Elevated L1 expression in ataxia telangiectasia likely explained by an RNA-seq batch effect

Abstract

A recent study (Takahashi et al., Neuron, 2022) concluded LINE-1 (L1) retrotransposon activation drives cerebellar ataxia and neurodegeneration. This position was based on L1 upregulation in ataxia telangiectasia (AT) patient cerebellum samples, as measured by RNA-seq, and observation of ataxia and neurodegeneration in mice where cerebellar L1 expression was induced via dCas9-CRISPR. Here, a re-analysis of the RNA-seq data, which were obtained by rRNA depletion rather than polyA+ selection, revealed a high fraction (38.4%) of intronic reads. Significantly (p=0.034) more intronic reads were present in the AT data than the matched controls. This finding provides an alternative and robust explanation for a key result reported by Takahashi et al.: intronic L1 sequences are abundant in pre-mRNAs, and more pre-mRNAs were retained in the AT libraries. This apparent batch effect deserves further examination, as claims of L1-mediated pathogenesis could shape future efforts to treat AT by trying to attenuate L1 activity.