosage alterations of the unique Drosophila orthologues of candidate genes from de novo CNVs that harbour only a single candidate gene display neurological defects similar to those previously reported in Drosophila models of ASD-associated variants. We then considered pairwise dosage changes within the set of orthologues of candidate genes that were affected by the same single human de novo CNV. For three of four CNVs with complete orthologous relationships, we observed significant synergistic effects following the simultaneous dosage change of gene pairs drawn from a single CNV. The phenotypic variation observed at the Drosophila synapse that results from these interacting genetic variants supports a concordant phenotypic outcome across all interacting gene pairs following the direction of human gene copy number change. We observe both specificity and transitivity between interactors, both within and between CNV candidate gene sets, supporting shared and distinct genetic aetiologies. We then show that different interactions affect divergent synaptic processes, demonstrating distinct molecular aetiologies. Our study illustrates mechanisms through which synergistic effects resulting from large structural variation can contribute to human disease. Autism spectrum disorders (ASDs), which are characterised by poor social interaction and repetitive behaviours, are in part caused by genetic variation. A number of genes that vary in copy number in ASD patients have been identified, many of which were known to function at the neuronal synapse. We theorised that in some cases the dosage change of multiple genes simultaneously, rather than singularly, may lead to faulty neuronal development, and contribute to ASD. To test this, we asked whether alterations in these candidate genes would cause neuronal synapse and sleep/rest changes using the fruit fly Drosophila, and validated this model using single-gene models. We considered the simultaneous change of pairs of genes that were jointly affected by a large human copy number variant (CNVs), which are structural changes in the genome. In three of four CNVs, mutations in subsets of genes synergistically interacted to cause neuronal changes comparable to the single gene candidates. We also observed that the changes in synapse size followed the direction of the human gene copy number change. Finally, we show that different interactions affect the development of the synapse through different mechanisms, allowing us to identify distinct molecular alterations that illuminate the etiological heterogeneity of ASD.
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影响因子：
16.2
作者：
Edbauer, Dieter;Neilson, Joel R.;Foster, Kelly A.;Wang, Chi-Fong;Seeburg, Daniel P.;Batterton, Matthew N.;Tada, Tomoko;Dolan, Bridget M.;Sharp, Phillip A.;Sheng, Morgan
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64.8
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影响因子：
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通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
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影响因子：
64.8
作者：
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