Phenotypic variation within European carriers of the Y-chromosomal gr/gr deletion is independent of Y-chromosomal background

Csilla Krausz ^1*, Claudia Giachini ¹, Yali Xue ², Moira K. O'Bryan ³, Joerg Gromoll ⁴, Ewa Rajpert-de Meyts ⁵, Rafael Oliva ⁶, Isabelle Aknin-Seifer ⁷, Edit Erdei ⁸, Niels Jorgensen ⁵, Manuela Simoni ⁴, José Luis Ballescà ⁹, Rachel Levy ¹⁰, Giancarlo Balercia ¹¹, Paola Piomboni ¹², Eberhart Nieschlag ⁴, Gianni Forti ¹³, Rob McLachlan ¹⁴ and Chris Tyler-Smith ²

¹ University of Florence, Dep. of Clinical Physiopathology, Andrology Unit, Italy
² The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus Hinxton, United Kingdom
³ Monash University, Monash Institute of Medical Research and the Australian Research Centre of Excel, Australia
⁴ Institute of Reproductive Medicine University of Muenster, Germany
⁵ Dept. of Growth and Reproduction Copenhagen, University Hospital Rigshospitalet, Denmark
⁶ Hospital Clínic, Faculty of Medicine, University of Barcelona, Spain
⁷ Hôpital Nord Saint-Etienne, Laboratoire de Biologie de la Reproduction, France
⁸ Andrology-Urology Division, National Health Center, Budapest, Hungary
⁹ Institut Clínic of Gynecology, Obstetrics and Neonatology, Hospital Clínic,, Spain
¹⁰ Laboratoire d’Histologie Embryologie Cytogénétique Biologie de la reproduction CECOS, France
¹¹ Division of Endocrinology, Institute of Internal Medicine Polytechnic University of Marche,, Italy
¹² Dept. of Surgery - Biology Section, University of Siena, Italy
¹³ Andrology Unit, Department of Clinical Physiopathology, University of Florence, Italy
¹⁴ Prince Henry's Institute, Monash Medical Centre, Australia

^* To whom correspondence should be addressed. E-mail: c.krausz{at}dfc.unifi.it.

Accepted 17 August 2008

Abstract

Background: Men with partial (gr/gr) deletions within the AZFc region of the Y chromosome can exhibit a sperm phenotype that ranges from normozoospermia to azoospermia. The basis of this variation is unknown, but differences in the genes removed by independent gr/gr deletions, the occurrence of subsequent duplications or the presence of linked modifying variants elsewhere on the chromosome have been suggested as possible causal factors. We set out to test these possibilities in a large sample of gr/gr carriers with known phenotypes spanning the complete range.

Results: We assembled a collection of 169 men diagnosed with gr/gr deletions from six centres in Europe and one in Australia, and characterized the DAZ and CDY1 copies retained, the presence or absence of duplications and the Y-chromosomal haplogroup. Although our study had good power to detect factors that accounted for ¡5.5% of the variation in sperm concentration, no such factor was detected. A negative effect of gr/gr deletions followed by b2/b4 duplication was observed within the normospermic group, which remains to be further explored in a larger study population. Finally, we observed significant geographical differences in the frequency of different subtypes of gr/gr deletions which may have relevance for the interpretation of case controls studies dealing with admixed populations.

Conclusions: We conclude that the phenotypic variation of gr/gr carriers in men of European origin is largely independent of the Y-chromosomal background.