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The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men

Abstract

Deletions of the AZFc (azoospermia factor c) region of the Y chromosome are the most common known cause of spermatogenic failure. We determined the complete nucleotide sequence of AZFc by identifying and distinguishing between near-identical amplicons (massive repeat units) using an iterative mapping–sequencing process. A complex of three palindromes, the largest spanning 3 Mb with 99.97% identity between its arms, encompasses the AZFc region. The palindromes are constructed from six distinct families of amplicons, with unit lengths of 115–678 kb, and may have resulted from tandem duplication and inversion during primate evolution. The palindromic complex contains 11 families of transcription units, all expressed in testis. Deletions of AZFc that cause infertility are remarkably uniform, spanning a 3.5-Mb segment and bounded by 229-kb direct repeats that probably served as substrates for homologous recombination.

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Figure 1: Amplicons and palindromes in 4.5-Mb portion of the human Y chromosome that includes AZFc.
Figure 2: Sequence-based map of STSs, deletions, transcription units and autosomal homologies.
Figure 3: PCR assays of selected STSs in the DNA of four men with AZFc deletions (and, in three cases, their fathers).
Figure 4: Comparison of 78-kb segment of human chromosome 3 with two segments of Y chromosome totaling 540 kb.
Figure 5: Proposed model of origins of the P1 palindrome through Alu-mediated tandem duplication and subsequent inversion.

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Acknowledgements

We thank C. Tilford and R. Saxena for scientific contributions, L. Hillier for project management, M. Goodheart, L. Pooler, T.V. Pyntikova and M. Velez-Stringer for technical contributions, C. Bruning, V. Cardone, A. de la Chapelle, B. Gilbert, W.A. Hogge, R. Newton, P. Patrizio, M. Summers and D.Van Dyke for patient samples and D. Berry, A. Bortvin, S. Repping and M. Royce-Tolland for comments on the manuscript. This work was supported by National Institutes of Health and Howard Hughes Medical Institute.

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Kuroda-Kawaguchi, T., Skaletsky, H., Brown, L. 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). https://doi.org/10.1038/ng757

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