Tissue specific transcriptional profiling of the consequences of 16p11.2 deletion and duplication in Mouse

16p11.2 microdeletion/microduplication syndrome is one of the common genetic causes of autism spectrum disorder, although it is not wholly penetrant with a wide range of phenotypic manifestations. We have previously explored the transcriptional consequences of the copy number variant (CNV) in cortical tissue of mouse models of the CNV within the syntenic 7qF3 region (Blumenthal et al 2014). We found that the strongest effects were from genes within the region itself, with no evidence for dosage compensation for any gene. Importantly, we found that global transcriptional effects due to the CNV were associated with multiple hypotheses for ASD pathogenesis, at the level of individual genes, networks and functional enrichments. To delineate tissue-specificity effects of the CNV, we embarked on exploration of the transcriptional landscape across multiple tissues for all mice from our earlier study. Specifically to disentangle brain-specific effects from others, we chose two additional brain tissues, namely Cerebellum and Striatum, as well as three other non-neuronal tissues, namely Liver, White Fat and Brown Fat. We present strand-specific RNAseq data for these five tissues in addition to the data for the Cortical tissue from our previous publication. Preliminary analyses of the data suggest that there are strong tissue-specific consequences of the CNV, with the effect being strongest in the Cortical tissue relative to other tissues, and observe low overlaps in differentially expressed genes across tissue. Furthermore, we see that the genes within the CNV region behave in a strong-tissue specific manner, with differences being more pronounced among the neuronal and non-neuronal tissues, relative to within tissue classes. Interestingly, we see that in non-neuronal tissues dosage compensation occurs for a handful of genes, when expressed. Finally, we see that genes within the CNV region show the strongest effects relative to the overall transcriptome in neuronal tissues and these effects are ameliorated in non-neuronal tissues. Transcriptomic profiles for mRNa were generated for 16 mice across 3 genotypes for 6 tissues, 3 from brain (Cortex, Cerebellum and Striatum) and 3 non-brain tissues (Liver, White Fat and Brown Fat) using paired-end illumina sequencing16p11.2微缺失/微重复综合征是自闭症谱系障碍（Autism Spectrum Disorder, ASD）常见的遗传病因之一，但其外显率并不完全，且表型谱范围宽泛。我们此前已针对位于同源7qF3区域的拷贝数变异（Copy Number Variant, CNV），在该CNV小鼠模型的皮层组织中探究了其转录组学效应（Blumenthal等，2014）。研究发现，效应最强的为该区域内的基因，未检测到任何基因存在剂量补偿现象。值得注意的是，该CNV引发的全局转录组效应，在单个基因、调控网络及功能富集层面，均与ASD发病机制的多种假说存在关联。 为阐明该CNV的组织特异性效应，我们对此前研究中所有小鼠的多组织转录组景观展开了探究。为区分脑特异性效应与其他组织的效应，我们额外选取了两种脑组织——小脑与纹状体，以及三种非神经元组织——肝脏、白色脂肪与棕色脂肪。除此前已发表的皮层组织测序数据外，本研究还提供了上述五种组织的链特异性RNA测序数据。 对该数据的初步分析显示，该CNV存在显著的组织特异性效应：相较于其他组织，其在皮层组织中的效应最为强烈，且不同组织间的差异表达基因重叠度较低。进一步分析发现，CNV区域内的基因呈现出强烈的组织特异性表达模式，相较于同一组织类群内部，神经元与非神经元组织间的差异更为显著。有趣的是，我们观察到在非神经元组织中，少数基因在表达时存在剂量补偿现象。最后，我们发现CNV区域内的基因在神经元组织中相较于整体转录组表现出最强的效应，而该效应在非神经元组织中有所减弱。 本研究针对16只小鼠的3种基因型，在6种组织（3种脑组织：皮层、小脑、纹状体；3种非脑组织：肝脏、白色脂肪、棕色脂肪）中生成了信使RNA（mRNA）的转录组学图谱，测序方式采用双端Illumina测序。