Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism

By Neelroop Parikshak, V. Swarup, T. G. Belgard, Manuel Irimia, Gokul Ramaswami, Michael Jeffrey Gandal, C. Hartl, Virpi Leppa, L. La, Torre Ubieta and 5 more. Nature, 2016

654 citations recorded by the source corpus.

Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis reveals ASD-associated dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuron-specific exons, and attenuation of normal differences in gene expression between the frontal and temporal lobes. Our data suggest that SOX5, a transcription factor involved in neuron fate specification, contributes to this reduction in regional differences. We further demonstrate that a genetically defined subtype of ASD, chromosome 15q11.2-13.1 duplication syndrome (dup15q), shares the core transcriptomic signature observed in idiopathic ASD. Co-expression network analysis reveals that individuals with ASD show age-related changes in the trajectory of microglial and synaptic function over the first two decades, and suggests that genetic risk for ASD may influence changes in regional cortical gene expression. Our findings illustrate how diverse genetic perturbations can lead to phenotypic convergence at multiple biological levels in a complex neuropsychiatric disorder.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/16b7fc7c9c26dd8a077bd54c3c7ae75b50e9dc8d

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In Molecular Biology

Citations in the corpus

Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. (2019, positive): “We used the biweight midcorrelation to assess correlations between log2[adjusted FPKM] and parameters for network analysis are previously described (Parikshak et al., 2016).”
Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018, neutral): “this signal from astrocyte and microglial populations (13, 19).”
Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice (2019, methodology): “…brains exhibited differential patterns of alternative splicing (AS), a feature found in human ASD brains (Gandal et al., 2018; Irimia et al., 2014; Parikshak et al., 2016; Parras et al., 2018). rMATS analysis (Shen et al., 2014) identiﬁed 560 genes that showed different AS events between oASD and…”