Many animal species use a chromosome-based mechanism of sex determination, which has led to the coordinate evolution of dosage-compensation systems. Dosage compensation not only corrects the imbalance in the number of X chromosomes between the sexes but also is hypothesized to correct dosage imbalance within cells that is due to monoallelic X-linked expression and biallelic autosomal expression, by upregulating X-linked genes twofold (termed 'Ohno's hypothesis'). Although this hypothesis is well supported by expression analyses of individual X-linked genes and by microarray-based transcriptome analyses, it was challenged by a recent study using RNA sequencing and proteomics. We obtained new, independent RNA-seq data, measured RNA polymerase distribution and reanalyzed published expression data in mammals, C. elegans and Drosophila. Our analyses, which take into account the skewed gene content of the X chromosome, support the hypothesis of upregulation of expressed X-linked genes to balance expression of the genome.
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We thank A. Nelson and C. Ware (University of Washington) for expert assistance with ES cell culture and N. Brockdorff (Oxford University) for the female ES cell line PGK12.1. We thank R. Beyer (University of Washington) and X. Deng (University of Wisconsin–Madison) for help with statistical analyses and F. Yang (University of Washington) for helpful discussions. We thank I. Khrebtukova (Illumina) for RNA-seq data on human tissues. This work was supported by grants from the US National Institutes of Health GM079537 (C.M.D.), modENCODE grants HG004270 (J.D.L.), HG004263 (R.H.W.) and AG039173 (J.B.H.), ENCODE Transcriptome Project grant HG004557 (T.R.G.) and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (B.O.), the William H. Gates III Endowed Chair of Biomedical Sciences (R.H.W.) and a fellowship from the Achievement Rewards for College Scientists (J.B.H.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
The authors declare no competing financial interests.
Supplementary Figs 1–5 and Supplementary Table 1 (PDF 6343 kb)
Comparisons of X-linked and autosomal gene expression by RNA-seq in human and mouse (XLS 33 kb)
Expression of testis-expressed X-linked genes is low in human somatic tissues. (XLS 33 kb)
Expression of reproduction-related X-linked genes in mouse somatic tissues. (XLS 34 kb)
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Deng, X., Hiatt, J., Nguyen, D. et al. Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nat Genet 43, 1179–1185 (2011). https://doi.org/10.1038/ng.948
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