Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Independent specialization of the human and mouse X chromosomes for the male germ line

Nature Genetics volume 45, pages 1083–1087 (2013)Cite this article

Subjects

Abstract

We compared the human and mouse X chromosomes to systematically test Ohno's law, which states that the gene content of X chromosomes is conserved across placental mammals1. First, we improved the accuracy of the human X-chromosome reference sequence through single-haplotype sequencing of ampliconic regions. The new sequence closed gaps in the reference sequence, corrected previously misassembled regions and identified new palindromic amplicons. Our subsequent analysis led us to conclude that the evolution of human and mouse X chromosomes was bimodal. In accord with Ohno's law, 94–95% of X-linked single-copy genes are shared by humans and mice; most are expressed in both sexes. Notably, most X-ampliconic genes are exceptions to Ohno's law: only 31% of human and 22% of mouse X-ampliconic genes had orthologs in the other species. X-ampliconic genes are expressed predominantly in testicular germ cells, and many were independently acquired since divergence from the common ancestor of humans and mice, specializing portions of their X chromosomes for sperm production.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A dot-plot comparison of the nucleotide sequences of the human and mouse X chromosomes shows large, divergent ampliconic regions on the mouse X chromosome.
Figure 2: Comparison of mosaic and SHIMS-based sequence assemblies across one region of the human X chromosome.
Figure 3: Comparison of X-linked gene classes between humans and mice.

Similar content being viewed by others

Accession codes

Primary accessions

NCBI Reference Sequence

Sequence Read Archive

References

  1. Ohno, S. Sex Chromosomes and Sex-Linked Genes (Springer, Berlin, 1967).

  2. Kuroiwa, A. et al. Conservation of the rat X chromosome gene order in rodent species. Chromosome Res. 9, 61–67 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Delgado, C.L., Waters, P.D., Gilbert, C., Robinson, T.J. & Graves, J.A. Physical mapping of the elephant X chromosome: conservation of gene order over 105 million years. Chromosome Res. 17, 917–926 (2009).

    Article  PubMed  Google Scholar 

  4. Prakash, B., Kuosku, V., Olsaker, I., Gustavsson, I. & Chowdhary, B.P. Comparative FISH mapping of bovine cosmids to reindeer chromosomes demonstrates conservation of the X-chromosome. Chromosome Res. 4, 214–217 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Ross, M.T. et al. The DNA sequence of the human X chromosome. Nature 434, 325–337 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Veyrunes, F. et al. Bird-like sex chromosomes of platypus imply recent origin of mammal sex chromosomes. Genome Res. 18, 965–973 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Watanabe, T.K. et al. A radiation hybrid map of the rat genome containing 5,255 markers. Nat. Genet. 22, 27–36 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Raudsepp, T. et al. Exceptional conservation of horse-human gene order on X chromosome revealed by high-resolution radiation hybrid mapping. Proc. Natl. Acad. Sci. USA 101, 2386–2391 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Band, M.R. et al. An ordered comparative map of the cattle and human genomes. Genome Res. 10, 1359–1368 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Murphy, W.J., Sun, S., Chen, Z.Q., Pecon-Slattery, J. & O'Brien, S.J. Extensive conservation of sex chromosome organization between cat and human revealed by parallel radiation hybrid mapping. Genome Res. 9, 1223–1230 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Spriggs, H.F. et al. Construction and integration of radiation-hybrid and cytogenetic maps of dog chromosome X. Mamm. Genome 14, 214–221 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Palmer, S., Perry, J. & Ashworth, A. A contravention of Ohno's law in mice. Nat. Genet. 10, 472–476 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Rugarli, E.I. et al. Different chromosomal localization of the Clcn4 gene in Mus spretus and C57BL/6J mice. Nat. Genet. 10, 466–471 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. She, X. et al. Shotgun sequence assembly and recent segmental duplications within the human genome. Nature 431, 927–930 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Olivier, M. et al. A high-resolution radiation hybrid map of the human genome draft sequence. Science 291, 1298–1302 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Dietrich, W.F. et al. A comprehensive genetic map of the mouse genome. Nature 380, 149–152 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Church, D.M. et al. Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol. 7, e1000112 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Tishkoff, S.A. & Kidd, K.K. Implications of biogeography of human populations for 'race' and medicine. Nat. Genet. 36, S21–S27 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Bovee, D. et al. Closing gaps in the human genome with fosmid resources generated from multiple individuals. Nat. Genet. 40, 96–101 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Kidd, J.M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Skaletsky, H. et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423, 825–837 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Hughes, J.F. et al. Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content. Nature 463, 536–539 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kuroda-Kawaguchi, T. et al. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat. Genet. 29, 279–286 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Bellott, D.W. et al. Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition. Nature 466, 612–616 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Wade, C.M. et al. Genome sequence, comparative analysis, and population genetics of the domestic horse. Science 326, 865–867 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. International Chicken Genome Sequencing Consortium. Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432, 695–716 (2004).

  28. Wang, E.T. et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470–476 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mortazavi, A., Williams, B.A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods 5, 621–628 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Bradley, R.K., Merkin, J., Lambert, N.J. & Burge, C.B. Alternative splicing of RNA triplets is often regulated and accelerates proteome evolution. PLoS Biol. 10, e1001229 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Handel, M.A. & Eppig, J.J. Sertoli cell differentiation in the testes of mice genetically deficient in germ cells. Biol. Reprod. 20, 1031–1038 (1979).

    Article  CAS  PubMed  Google Scholar 

  32. Mueller, J.L. et al. The mouse X chromosome is enriched for multicopy testis genes showing postmeiotic expression. Nat. Genet. 40, 794–799 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Coyne, J.A. & Orr, H.A. Speciation (Sinauer Associates, Sunderland, MA, 2004).

  34. Elliott, R.W. et al. Genetic analysis of testis weight and fertility in an interspecies hybrid congenic strain for chromosome X. Mamm. Genome 12, 45–51 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Elliott, R.W., Poslinski, D., Tabaczynski, D., Hohman, C. & Pazik, J. Loci affecting male fertility in hybrids between Mus macedonicus and C57BL/6. Mamm. Genome 15, 704–710 (2004).

    Article  PubMed  Google Scholar 

  36. Storchová, R. et al. Genetic analysis of X-linked hybrid sterility in the house mouse. Mamm. Genome 15, 515–524 (2004).

    Article  PubMed  Google Scholar 

  37. Fujita, P.A. et al. The UCSC Genome Browser database: update 2011. Nucleic Acids Res. 39, D876–D882 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Schwartz, S. et al. Human-mouse alignments with BLASTZ. Genome Res. 13, 103–107 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bailey, J.A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Osoegawa, K. et al. A bacterial artificial chromosome library for sequencing the complete human genome. Genome Res. 11, 483–496 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Salido, E.C. et al. Cloning and expression of the mouse pseudoautosomal steroid sulphatase gene (Sts). Nat. Genet. 13, 83–86 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Yeh, R.F., Lim, L.P. & Burge, C.B. Computational inference of homologous gene structures in the human genome. Genome Res. 11, 803–816 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

    Article  CAS  PubMed  Google Scholar 

  44. Thornton, K. & Long, M. Rapid divergence of gene duplicates on the Drosophila melanogaster X chromosome. Mol. Biol. Evol. 19, 918–925 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Trapnell, C., Pachter, L. & Salzberg, S.L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Trapnell, C. et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28, 511–515 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Brawand, D. et al. The evolution of gene expression levels in mammalian organs. Nature 478, 343–348 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Deng, X. et al. Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nat. Genet. 43, 1179–1185 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank D. Albracht, J. Collins, M. Gill, N. Koutseva, C. Kremitzki, A. van der Veen and J. Wood for technical assistance and D. Bellott, R. Desgraz, G. Dokshin, T. Endo, A. Godfrey, Y. Hu, J. Hughes, M. Kojima, B. Lesch, L. Okumura, K. Romer and Y. Soh for comments on the manuscript. This work was supported by the US National Institutes of Health and the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Whitehead Institute, Cambridge, Massachusetts, USA

    Jacob L Mueller, Helen Skaletsky, Laura G Brown, Sara Zaghlul & David C Page

  2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Helen Skaletsky, Laura G Brown & David C Page

  3. The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA

    Susan Rock, Tina Graves, Wesley C Warren & Richard K Wilson

  4. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

    Katherine Auger

  5. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    David C Page

Authors
  1. Jacob L Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helen Skaletsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura G Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara Zaghlul
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Susan Rock
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tina Graves
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katherine Auger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wesley C Warren
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Richard K Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David C Page
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.L.M., H.S., W.C.W., R.K.W. and D.C.P. planned the project. J.L.M. and L.G.B. performed BAC mapping. J.L.M. performed RNA deep sequencing. T.G., S.R., K.A. and S.Z. were responsible for finished BAC sequencing. J.L.M. and H.S. performed sequence analyses. J.L.M. and D.C.P. wrote the manuscript.

Corresponding author

Correspondence to David C Page.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–6 and Supplementary Tables 1, 5 and 9 (PDF 5830 kb)

Supplementary Table 2

Genes shared between human and mouse X chromosomes (XLS 155 kb)

Supplementary Table 3

Human X-linked genes with no detectable ortholog on the mouse X chromosome (XLS 53 kb)

Supplementary Table 4

Mouse X-linked genes with no detectable ortholog on the human X chromosome (XLS 62 kb)

Supplementary Table 6

Tissue expression of X-linked genes shared between human and mouse (XLS 239 kb)

Supplementary Table 7

Expression patterns of independently acquired human X-linked genes (XLS 52 kb)

Supplementary Table 8

Expression patterns of independently acquired mouse X-linked genes (XLS 57 kb)

Supplementary Table 10

Expression patterns of all human autosomal genes (XLS 3622 kb)

Supplementary Table 11

Expression patterns of all mouse autosomal genes (XLS 2626 kb)

Supplementary Table 12

All OMIM X-linked phenotypes where the molecular basis is known (XLS 62 kb)

Supplementary Table 13

Expression patterns between the sexes, in the heart and kidney, of human genes that follow Ohno's law (XLSX 60 kb)

Supplementary Table 14

Expression patterns between the sexes, in the heart and kidney, of mouse genes that follow Ohno's law (XLSX 65 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mueller, J., Skaletsky, H., Brown, L. et al. Independent specialization of the human and mouse X chromosomes for the male germ line. Nat Genet 45, 1083–1087 (2013). https://doi.org/10.1038/ng.2705

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2705

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research