Human Molecular Genetics Advance Access originally published online on September 22, 2004
Human Molecular Genetics 2004 13(22):2875-2883; doi:10.1093/hmg/ddh302
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Human Molecular Genetics, Vol. 13, No. 22 © Oxford University Press 2004; all rights reserved
Defective recombination in infertile men
1Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, 2Department of Urology and 3Department of Physiology, Programs in Human Genetics, Cancer Genetics and Developmental and Stem Cell Biology, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0556, USA, 4Department of Medical Genetics, Faculty of Medicine, University of Calgary, Alberta T2T 5C7, Canada, 5Department of Genetics, Alberta Children's Hospital, 1820 Richmond Road SW, Calgary, Alberta T2T 5C7, Canada, 6Department of Urology, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA, 7Center for Biomedical Research, The Population Council, New York, NY 10021, USA and 8Department of Obstetrics and Gynecology, Faculty of Medicine, University of Calgary, Alberta T2N 4N1, Canada
Received August 5, 2004; Accepted September 14, 2004
Two percent of men are infertile owing to defects in sperm production. In 10–15% of cases, Y chromosome deletions that encompass critical spermatogenesis genes are detected; in the remaining cases, the cause of infertility is unknown. In model organisms, defects in recombination genes cause infertility, germ cell aneuploidy and subsequent development of inviable or abnormal progeny. Several studies have also linked infertility and higher rates of germ cell aneuploidy in men and women. Thus, we reasoned that defective recombination may be a major cause of infertility in men with poor or no sperm production and we performed the first comparison of recombination parameters within populations of single spermatocytes from infertile and fertile men who reported for assisted reproduction. We observed that 10% of non-obstructive azoospermic men had significantly lower recombination frequencies than men with normal spermatogenesis. Furthermore, when we focused our analysis only on those men who had a pathological diagnosis of ‘maturation arrest’ due to arrest during sperm development, about half had detectable defects in recombination. In contrast, none of the men with normal spermatogenesis had defects in recombination. Thus, this study provides direct evidence that defects in recombination are linked to poor sperm production in a significant percentage of infertile men. Implications of this observation for the use of assisted reproductive technologies are especially relevant to consider, given that recombination is required to both introduce genetic variation and insure proper chromosome separation during meiosis.
* To whom correspondence should be addressed at: University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0546, USA. Tel: +1 4154763178; Fax: +1 4154763121; Email: reijo{at}itsa.ucsf.edu
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