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Open Access Research article

Determination of dosage compensation of the mammalian X chromosome by RNA-seq is dependent on analytical approach

Nathaniel K Jue, Michael B Murphy, Seth D Kasowitz, Sohaib M Qureshi, Craig J Obergfell, Sahar Elsisi, Robert J Foley, Rachel J O’Neill and Michael J O’Neill*

Author Affiliations

Department of Molecular and Cell Biology, University of Connecticut, 354 Mansfield Rd. U-2131, Storrs, CT 06235, USA

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BMC Genomics 2013, 14:150  doi:10.1186/1471-2164-14-150

Published: 6 March 2013

Abstract

Background

An enduring question surrounding sex chromosome evolution is whether effective hemizygosity in the heterogametic sex leads inevitably to dosage compensation of sex-linked genes, and whether this compensation has been observed in a variety of organisms. Incongruence in the conclusions reached in some recent reports has been attributed to different high-throughput approaches to transcriptome analysis. However, recent reports each utilizing RNA-seq to gauge X-linked gene expression relative to autosomal gene expression also arrived at diametrically opposed conclusions regarding X chromosome dosage compensation in mammals.

Results

Here we analyze RNA-seq data from X-monosomic female human and mouse tissues, which are uncomplicated by genes that escape X-inactivation, as well as published RNA-seq data to describe relative X expression (RXE). We find that the determination of RXE is highly dependent upon a variety of computational, statistical and biological assumptions underlying RNA-seq analysis. Parameters implemented in short-read mapping programs, choice of reference genome annotation, expression data distribution, tissue source for RNA and RNA-seq library construction method have profound effects on comparing expression levels across chromosomes.

Conclusions

Our analysis shows that the high number of paralogous gene families on the mammalian X chromosome relative to autosomes contributes to the ambiguity in RXE calculations, RNA-seq analysis that takes into account that single- and multi-copy genes are compensated differently supports the conclusion that, in many somatic tissues, the mammalian X is up-regulated compared to the autosomes.

Keywords:
RNA-seq; X chromosome; Dosage compensation