Abstract
Approximately 0.03% of men carry a Y-chromosomal defect that leads to azoospermia, the absence of sperm cells from semen. Deletion mapping of the Y chromosomes of azoospermic or oligozoospermic men suggested that loss of three nonoverlapping regions, AZFa, AZFb, and AZFc, could be responsible. When the finished Y-chromosomal reference sequence became available, the recurrent deletion of each of these intervals could be explained largely by non-allelic homologous recombination between direct repeats. However, in contrast to the conclusion from deletion mapping, AZFb deletions were found to overlap with AZFc deletions. In addition, a background level of nonhomologous recombination was found to generate a minority of deletions of these intervals. USP9Y appears to be the critical gene underlying the AZFa phenotype, but the critical genes lost in the AZFb and AZFc deletions have not yet been identified. Inspection of the sequence allowed additional duplications, inversions, and partial deletions of the AZF intervals to be anticipated, and many of the predicted structures have subsequently been identified in the population. The phenotypic consequences of these additional rearrangements of the AZFc region are unclear. High levels of gene conversion homogenize duplicated sequences in both direct and inverted orientations on the Y, which could potentiate subsequent rearrangements. The Y chromosome provides an excellent model for understanding genomic disorders; however, more finished sequences and new methodologies are needed.
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References
Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 2003;423:825–837.
Eliasson R. Basic semen analysis. In: Current Topics inAndrology (Matson P, ed.), Perth, Australia: Ladybrook Publishing, 2003; pp. 35–89.
Tiepolo L, Zuffardi O. Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm. Hum Genet 1976;34:119–124.
Vergnaud G, Page DC, Simmler MC, et al. A deletion map of the human Y chromosome based on DNA hybridization. Am J Hum Genet 1986;38:109–124.
Vogt P, Chandley AC, Hargreave TB, Keil R, Ma K, Sharkey A. Microdeletions in interval 6 of the Y chromosome of males with idiopathic sterility point to disruption of AZF, a human spermatogenesis gene. Hum Genet 1992;89:491–496.
Vogt PH, Edelmann A, Kirsch S, et al. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet 1996;5:933–943.
Chang PL, Sauer MV, Brown S. Y chromosome microdeletion in a father and his four infertile sons. Hum Reprod 1999; 14:2689–2694.
Saut N, Terriou P, Navarro A, Levy N, Mitchell MJ. The human Y chromosome genes BPY2, CDY1 and DAZ are not essential for sustained fertility. Mol Hum Reprod 2000;6:789–793.
Gatta V, Stuppia L, Calabrese G, Morizio E, Guanciali-Franchi P, Palka G. A new case of Yq microdeletion transmitted from a normal father to two infertile sons. J Med Genet 2002;39:E27.
Disteche CM, Casanova M, Saal H, et al. Small deletions of the short arm of the Y chromosome in 46,XY females. Proc Natl Acad Sci USA 1986;83:7841–7844.
Jobling MA, Samara V, Pandya A, et al. Recurrent duplication and deletion polymorphisms on the long arm of the Y chromosome in normal males. Hum Mol Genet 1996;5:1767–1775.
Kent-First M, Muallem A, Shultz J, et al. Defining regions of the Y-chromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y-chromosome microdeletion detection. Mol Reprod Dev 1999;53:27–41.
Simoni M, Bakker E, Krausz C. EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromo-somal microdeletions. State of the art 2004. Int J Androl 2004;27:240–249.
Blanco P, Shlumukova M, Sargent CA, Jobling MA, Affara N, and Hurles ME. Divergent outcomes of intrachromosomal recombination on the human Y chromosome: male infertility and recurrent polymorphism. J Med Genet 2000;37:752–758.
Kamp C, Hirschmann P, Voss H, Huellen K, Vogt PH. Two long homologous retroviral sequence blocks in proximal Yq1 1 cause AZFa microdeletions as a result of intrachromosomal recombination events. Hum Mol Genet 2000;9:2563–2572.
Sun C, Skaletsky H, Rezen S, et al. Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses. Hum Mol Genet 2000;9:2291–2296.
Sun C, Skaletsky H, Birren B, et al. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nat Genet 1999;23:429–432.
Ditton HJ, Zimmer J, Kamp C, Rajpert-De Meyts E, Vogt PH. The AZFa gene DBY (DDX3Y) is widely transcribed but the protein is limited to the male germ cells by translation control. Hum Mol Genet 2004;13:2333–2341.
Kuroda-Kawaguchi T, Skaletsky H, Brown LG, et al. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet 2001;29:279–286.
Repping S, van Daalen SK, Korver CM, 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 2004;83:1046–1052.
Potocki L, Chen K-S, Park S-S, et al. Molecular mechanism for duplication 17p1 1.2-the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet 2000;24:84–87.
Bosch E, Jobling MA. Duplications of the AZFa region of the human Y chromosome are mediated by homologous recombination between HERVs and are compatible with male fertility. Hum Mol Genet 2003; 12: 341–347.
Bosch E, Hurles ME, Navarro A, Jobling MA. Dynamics of a human inter-paralog gene conversion hotspot. Genome Res 2004; 14:835–844.
Yen P. The fragility of fertility. Nat Genet 2001;29:243–244.
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 2003;35:247–251.
Underhill PA, Shen P, Lin AA, et al. Y chromosome sequence variation and the history of human populations. Nat Genet 2000;26:358–361.
Tyler-Smith C, McVean G. The comings and goings of a Y polymorphism. Nat Genet 2003;35:201–202.
Fernandes S, Paracchini S, Meyer LH, Floridia G, Tyler-Smith C, Vogt PH. A large AZFc deletion removes DAZ3/DAZ4 and nearby genes from men in Y haplogroup N. Am J Hum Genet 2004;74:180–187.
Zerj al T, Dashnyam B, Pandya A, et al. Genetic relationships of Asians and Northern Europeans, revealed by Y-chromosomal DNA analysis. Am J Hum Genet 1997;60:1174–1183.
Repping S, Skaletsky H, Lange J, et al. Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. Am J Hum Genet 2002;71:906–922.
Hurles ME, Jobling MA. A singular chromosome. Nat Genet 2003;34:246–247.
Foresta C, Ferlin A, Moro E. Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DB Y in male infertility. Hum Mol Genet 2000;9:1161–1169.
Wilson IJ, Balding DJ. Genealogical inference from microsatellite data. Genetics 1998; 150:499–510.
Sabeti PC, Reich DE, Higgins JM, et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 2002;419:832–837.
Jobling MA, Tyler-Smith C. The human Y chromosome: an evolutionary marker comes of age. Nat Rev Genet 2003;4:598–612.
Rozen S, Skaletsky H, Marszalek JD, et al. Abundant gene conversion between arms of palindromes in human and ape Y chromosomes. Nature 2003;423:873–876.
Hurles ME, Willey D, Matthews L, Hussain SS. Origins of chromosomal rearrangement hotspots in the human genome: evidence from the AZFa deletion hotspots. Genome Biol 2004;5:R55.
Innan H. A method for estimating the mutation, gene conversion and recombination parameters in small multigene families. Genetics 2002; 161:865–872.
Waldman AS, Liskay RM. Dependence of intrachromosomal recombination in mammalian cells on uninterrupted homology. Mol Cell Biol 1988;8:5350–5357.
Arnheim N, Calabrese P, Nordborg M. Hot and cold spots of recombination in the human genome: the reason we should find them and how this can be achieved. Am J Hum Genet 2003;73:5–16.
Mitra RD, Butty VL, Shendure J, Williams BR, Housman DE, Church GM. Digital genotyping and haplotyping with polymerase colonies. Proc Natl Acad Sci USA 2003;100:5926–5931.
Guzick DS, Overstreet JW, Factor-Litvak P, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001;345:1388–1393.
Choudhuri JV, Schleiermacher C, Kurtz S, Giegerich R. GenAlyzer: interactive visualization of sequence similarities between entire genomes. Bioinformatics 2004;20:1964–1965.
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© 2006 Humana Press Inc., Totowa, NJ
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Hurles, M.E., Tyler-Smith, C. (2006). Y-Chromosomal Rearrangements and Azoospermia. In: Lupski, J.R., Stankiewicz, P. (eds) Genomic Disorders. Humana Press. https://doi.org/10.1007/978-1-59745-039-3_19
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DOI: https://doi.org/10.1007/978-1-59745-039-3_19
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