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Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection

Nature Genetics volume 35, pages 247–251 (2003)Cite this article

Abstract

Many human Y-chromosomal deletions are thought to severely impair reproductive fitness, which precludes their transmission to the next generation and thus ensures their rarity in the population. Here we report a 1.6-Mb deletion that persists over generations and is sufficiently common to be considered a polymorphism. We hypothesized that this deletion might affect spermatogenesis because it removes almost half of the Y chromosome's AZFc region, a gene-rich segment that is critical for sperm production1,2. An association study established that this deletion, called gr/gr, is a significant risk factor for spermatogenic failure. The gr/gr deletion has far lower penetrance with respect to spermatogenic failure than previously characterized Y-chromosomal deletions; it is often transmitted from father to son. By studying the distribution of gr/gr-deleted chromosomes across the branches of the Y chromosome's genealogical tree, we determined that this deletion arose independently at least 14 times in human history. We suggest that the existence of this deletion as a polymorphism reflects a balance between haploid selection, which culls gr/gr-deleted Y chromosomes from the population, and homologous recombination, which continues to generate new gr/gr deletions.

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Figure 1: The gr/gr deletion.
Figure 2: The b1/b3 deletion.
Figure 3: b2/b4 duplication arising in a gr/gr-deleted chromosome.
Figure 4: The genealogical tree of human Y chromosomes and branches in which the gr/gr deletion was observed.

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Acknowledgements

We thank D. Altshuler, A. Chakravarti, A.G. Clark, G.Q. Daley, M.J. Daly, J.N. Hirschhorn, L. Kruglyak, V.K. Mootha, S. Paabo and D.E. Reich for comments on the manuscript; M.F. Hammer and P.A. Underhill for assistance with genealogical studies; T. Ogata and the Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Japan, for support and advice; and C. Bruning, N.A. Ellis, S. Fallet, A. Garguilo, J. Gianotten, B.R. Gilbert, M.F. Hammer, W.A. Hogge, J. Hoo, T. Jenkins, K. Kepler, K. Monaghan, E. Pergament, B. Shapiro, M.C. Summers, U. Surti, L. Weiss and J. Weissenbach for DNA, cell and blood samples. This work was supported by the US National Institutes of Health, the Howard Hughes Medical Institute and the Academic Medical Center.

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Authors and Affiliations

  1. Whitehead Institute and Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA

    Sjoerd Repping, Helen Skaletsky, Laura Brown, Tatyana Pyntikova, Tomoko Kuroda-Kawaguchi, David C Page & Steve Rozen

  2. Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Academic Medical Center, Amsterdam, the Netherlands

    Sjoerd Repping, Saskia K M van Daalen, Cindy M Korver, Jan W A de Vries & Fulco van der Veen

  3. Reproduction Center, Tokyo Dental College, Ichikawa General Hospital, Ichikawa, Chiba, Japan

    Tomoko Kuroda-Kawaguchi

  4. Department of Urology, Boston University Medical Center, Boston, 02118, Massachusetts, USA

    Robert D Oates

  5. Infertility Center of St. Louis, St. Luke's Hospital, St. Louis, 63017, Missouri, USA

    Sherman Silber

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  1. Sjoerd Repping
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Correspondence to David C Page.

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Repping, S., Skaletsky, H., Brown, L. 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). https://doi.org/10.1038/ng1250

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