A Journey on Y Chromosomal Genes and Male Infertility

In the course of evolution Y chromosome has acquired an important role in sex determination owing to the differentiation of the SRY gene from its X homologue. Apart from the functionally specialized SRY gene, the Y chromosome harbors several genes responsible for normal fertility. Three different spermatogenic loci namely AZFa, AZFb and AZFc located in the long arm of Y chromosome (Yq) has the vital role in regulating normal spermatogenesis. A microdeletion occurring in any of these regions is attributed to spermatogenic failure leading to infertility in men. Genetic cause of male infertility is found to be 10-15% and the outcome is diverse ranging from no germ cells (Sertoli Cell Only syndrome) to hypospermatogenesis. Genes arrayed in the AZFc region have testis specific expression and deletion of the AZFc region is most common among the Y micro-deletions in men with azoospermia condition. Among the candidate genes of the AZFc region the deletion involving DAZ is considered to be the frequent cause leading to azoospermia. The mechanism of micro-deletion is found to be the same in case of AZFa and AZFc region. Among these two loci homologous recombination of flanking, identical sequences leads to microdeletion. But in case of AZFb region the proximal and distal breakpoints does not exhibit sequence homology although interspersed repeated sequences exist in proximity to the break points. Corresponding Author: Dr. S.S. Malini Telephone: 08212419784 (O) E-mail: [email protected] INTRODUCTION Y chromosome has occupied a unique status in the human genome owing to its size, organization and function. The haploid Y chromosome stands apart from the rest primarily due to three reasons, first one being, recombination confined to the extremities (5%) and the remaining region (95%) accounting for non recombining Male Specific region of the Y chromosome (MSY) (Skaletsky et al. 2003), second, for harboring genes exclusively for the expression of male characters (Huntington and Willard 2003) and finally due to gene conversion process occurring in the palindromic blocks, that rectifies mutations (Rozen et al. 2003). X and Y chromosomes have evolved from a pair of identical autosome around 300 million years ago from reptiles before the rise of mammals (Graves and Foster 1994). Differentiation of the SRY gene from its X homologue SOX3 is considered as the key event that led to the rise of sex chromosomes in mammals (Stevanovic et al. 1993; Foster and Graves 1994). During the course of evolution Y chromosome gradually acquired the genes for spermatogenesis (Marshall 2000). The recombination event between the X and Y chromosome began to cease gradually due to block wise mutations followed by large scale inversions in the Y chromosome (Lahn and Page 1999; Lahn et al. 2001). Very less change occurred in the X chromosome owing to 50% chance of recombination with another X chromosome (Rao 2003). The cessation of recombination led to the Y chromosome losing the key ability of homology based repair. This has led to the progressive degeneration of Y chromosome and as a consequence Y chromosome has occupied ‘one of the smallest human chromosome’ status (Ali and Hasnain 2001). Y ChromosomeCytogenetic Partitions Figure 1a shows the cytogenetic partitions of Y chromosome which consists of a short and long arm designated as Yp and Yq respectively. The euchromatic short arm is designated as Yp11 whereas long arm Yq is cytogenetically divided into a euchromatic proximal region Yq11 and heterochromatic distal region Yq12. The Yq11 band is subdivided into sub-bands Yq11.1, 11.21, 11.22, and 11.23 respectively (Foresta et al. 2001). Y chromosome Deletion Mapping With the advent of Y specific probes began the process of construction of deletion interval maps specific for the Y chromosome (Fig. 1b). Accordingly the Y was delineated into seven major intervals. The interval 1-4 harbors the Yp region and the centromere, distal to proximal. © Kamla-Raj 2011 Int J Hum Genet, 11(4): 203-215 (2011)