Apparent bias towards long gene misregulation in MeCP2 syndromes disappears after controlling for baseline variations

Ayush T Raman, Amy E Pohodich, Ying-Wooi Wan, Hari Krishna Yalamanchili, Bill Lowry, Huda Y Zoghbi, Zhandong Liu

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Received: 8th February 18

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.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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