The TSPY gene stands out from all other human protein-coding genes because of its high copy number and tandemly-repeated organization. Here, we review its evolutionary history in great apes in order to assess whether these unusual properties are more likely to result from a relaxation of constraint or an unusual functional role. Detailed comparisons with chimpanzee are possible because a finished sequence of the chimpanzee Y chromosome is available, together with more limited data from other apes. These comparisons suggest that the human-chimpanzee ancestral Y chromosome carried a tandem array of TSPY genes which expanded on the human lineage while undergoing multiple duplication events followed by pseudogene formation on the chimpanzee lineage. The protein coding region is the most highly conserved of the multi-copy Y genes in human-chimpanzee comparisons, and the analysis of the d N/d S ratio indicates that TSPY is evolutionarily highly constrained, but may have experienced positive selection after the human-chimpanzee split. We therefore conclude that the exceptionally high copy number in humans is most likely due to a human-specific but unknown functional role, possibly involving rapid production of a large amount of TSPY protein at some stage during？spermatogenesis.
Skaletsky, H.; Kuroda-Kawaguchi, T.; Minx, P.J.; Cordum, H.S.; Hillier, L.; Brown, L.G.; Repping, S.; Pyntikova, T.; Ali, J.; Bieri, T.; et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature？2003, 423, 825–837.
Repping, S.; van Daalen, S.K.; Brown, L.G.; Korver, C.M.; Lange, J.; Marszalek, J.D.; Pyntikova, T.; van der Veen, F.; Skaletsky, H.; Page, D.C.; et al. High mutation rates have driven extensive structural polymorphism among human Y chromosomes. Nat. Genet.？2006, 38, 463–467.
Murphy, K.M.; Cohen, J.S.; Goodrich, A.; Long, P.P.; Griffin, C.A. Constitutional duplication of a region of chromosome Yp encoding AMELY, PRKY, and TBL1Y: implications for sex chromosome analysis and bone marrow engraftment analysis. J. Mol. Diagn.？2007, 9, 408–413.
Jobling, M.A.; Lo, I.C.; Turner, D.J.; Bowden, G.R.; Lee, A.C.; Xue, Y.; Carvalho-Silva, D.; Hurles, M.E.; Adams, S.M.; Chang, Y.M.; et al. Structural variation on the short arm of the human Y chromosome: recurrent multigene deletions encompassing Amelogenin Y. Hum. Mol. Genet.？2007, 16, 307–316.
Zhang, J.S.; Yang-Feng, T.L.; Muller, U.; Mohandas, T.K.; de Jong, P.J.; Lau, Y.F. Molecular isolation and characterization of an expressed gene from the human Y chromosome. Hum. Mol. Genet.？1992, 1, 717–726.
Hughes, J.F.; Skaletsky, H.; Pyntikova, T.; Graves, T.A.; van Daalen, S.K.; Minx, P.J.; Fulton, R.S.; McGrath, S.D.; Locke, D.P.; Friedman, C.; et al. Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content. Nature？2010, 463, 536–539.
Fortna, A.; Kim, Y.; MacLaren, E.; Marshall, K.; Hahn, G.; Meltesen, L.; Brenton, M.; Hink, R.; Burgers, S.; Hernandez-Boussard, T. Lineage-specific gene duplication and loss in human and great ape evolution. PLoS Biol.？2004, 2, E207.
Sun, C.; Skaletsky, H.; Birren, B.; Devon, K.; Tang, Z.; Silber, S.; Oates, R.; Page, D.C. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nat. Genet.？1999, 23, 429–432.