Genome-wide analysis of differential RNA editing in epilepsy

Abstract

The recoding of genetic information through RNA editing contributes to proteomic diversity, but the extent and significance of RNA editing in disease is poorly understood. In particular, few studies have investigated the relationship between RNA editing and disease at a genome-wide level. Here, we developed a framework for the genome-wide detection of RNA sites that are differentially edited in disease. Using RNA-sequencing data from 100 hippocampi from mice with epilepsy (pilocarpine-temporal lobe epilepsy model) and 100 healthy control hippocampi, we identified 256 RNA sites (overlapping with 87 genes) that were significantly differentially edited between epileptic cases and controls. The degree of differential RNA editing in epileptic mice correlated with frequency of seizures, and the set of genes differentially RNA-edited between case and control mice were enriched for functional terms highly relevant to epilepsy, including "neuron projection" and "seizures." Genes with differential RNA editing were preferentially enriched for genes with a genetic association to epilepsy. Indeed, we found that they are significantly enriched for genes that harbor nonsynonymous de novo mutations in patients with epileptic encephalopathy and for common susceptibility variants associated with generalized epilepsy. These analyses reveal a functional convergence between genes that are differentially RNA-edited in acquired symptomatic epilepsy and those that contribute risk for genetic epilepsy. Taken together, our results suggest a potential role for RNA editing in the epileptic hippocampus in the occurrence and severity of epileptic seizures.

The evolution and adaptation of A-to-I RNA editing

“…For example, worms have impaired chemotaxis [ 36 ]; flies experience locomotion defects, age-dependent neurodegeneration, and other neurological phenotypes [ 25 ]; and mice without ADAR2 experience seizures and die shortly after birth [ 37 ]. In humans, several neurological diseases, including ALS [ 38 , 39 ], autism [ 40 ], depression [ 41 ], epilepsy [ 42 , 43 ], and schizophrenia [ 44 ], have also shown to be associated with altered editing levels. Thus, while the same sites are not always edited in different species, editing of recoding sites in all of these species is strongly associated with neurological function.…”

Integrated sequencing of exome and mRNA of large-sized single cells

“…5 ) 28 – 31 . However, the resulted RESs were not always detected in all samples, which might be caused by low genomic coverage overlap among samples due to low specificity of probe capture in exome-seq, or by the intrinsic nature of rare occurrence of RNA editing 48 . Another interesting topic in integrative genomic studies is regulatory variants, the study of which benefits from simultaneous DNA- and RNA-sequencing in a single cell 49 .…”

A-to-I RNA editing contributes to the persistence of predicted damaging mutations in populations

“…Accumulating evidence indicates that RNA editing is crucial in the neuronal dynamic in the mammalian central nervous system (Gal-Mark et al 2017). A handful of editing events have been demonstrated to be highly regulated during brain development or neural differentiation (Barbon et al 2003;Kawahara et al 2004;Wahlstedt et al 2009;Osenberg et al 2010) and involved in neuronal diseases, such as inflammation, epilepsy (Brusa et al 1995;Srivastava et al 2017), depression (Gurevich et al 2002), and amyotrophic lateral sclerosis (ALS) (Hideyama et al 2012). These above-mentioned observations reveal the obscurity of the RNA editing effect on genome evolution.…”