Posts Tagged ‘X chromosome’

Reporter: Aviva Lev-Ari, PhD, RN


Nature Genetics (2013) doi:10.1038/ng.2705

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

  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


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.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Nature Genetics (2013) doi:10.1038/ng.2705


 11 February 2013 Accepted

20 June 2013 Published online

21 July 2013

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.

Refined X Chromosome Assembly Hints at Possible Role in Sperm Production

July 22, 2013

NEW YORK (GenomeWeb News) – A US and UK team that delved into previously untapped stretches of sequence on the mammalian X chromosome has uncovered clues that sequences on the female sex chromosome may play a previously unappreciated role in sperm production.

The work, published online yesterday in Nature Genetics, also indicated such portions of the X chromosome may be prone to genetic changes that are more rapid than those described over other, better-characterized X chromosome sequences.

“We view this as the double life of the X chromosome,” senior author David Page, director of the Whitehead Institute, said in a statement.

“[T]he story of the X has been the story of X-linked recessive diseases, such as color blindness, hemophilia, and Duchenne’s muscular dystrophy,” he said. “But there’s another side to the X, a side that is rapidly evolving and seems to be attuned to the reproductive needs of males.”

As part of a mouse and human X chromosome comparison intended to assess the sex chromosome’s similarities across placental mammals, Page and his colleagues used a technique called single-haplotype iterative mapping and sequencing, or SHIMS, to scrutinize human X chromosome sequence and structure in more detail than was available previously.

With the refined human X chromosome assembly and existing mouse data, the team did see cross-mammal conservation for many X-linked genes, particularly those present in single copies. But that was not the case for a few hundred species-specific genes, many of which fell in segmentally duplicated, or “ampliconic,” parts of the X chromosome. Moreover, those genes were prone to expression by germ cells in male testes tissue, pointing to a potential role in sperm production-related processes.

“X-ampliconic genes are expressed predominantly in testicular germ cells,” the study authors noted, “and many were independently acquired since divergence from the common ancestor of humans and mice, specializing portions of their X chromosomes for sperm production.”

The work was part of a larger effort to look at a theory known as Ohno’s law, which predicts extensive X-linked gene similarities from one placental mammal to the next, Page and company turned to the same SHIMS method they used to get a more comprehensive view of the Y chromosome for previous studies.

Using that sequencing method, the group resequenced portions of the human X chromosome, originally assembled from a mishmash of sequence from the 16 or more individuals whose DNA was used to sequence the human X chromosome reference.

Their goal: to track down sections of segmental duplication, called ampliconic regions, that may have been missed or assembled incorrectly in the mosaic human X chromosome sequence.

“Ampliconic regions assembled from multiple haplotypes may have expansions, contractions, or inversions that do not accurately reflect the structure of any extant haplotype,” the study’s authors explained.

“To thoroughly test Ohno’s law,” they wrote, “we constructed a more accurate assembly of the human X chromosome’s ampliconic regions to compare the gene contents of the human and mouse X chromosomes.”

The team focused their attention on 29 predicted ampliconic regions of the human X chromosome, using SHIMS to generate millions of bases of non-overlapping X chromosome sequence.

With that sequence in hand, they went on to refine the human X chromosome assembly before comparing it with the reference sequence for the mouse X chromosome, which already represented just one mouse haplotype.

The analysis indicated that 144 of the genes on the human X chromosome don’t have orthologs in mice, while 197 X-linked mouse genes lack human orthologs.

A minority of those species-specific genes arose as the result of gene duplication or gene loss events since the human and mouse lineages split from one around 80 million years ago, researchers determined. But most appear to have resulted from retrotransposition or transposition events involving sequences from autosomal chromosomes.

And when the team used RNA sequencing and existing gene expression data to look at which mouse and human tissues flip on particular genes, it found that many of the species-specific genes on the X chromosome showed preferential expression in testicular cells known for their role in sperm production.

Based on such findings, the study’s authors concluded that “the gene repertoires of the human and mouse X chromosomes are products of two complementary evolutionary processes: conservation of single-copy genes that serve in functions shared by the sexes and ongoing gene acquisition, usually involving the formation of amplicons, which leads to the differentiation and specialization of X chromosomes for functions in male gametogenesis.”

The group plans to incorporate results of its SHIMS-based assembly into the X chromosome portion of the human reference genome.

“This is a collection of genes that has largely eluded medical geneticists,” the study’s first author Jacob Mueller, a post-doctoral researcher in Page’s Whitehead lab, said in a statement. “Now that we’re confident of the assembly and gene content of these highly repetitive regions on the X chromosome, we can start to dissect their biological significance.”

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REFERENCES in the Nature Genetics

  • Ohno, S. Sex Chromosomes and Sex-Linked Genes (Springer, Berlin, 1967).
  1. Kuroiwa, A. et al. Conservation of the rat X chromosome gene order in rodent species.Chromosome Res. 9, 61–67 (2001).
  2. 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).
  3. 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).
  4. Ross, M.T. et al. The DNA sequence of the human X chromosome. Nature 434, 325–337(2005).
  5. Veyrunes, F. et al. Bird-like sex chromosomes of platypus imply recent origin of mammal sex chromosomes. Genome Res. 18, 965–973 (2008).
  6. Watanabe, T.K. et al. A radiation hybrid map of the rat genome containing 5,255 markers.Nat. Genet. 22, 27–36 (1999).
  7. 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).
  8. Band, M.R. et al. An ordered comparative map of the cattle and human genomes. Genome Res. 10, 1359–1368 (2000).
  9. 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).
  10. Spriggs, H.F. et al. Construction and integration of radiation-hybrid and cytogenetic maps of dog chromosome X. Mamm. Genome 14, 214–221 (2003).
  11. Palmer, S., Perry, J. & Ashworth, A. A contravention of Ohno’s law in mice. Nat. Genet. 10,472–476 (1995).
  12. 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).
  13. She, X. et al. Shotgun sequence assembly and recent segmental duplications within the human genome. Nature 431, 927–930 (2004).
  14. Olivier, M. et al. A high-resolution radiation hybrid map of the human genome draft sequence. Science 291, 1298–1302 (2001).
  15. Dietrich, W.F. et al. A comprehensive genetic map of the mouse genome. Nature 380,149–152 (1996).
  16. Church, D.M. et al. Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol. 7, e1000112 (2009).
  17. Tishkoff, S.A. & Kidd, K.K. Implications of biogeography of human populations for ‘race’ and medicine. Nat. Genet. 36, S21–S27 (2004).
  18. Bovee, D. et al. Closing gaps in the human genome with fosmid resources generated from multiple individuals. Nat. Genet. 40, 96–101 (2008).
  19. Kidd, J.M. et al. Mapping and sequencing of structural variation from eight human genomes.Nature 453, 56–64 (2008).
  20. 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).
  21. Hughes, J.F. et al. Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content. Nature 463, 536–539 (2010).
  22. 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).
  23. Bellott, D.W. et al. Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition. Nature 466, 612–616 (2010).
  24. Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005).
  25. Wade, C.M. et al. Genome sequence, comparative analysis, and population genetics of the domestic horse. Science 326, 865–867 (2009).
  26. International Chicken Genome Sequencing Consortium. Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432,695–716 (2004).
  27. Wang, E.T. et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456,470–476 (2008).
  28. 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).
  29. 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).
  30. 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).
  31. Mueller, J.L. et al. The mouse X chromosome is enriched for multicopy testis genes showing postmeiotic expression. Nat. Genet. 40, 794–799 (2008).
  32. Coyne, J.A. & Orr, H.A. Speciation (Sinauer Associates, Sunderland, MA, 2004).
  33. 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).
  34. 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).
  35. Storchová, R. et al. Genetic analysis of X-linked hybrid sterility in the house mouse. Mamm. Genome 15, 515–524 (2004).
  36. Fujita, P.A. et al. The UCSC Genome Browser database: update 2011. Nucleic Acids Res.39, D876–D882 (2011).
  37. Schwartz, S. et al. Human-mouse alignments with BLASTZ. Genome Res. 13, 103–107(2003).
  38. Bailey, J.A. et al. Recent segmental duplications in the human genome. Science 297,1003–1007 (2002).
  39. Osoegawa, K. et al. A bacterial artificial chromosome library for sequencing the complete human genome. Genome Res. 11, 483–496 (2001).
  40. Salido, E.C. et al. Cloning and expression of the mouse pseudoautosomal steroid sulphatase gene (Sts). Nat. Genet. 13, 83–86 (1996).
  41. 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).
  42. 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).
  43. Thornton, K. & Long, M. Rapid divergence of gene duplicates on the Drosophila melanogaster X chromosome. Mol. Biol. Evol. 19, 918–925 (2002).
  44. Trapnell, C., Pachter, L. & Salzberg, S.L. TopHat: discovering splice junctions with RNA-Seq.Bioinformatics 25, 1105–1111 (2009).
  45. 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).
  46. Brawand, D. et al. The evolution of gene expression levels in mammalian organs. Nature478, 343–348 (2011).
  47. 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).


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