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

Nature Genetics volume 38, pages 463–467 (2006)Cite this article

Abstract

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.

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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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Whitehead Institute,

    Sjoerd Repping, Laura G Brown, Julian Lange, Janet D Marszalek, Tatyana Pyntikova, Helen Skaletsky, David C Page & Steve Rozen

  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA

    Sjoerd Repping, Laura G Brown, Julian Lange, Janet D Marszalek, Tatyana Pyntikova, Helen Skaletsky, David C Page & Steve Rozen

  3. Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands

    Sjoerd Repping, Saskia K M van Daalen, Cindy M Korver & Fulco van der Veen

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Correspondence to David C Page.

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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)

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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). https://doi.org/10.1038/ng1754

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