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Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster

Nature Genetics volume 43, pages 1179–1185 (2011)Cite this article

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Abstract

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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Figure 1: Distributions of gene expression are similar between the X chromosome and autosomes in human, except for reproduction-related X-linked genes not expressed in somatic tissues.
Figure 2: Distributions of gene expression are similar between the X chromosome and autosomes in mouse tissues.
Figure 3: Expressed X-linked genes are enriched in RNA PolII-S5p.
Figure 4: X:A expression ratios in adult C. elegans result from the presence of germ cells in which the X chromosomes are silenced.
Figure 5: X chromosome dosage compensation in early mitotic cells in the Drosophila germline.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA

    Xinxian Deng, Di Kim Nguyen & Christine M Disteche

  2. Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA

    Joseph B Hiatt, Jay Shendure & Robert H Waterston

  3. Department of Biology and Center for Genomics and Systems Biology, New York University, New York, New York, USA

    Sevinc Ercan

  4. Section of Developmental Genomics, Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    David Sturgill & Brian Oliver

  5. Genome Sequencing Center, Washington University School of Medicine, Saint Louis, Missouri, USA

    LaDeana W Hillier

  6. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA

    Felix Schlesinger, Carrie A Davis & Thomas R Gingeras

  7. Department of Genetics, Yale University, New Haven, Connecticut, USA

    Valerie J Reinke

  8. Department of Biology, Carolina Center for the Genome Sciences and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Jason D Lieb

  9. Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA

    Christine M Disteche

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Contributions

X.D., C.M.D., J.D.L. and B.O. conceived the project and wrote the manuscript. X.D., J.B.H., D.K.N., F.S., C.A.D., T.R.G., J.S., C.M.D. and B.O. analyzed the mammalian data; R.H.W., L.W.H., J.D.L., V.J.R. and S.E. analyzed the C. elegans data; B.O. and D.S. analyzed the Drosophila data; X.D., J.B.H. and J.S. performed or analyzed the RNA-seq and ChIP-seq data from mouse ES cells.

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Correspondence to Brian Oliver, Jason D Lieb or Christine M Disteche.

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Supplementary information

Supplementary Text and Figures

Supplementary Figs 1–5 and Supplementary Table 1 (PDF 6343 kb)

Supplementary Table 2

Comparisons of X-linked and autosomal gene expression by RNA-seq in human and mouse (XLS 33 kb)

Supplementary Table 3

Expression of testis-expressed X-linked genes is low in human somatic tissues. (XLS 33 kb)

Supplementary Table 4

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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