© Kamla-Raj 2005 Int J Hum Genet, 5(4): 225-235 (2005) Y Chromosome and Male Infertility Arvind Rup Singh, Radek Vrtel, Radek Vodicka, Ishraq Dhaifalah, David Konvalinka, Maria Janikova and Jiri Santavy Department of Medical Genetics & Fetal Medicine, University Hospital, Palacky University, I.P. Pavlova 6, Olomouc 775 20, Czech Republic KEYWORDS Y chromosome; male infertility; microdeletions; SRY; TSPY; AZF; DAZ; CDY1; BPY2; PRY; TTY2 ABSTRACT The Y chromosome though representing only 2-3% of the haploid genome harbours about 107 genes and pseudogenes. Many of these are responsible for spermatogenesis and other male-related functions and deletion of any of these can result in infertility. The association of azoospermia with deletions involving long arm of the Y- chromosome, led to the proposition of an azoospermic factor (AZF). Further mapping of the Y-chromosome resulted in the identification of three regions viz., AZFa, AZFb, and AZFc associated with spermatogenic failure. The microdeletions involving the AZF have been extensively reported to cause male infertility. The genes of the “non- recombing region of Y-chromosome” (NRY) or the “male specific region of Y chromosome” (MSY) play an important role in male fertility. Some important genes identified in this region and associated with male infertility are: SRY, TSPY, USP9Y, DBY, UTY, E1F1AY, RBMY, DAZ, CDY1, BPY2, PRY, and TTY2. Their relative contributions to male infertility are discussed. Y CHROMOSOME Y chromosome is the smallest chromosome of the human genome. It has only about 60 million DNA base sequences and has the least number of genes as compared to any other human chromosome (Harris et al. 1986). About 107 genes and pseudogenes have been mapped to the Y- chromosome (http://gdbwww.gdb.com) and it has a high proportion of repetitive elements (Ali and Hasnain 2002). There are two pseduoautosomal regions, PAR1 and PAR2, on the short (Yp) and long (Yq) arms of Y chromosome that recombine, respectively, with their homologues on the X chromosome. The rest of the Y chromosome (~95 %) is know as ‘non-recombining region’ (NRY) or as ‘male specific region’ (MSY) (Fig. 1). The NRY contains intra-chromosomal repetitive elements that may be homologous to regions on X chromosome or Y chromosome (Tilford et al. 2001). The NRY region can be divided into euchromatic, centromeric and heterochromatic regions (Foote et al. 1992). The euchromatic region, cytogenetically known as Yq11 (subdivided into Yq11.21, Yq11.22, Yq11.23), is about 24 Mb. The heterochromatic Yq12 region contains 30 Mb sequences (Vollrath et al., 1992) and it has two major repeating domains viz., DYZ1 and DYZ2 (Cooke 1976). However, Ali and Hasnain (2002, 2003) divide the Y chromosome in five broad sections e.g., i) Pseudoautosomal boundary regions (PABY), ii) a Pericentric region on the short arm harbouring the sex determining (SRY) gene, iii) an Euchromatic region (DYS1) on the proximal long arm, iv) a Heterochromatic region (DYZ1) on the distal long arm, and (v) an important DYZ3 region that is critical for the survival and propagation of the Y chromosome. Relationship of Y Chromosome with Infertility The Y chromosome represents only 2-3% of the human haploid genome. It along with X chromosome, originated from a pair of autosomes around 300 million years ago among reptiles, much before mammals arose (Foster and Graves 1994). These chromosomes, in mammals, most probably arose due to differentiation of SRY gene from SOX3, which has a structural homologue on the X chromosome (Foster and Graves 1994; Stevanovic et al. 1993). The lack of recombination between X and Y chromosome is thought to be responsible for the decay of Y chromosome linked genes (Lahn et al. 2001) and this hypothesis seems to explain the small size of Y chromosome as compared to X chromosome (Graves 1995; Lahn and Page 1999). However, according to Ali and Hasnain (2003), the identification of different Corresponding author: Dr. Arvind Rup Singh Department of Medical Genetics & Fetal Medicine, University Hospital, Palacky University, I.P. Pavlova 6, Olomouc 775 20, Czech Republic Fax: 00420-585-414-906 E-mail: dravi@carolina.rr.com