Skip to main content

Thank you for visiting 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:

High mutation rates have driven extensive structural polymorphism among human Y chromosomes


Although much structural polymorphism in the human genome has been catalogued1,2,3,4,5, the kinetics of underlying change remain largely unexplored. Because human Y chromosomes are clonally inherited, it has been possible to capture their detailed relationships in a robust, worldwide genealogical tree6,7. Examination of structural variation across this tree opens avenues for investigating rates of underlying mutations. We selected one Y chromosome from each of 47 branches of this tree and searched for large-scale variation. Four chromosomal regions showed extensive variation resulting from numerous large-scale mutations. Within the tree encompassed by the studied chromosomes, the distal-Yq heterochromatin changed length ≥12 times, the TSPY gene array changed length ≥23 times, the 3.6-Mb IR3/IR3 region changed orientation ≥12 times and the AZFc region was rearranged ≥20 times. After determining the total time spanned by all branches of this tree (1.3 million years or 52,000 generations), we converted these mutation counts to lower bounds on rates: ≥2.3 × 10−4, ≥4.4 × 10−4, ≥2.3 × 10−4 and ≥3.8 × 10−4 large-scale mutations per father-to-son Y transmission, respectively. Thus, high mutation rates have driven extensive structural polymorphism among human Y chromosomes. At the same time, we found limited variation in the copy number of Y-linked genes, which raises the possibility of selective constraints.

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

Access options

Buy this article

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

Figure 1: Overview of potential structural variation in the human Y chromosome.
Figure 2: Y chromosome genealogical tree (left) and identified structural polymorphisms (right).
Figure 3: Assaying variation in heterochromatin length, TSPY array length and IR3/IR3 orientation.
Figure 5: Summary of identified Y chromosome structural variation.
Figure 4: Detecting architectural variation in AZFc.

Similar content being viewed by others

Accession codes




  1. Iafrate, A.J. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (2004).

    Article  CAS  Google Scholar 

  2. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    Article  CAS  Google Scholar 

  3. Sharp, A.J. et al. Segmental duplications and copy-number variation in the human genome. Am. J. Hum. Genet. 77, 78–88 (2005).

    Article  CAS  Google Scholar 

  4. Stefansson, H. et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).

    Article  CAS  Google Scholar 

  5. Tuzun, E. et al. Fine-scale structural variation of the human genome. Nat. Genet. 37, 727–732 (2005).

    Article  CAS  Google Scholar 

  6. Underhill, P.A. et al. Y chromosome sequence variation and the history of human populations. Nat. Genet. 26, 358–361 (2000).

    Article  CAS  Google Scholar 

  7. The Y Chromosome Consortium. A nomenclature system for the tree of human Y-chromosomal binary haplogroups. Genome Res. 12, 339–348 (2002).

  8. Vignaud, P. et al. Geology and palaeontology of the Upper Miocene Toros-Menalla hominid locality, Chad. Nature 418, 152–155 (2002).

    Article  CAS  Google Scholar 

  9. Hughes, J.F. et al. Conservation of Y-linked genes during human evolution revealed by comparative sequencing in chimpanzee. Nature 437, 100–103 (2005).

    Article  Google Scholar 

  10. Rozen, S. et al. Abundant gene conversion between arms of palindromes in human and ape Y chromosomes. Nature 423, 873–876 (2003).

    Article  CAS  Google Scholar 

  11. Tyler-Smith, C., Taylor, L. & Muller, U. Structure of a hypervariable tandemly repeated DNA sequence on the short arm of the human Y chromosome. J. Mol. Biol. 203, 837–848 (1988).

    Article  CAS  Google Scholar 

  12. Grace, H.J., Ally, F.E. & Paruk, M.A. 46,Xinv(Yp+q-) in four generations of an Indian family. J. Med. Genet. 9, 293–297 (1972).

    Article  CAS  Google Scholar 

  13. Bernstein, R., Wadee, A., Rosendorff, J., Wessels, A. & Jenkins, T. Inverted Y chromosome polymorphism in the Gujerati Muslim Indian population of South Africa. Hum. Genet. 74, 223–229 (1986).

    Article  CAS  Google Scholar 

  14. Repping, S. et al. Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection. Nat. Genet. 35, 247–251 (2003).

    Article  CAS  Google Scholar 

  15. Repping, S. et al. A family of human Y chromosomes has dispersed throughout northern Eurasia despite a 1.8-Mb deletion in the azoospermia factor c region. Genomics 83, 1046–1052 (2004).

    Article  CAS  Google Scholar 

  16. 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  Google Scholar 

  17. Manz, E., Schnieders, F., Muller Brechlin, A. & Schmidtke, J. TSPY-related sequences represent a microheterogeneous gene family organized as constitutive elements in DYZ5 tandem repeat units on the human Y chromosome. Genomics 17, 726–731 (1993).

    Article  CAS  Google Scholar 

  18. Affara, N.A. et al. Variable transfer of Y-specific sequences in XX males. Nucleic Acids Res. 14, 5375–5387 (1986).

    Article  CAS  Google Scholar 

  19. Page, D.C. Sex reversal: deletion mapping the male-determining function of the human Y chromosome. Cold Spring Harb. Symp. Quant. Biol. 51, 229–235 (1986).

    Article  CAS  Google Scholar 

  20. Tilford, C. et al. A physical map of the human Y chromosome. Nature 409, 943–945 (2001).

    Article  CAS  Google Scholar 

  21. 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  Google Scholar 

  22. Sankoff, D. Minimal mutation trees of sequences. SIAM J. Appl. Math. 28, 35–42 (1975).

    Article  Google Scholar 

  23. Machev, N. et al. Sequence family variant loss from the AZFc interval of the human Y chromosome, but not gene copy loss, is strongly associated with male infertility. J. Med. Genet. 41, 814–825 (2004).

    Article  CAS  Google Scholar 

  24. de Llanos, M., Ballesca, J.L., Gazquez, C., Margarit, E. & Oliva, R. High frequency of gr/gr chromosome Y deletions in consecutive oligospermic ICSI candidates. Hum. Reprod. 20, 216–220 (2005).

    Article  CAS  Google Scholar 

  25. Ferlin, A. et al. Association of partial AZFc region deletions with spermatogenic impairment and male infertility. J. Med. Genet. 42, 209–213 (2005).

    Article  CAS  Google Scholar 

  26. Hucklenbroich, K. et al. Partial deletions in the AZFc region of the Y chromosome occur in men with impaired as well as normal spermatogenesis. Hum. Reprod. 20, 191–197 (2005).

    Article  CAS  Google Scholar 

  27. Lynch, M. et al. The Y chromosome gr/gr subdeletion is associated with male infertility. Mol. Hum. Reprod. 11, 507–512 (2005).

    Article  CAS  Google Scholar 

  28. Collins, F.S., Brooks, L.D. & Chakravarti, A.A. DNA polymorphism discovery resource for research on human genetic variation. Genome Res. 8, 1229–1231 (1998).

    Article  CAS  Google Scholar 

  29. Schnedl, W. Flurescenzuntersuchungen ueber die langenvariabilitaet des Y-chromosoms beim menschen. Humangenetik 12, 188–194 (1971).

    Article  CAS  Google Scholar 

  30. Saxena, R. et al. Four DAZ genes in two clusters found in the AZFc region of the human Y chromosome. Genomics 67, 256–267 (2000).

    Article  CAS  Google Scholar 

Download references


We thank G. Farino for DNA sequencing; V. Frazzoni and G. Rogers for tissue culture; N.A. Ellis, M.F. Hammer, T. Jenkins, R.D. Oates and S. Silber for cell lines and blood samples; J. de Vries, N. Leschot and P. Underhill for technical and scientific advice; J.E. Alfoldi, A.E. Baltus, D.W. Bellott, A. Chakravarti, M.J. Daly, J.F. Hughes, L. Kruglyak, Y.-H. Lim, J.L. Mueller and D.E. Reich for comments on the manuscript and A.G. Clark for advice and guidance on studies of mutation rates. This work was supported by the US National Institutes of Health, the Howard Hughes Medical Institute, the Netherlands Organization for Scientific Research and the Academic Medical Center.

Author information

Authors and Affiliations


Corresponding author

Correspondence to David C Page.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Y-chromosome genealogical tree and structural polymorphisms identified, with sample identifiers and haplotype designations. (PDF 124 kb)

Supplementary Fig. 2

AZFc architectures that can be generated from the reference sequence in three or fewer homologous recombination events. (PDF 1128 kb)

Supplementary Fig. 3

Deletion at center of palindrome P3 in sample PD339. (PDF 11 kb)

Supplementary Fig. 4

Structural variant in sample YCC038. (PDF 783 kb)

Supplementary Fig. 5

Mutational event that can generate AZFc architecture c6. (PDF 168 kb)

Supplementary Fig. 6

Mutational pathway that can generate AZFc architecture c36. (PDF 178 kb)

Supplementary Fig. 7

Mutational pathways that can generate AZFc architecture c38. (PDF 354 kb)

Supplementary Fig. 8

Copy number of BPY2 and CDY1 genes. (PDF 87 kb)

Supplementary Table 1

Summary of samples and experimental results. (PDF 17 kb)

Supplementary Table 2

AZFc architectures that can be generated from the reference sequence in three or fewer homologous recombination events. (PDF 76 kb)

Supplementary Methods (PDF 1044 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Repping, S., van Daalen, S., Brown, L. et al. High mutation rates have driven extensive structural polymorphism among human Y chromosomes. Nat Genet 38, 463–467 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing