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TSPY1 Copy Number Variation Influences Spermatogenesis and Shows Differences among Y Lineages

Andrology Unit (C.G., F.N., I.L., F.D., G.F., C.K.), Department of Clinical Physiopathology, University of Florence, Florence 50139, Italy; and The Wellcome Trust Sanger Institute (D.J.T., Y.X., C.T.-S.), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom

Address all correspondence and requests for reprints to: Csilla Krausz, M.D., Ph.D., Andrology Unit, Department of Clinical Physiopathology, Viale Pieraccini 6, 50139 Firenze, Italy. E-mail: c.krausz{at}dfc.unifi.it.

Context: TSPY1 is a tandemly-repeated gene on the human Y chromosome forming an array of approximately 21–35 copies. The testicular expression pattern and the inferred function of the TSPY1 protein suggest possible involvement in spermatogenesis. However, data are scarce on TSPY1 copy number variation in different Y lineages and its role in spermatogenesis.

Objectives: We sought to define: 1) the extent of TSPY1 copy number variation within and among Y chromosome haplogroups; and 2) the role of TSPY1 dosage in spermatogenic efficiency.

Materials and Methods: A total of 154 idiopathic infertile men and 130 normozoospermic controls from Central Italy were analyzed. We used a quantitative PCR assay to measure TSPY1 copy number and also defined Y haplogroups in all subjects.

Results: We provide evidence that TSPY1 copy number shows substantial variation among Y haplogroups and thus that population stratification does represent a potential bias in case-control association studies. We also found: 1) a significant positive correlation between TSPY1 copy number and sperm count (P < 0.001); 2) a significant difference in mean TSPY1 copy number between patients and controls (28.4 ± 8.3 vs. 33.9 ± 10.7; P < 0.001); and 3) a 1.5-fold increased risk of abnormal sperm parameters in men with less than 33 copies (P < 0.001).

Conclusions: TSPY copy number variation significantly influences spermatogenic efficiency. Low TSPY1 copy number is a new risk factor for male infertility with potential clinical consequences.