Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2004 Nov;41(11):814–825. doi: 10.1136/jmg.2004.022111

Sequence family variant loss from the AZFc interval of the human Y chromosome, but not gene copy loss, is strongly associated with male infertility

N Machev 1, N Saut 1, G Longepied 1, P Terriou 1, A Navarro 1, N Levy 1, M Guichaoua 1, C Metzler-Guillemai 1, P Collignon 1, A Frances 1, J Belougne 1, E Clemente 1, J Chiaroni 1, C Chevillard 1, C Durand 1, A Ducourneau 1, N Pech 1, K McElreavey 1, M Mattei 1, M Mitchell 1
PMCID: PMC1735624  PMID: 15520406

Abstract

Background: Complete deletion of the complete AZFc interval of the Y chromosome is the most common known genetic cause of human male infertility. Two partial AZFc deletions (gr/gr and b1/b3) that remove some copies of all AZFc genes have recently been identified in infertile and fertile populations, and an association study indicates that the resulting gene dose reduction represents a risk factor for spermatogenic failure.

Methods: To determine the incidence of various partial AZFc deletions and their effect on fertility, we combined quantitative and qualitative analyses of the AZFc interval at the DAZ and CDY1 loci in 300 infertile men and 399 control men.

Results: We detected 34 partial AZFc deletions (32 gr/gr deletions), arising from at least 19 independent deletion events, and found gr/gr deletion in 6% of infertile and 3.5% of control men (p>0.05). Our data provide evidence for two large AZFc inversion polymorphisms, and for relative hot and cold spots of unequal crossing over within the blocks of homology that mediate gr/gr deletion. Using SFVs (sequence family variants), we discriminate DAZ1/2, DAZ3/4, CDY1a (proximal), and CDY1b (distal) and define four types of DAZ-CDY1 gr/gr deletion.

Conclusions: The only deletion type to show an association with infertility was DAZ3/4-CDY1a (p = 0.042), suggesting that most gr/gr deletions are neutral variants. We see a stronger association, however, between loss of the CDY1a SFV and infertility (p = 0.002). Thus, loss of this SFV through deletion or gene conversion could be a major risk factor for male infertility.

Full Text

The Full Text of this article is available as a PDF (431.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bienvenu T., Patrat C., McElreavey K., de Almeida M., Jouannet P. Reduction in the DAZ gene copy number in two infertile men with impaired spermatogenesis. Ann Genet. 2001 Jul-Sep;44(3):125–128. doi: 10.1016/s0003-3995(01)01078-4. [DOI] [PubMed] [Google Scholar]
  2. Brownstein M. J., Carpten J. D., Smith J. R. Modulation of non-templated nucleotide addition by Taq DNA polymerase: primer modifications that facilitate genotyping. Biotechniques. 1996 Jun;20(6):1004-6, 1008-10. doi: 10.2144/96206st01. [DOI] [PubMed] [Google Scholar]
  3. Chang P. L., Sauer M. V., Brown S. Y chromosome microdeletion in a father and his four infertile sons. Hum Reprod. 1999 Nov;14(11):2689–2694. doi: 10.1093/humrep/14.11.2689. [DOI] [PubMed] [Google Scholar]
  4. Dorus Steve, Gilbert Sandra L., Forster Michele L., Barndt Robert J., Lahn Bruce T. The CDY-related gene family: coordinated evolution in copy number, expression profile and protein sequence. Hum Mol Genet. 2003 Jul 15;12(14):1643–1650. doi: 10.1093/hmg/ddg185. [DOI] [PubMed] [Google Scholar]
  5. Ewis Ashraf A., Lee Juwon, Shinka Toshikatsu, Nakahori Yutaka. Microdeletions of a Y-specific marker, Yfm1, and implications for a role in spermatogenesis. J Hum Genet. 2002;47(5):257–261. doi: 10.1007/s100380200035. [DOI] [PubMed] [Google Scholar]
  6. Fernandes S., Huellen K., Goncalves J., Dukal H., Zeisler J., Rajpert De Meyts E., Skakkebaek N. E., Habermann B., Krause W., Sousa M. High frequency of DAZ1/DAZ2 gene deletions in patients with severe oligozoospermia. Mol Hum Reprod. 2002 Mar;8(3):286–298. doi: 10.1093/molehr/8.3.286. [DOI] [PubMed] [Google Scholar]
  7. Fernandes S., Paracchini S., Meyer L. H., Floridia G., Tyler-Smith C., Vogt P. H. A large AZFc deletion removes DAZ3/DAZ4 and nearby genes from men in Y haplogroup N. Am J Hum Genet. 2003 Nov 21;74(1):180–187. doi: 10.1086/381132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hammer M. F., Horai S. Y chromosomal DNA variation and the peopling of Japan. Am J Hum Genet. 1995 Apr;56(4):951–962. [PMC free article] [PubMed] [Google Scholar]
  9. Hurles M. E., Irven C., Nicholson J., Taylor P. G., Santos F. R., Loughlin J., Jobling M. A., Sykes B. C. European Y-chromosomal lineages in Polynesians: a contrast to the population structure revealed by mtDNA. Am J Hum Genet. 1998 Dec;63(6):1793–1806. doi: 10.1086/302147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jobling M. A., Samara V., Pandya A., Fretwell N., Bernasconi B., Mitchell R. J., Gerelsaikhan T., Dashnyam B., Sajantila A., Salo P. J. Recurrent duplication and deletion polymorphisms on the long arm of the Y chromosome in normal males. Hum Mol Genet. 1996 Nov;5(11):1767–1775. doi: 10.1093/hmg/5.11.1767. [DOI] [PubMed] [Google Scholar]
  11. Kuroda-Kawaguchi T., Skaletsky H., Brown L. G., Minx P. J., Cordum H. S., Waterston R. H., Wilson R. K., Silber S., Oates R., Rozen S. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet. 2001 Nov;29(3):279–286. doi: 10.1038/ng757. [DOI] [PubMed] [Google Scholar]
  12. Kuroki Y., Iwamoto T., Lee J., Yoshiike M., Nozawa S., Nishida T., Ewis A. A., Nakamura H., Toda T., Tokunaga K. Spermatogenic ability is different among males in different Y chromosome lineage. J Hum Genet. 1999;44(5):289–292. doi: 10.1007/s100380050162. [DOI] [PubMed] [Google Scholar]
  13. Lahn Bruce T., Tang Zhao Lan, Zhou Jianxin, Barndt Robert J., Parvinen Martti, Allis C. David, Page David C. Previously uncharacterized histone acetyltransferases implicated in mammalian spermatogenesis. Proc Natl Acad Sci U S A. 2002 Jun 18;99(13):8707–8712. doi: 10.1073/pnas.082248899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ma K., Sharkey A., Kirsch S., Vogt P., Keil R., Hargreave T. B., McBeath S., Chandley A. C. Towards the molecular localisation of the AZF locus: mapping of microdeletions in azoospermic men within 14 subintervals of interval 6 of the human Y chromosome. Hum Mol Genet. 1992 Apr;1(1):29–33. doi: 10.1093/hmg/1.1.29. [DOI] [PubMed] [Google Scholar]
  15. Reijo R., Lee T. Y., Salo P., Alagappan R., Brown L. G., Rosenberg M., Rozen S., Jaffe T., Straus D., Hovatta O. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet. 1995 Aug;10(4):383–393. doi: 10.1038/ng0895-383. [DOI] [PubMed] [Google Scholar]
  16. Repping Sjoerd, Skaletsky Helen, Brown Laura, van Daalen Saskia K. M., Korver Cindy M., Pyntikova Tatyana, Kuroda-Kawaguchi Tomoko, de Vries Jan W. A., Oates Robert D., Silber Sherman. Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection. Nat Genet. 2003 Oct 5;35(3):247–251. doi: 10.1038/ng1250. [DOI] [PubMed] [Google Scholar]
  17. Rosser Z. H., Zerjal T., Hurles M. E., Adojaan M., Alavantic D., Amorim A., Amos W., Armenteros M., Arroyo E., Barbujani G. Y-chromosomal diversity in Europe is clinal and influenced primarily by geography, rather than by language. Am J Hum Genet. 2000 Nov 9;67(6):1526–1543. doi: 10.1086/316890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rozen Steve, Skaletsky Helen, Marszalek Janet D., Minx Patrick J., Cordum Holland S., Waterston Robert H., Wilson Richard K., Page David C. Abundant gene conversion between arms of palindromes in human and ape Y chromosomes. Nature. 2003 Jun 19;423(6942):873–876. doi: 10.1038/nature01723. [DOI] [PubMed] [Google Scholar]
  19. Saut N., Terriou P., Navarro A., Lévy N., Mitchell M. J. The human Y chromosome genes BPY2, CDY1 and DAZ are not essential for sustained fertility. Mol Hum Reprod. 2000 Sep;6(9):789–793. doi: 10.1093/molehr/6.9.789. [DOI] [PubMed] [Google Scholar]
  20. Saxena R., de Vries J. W., Repping S., Alagappan R. K., Skaletsky H., Brown L. G., Ma P., Chen E., Hoovers J. M., Page D. C. Four DAZ genes in two clusters found in the AZFc region of the human Y chromosome. Genomics. 2000 Aug 1;67(3):256–267. doi: 10.1006/geno.2000.6260. [DOI] [PubMed] [Google Scholar]
  21. Seboun E., Barbaux S., Bourgeron T., Nishi S., Agulnik A., Egashira M., Nikkawa N., Bishop C., Fellous M., McElreavey K. Gene sequence, localization, and evolutionary conservation of DAZLA, a candidate male sterility gene. Genomics. 1997 Apr 15;41(2):227–235. doi: 10.1006/geno.1997.4635. [DOI] [PubMed] [Google Scholar]
  22. Skaletsky Helen, Kuroda-Kawaguchi Tomoko, Minx Patrick J., Cordum Holland S., Hillier LaDeana, Brown Laura G., Repping Sjoerd, Pyntikova Tatyana, Ali Johar, Bieri Tamberlyn. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature. 2003 Jun 19;423(6942):825–837. doi: 10.1038/nature01722. [DOI] [PubMed] [Google Scholar]
  23. Tiepolo L., Zuffardi O. Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm. Hum Genet. 1976 Oct 28;34(2):119–124. doi: 10.1007/BF00278879. [DOI] [PubMed] [Google Scholar]
  24. Tilford C. A., Kuroda-Kawaguchi T., Skaletsky H., Rozen S., Brown L. G., Rosenberg M., McPherson J. D., Wylie K., Sekhon M., Kucaba T. A. A physical map of the human Y chromosome. Nature. 2001 Feb 15;409(6822):943–945. doi: 10.1038/35057170. [DOI] [PubMed] [Google Scholar]
  25. Underhill P. A., Jin L., Lin A. A., Mehdi S. Q., Jenkins T., Vollrath D., Davis R. W., Cavalli-Sforza L. L., Oefner P. J. Detection of numerous Y chromosome biallelic polymorphisms by denaturing high-performance liquid chromatography. Genome Res. 1997 Oct;7(10):996–1005. doi: 10.1101/gr.7.10.996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Vogt P. H., Edelmann A., Kirsch S., Henegariu O., Hirschmann P., Kiesewetter F., Köhn F. M., Schill W. B., Farah S., Ramos C. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet. 1996 Jul;5(7):933–943. doi: 10.1093/hmg/5.7.933. [DOI] [PubMed] [Google Scholar]
  27. Vogt P. H. Human chromosome deletions in Yq11, AZF candidate genes and male infertility: history and update. Mol Hum Reprod. 1998 Aug;4(8):739–744. doi: 10.1093/molehr/4.8.739. [DOI] [PubMed] [Google Scholar]
  28. Yen P. The fragility of fertility. Nat Genet. 2001 Nov;29(3):243–244. doi: 10.1038/ng1101-243. [DOI] [PubMed] [Google Scholar]
  29. Zerjal T., Dashnyam B., Pandya A., Kayser M., Roewer L., Santos F. R., Schiefenhövel W., Fretwell N., Jobling M. A., Harihara S. Genetic relationships of Asians and Northern Europeans, revealed by Y-chromosomal DNA analysis. Am J Hum Genet. 1997 May;60(5):1174–1183. [PMC free article] [PubMed] [Google Scholar]
  30. de Vries Jan W. A., Hoffer Mariëtte J. V., Repping Sjoerd, Hoovers Jan M. N., Leschot Nico J., van der Veen Fulco. Reduced copy number of DAZ genes in subfertile and infertile men. Fertil Steril. 2002 Jan;77(1):68–75. doi: 10.1016/s0015-0282(01)02935-1. [DOI] [PubMed] [Google Scholar]
  31. de Vries Jan W. A., Repping Sjoerd, van Daalen Saskia K. M., Korver Cindy M., Leschot Nico J., van der Veen Fulco. Clinical relevance of partial AZFc deletions. Fertil Steril. 2002 Dec;78(6):1209–1214. doi: 10.1016/s0015-0282(02)04390-x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES