Bias toward long gene misregulation in synaptic disorders can be an artefact of amplification-based methods

Several recent studies have suggested that genes that are longer than 100 kilobases are more likely to be misregulated in neurological diseases associated with synaptic dysfunction, such as autism and Rett syndrome. These length-dependent transcriptional changes are modest in Mecp2-mutant samples, b...

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Bibliographic Details
Published inbioRxiv
Main Authors Raman, Ayush T, Pohodich, Amy E, Ying-Wooi Wan, Yalamanchili, Hari Krishna, Lowry, Bill, Zoghbi, Huda Y, Liu, Zhandong
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 05.01.2018
Subjects
Autism
Bias
DNA microarrays
Gene expression
Genes
MeCP2 protein
Methyl-CpG binding protein
Neurological diseases
Rett syndrome
Ribonucleic acid
RNA
Transcription
Trends
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Summary:Several recent studies have suggested that genes that are longer than 100 kilobases are more likely to be misregulated in neurological diseases associated with synaptic dysfunction, such as autism and Rett syndrome. These length-dependent transcriptional changes are modest in Mecp2-mutant samples, but, given the low sensitivity of high-throughput transcriptome profiling technology, the statistical significance of these results needs to be re-evaluated. Here, we show that the apparent length dependent trends previously observed in MeCP2 microarray and RNA-Sequencing datasets, particularly in genes with low fold-changes, disappeared after accounting for baseline variability estimated from randomized control samples. As we found no similar bias with NanoString technology, this long-gene bias seems to be particular to PCR amplification-based platforms. In contrast, authentic long gene effects, such as those caused by topoisomerase inhibition, can be detected even after adjustment for baseline variability. Accurate detection of length-dependent trends requires establishing a baseline from randomized control samples.
DOI:10.1101/240705