Definitive genetic evidence that loci on the long arm of the human Y chromosome are required for the differentiation of germ cells has come from studies using molecular markers (such as sequence-tagged sites) that have been mapped at high density and ordered along the Y chromosome. At least three distinct, non-overlapping intervals, each associated with variable degrees of spermatogenic impairment, have been defined by numerous deletion-mapping studies (Refs 7, 8, 9, 10, 11, and references cited therein). These intervals, named AZFa, AZFb and AZFc for azoospermia factors a, b and c (see Fig. 2; fig002nac), indicate that at least three different loci on the long arm of the Y chromosome are critical for germ-cell differentiation. Similar deletion-analysis studies have defined critical intervals on the mouse Y chromosome. These studies have been reviewed elsewhere (Ref. 12), and have been considered here only if they are relevant to the analysis of the human Y chromosome.

Deletions of the AZFa region (the least common class of deletion) are most frequently associated with azoospermia manifested by Sertoli cell only syndrome (SCOS) and less often with oligozoospermia (Refs 8, 13, 14). SCOS is characterised by the complete absence of germ cells within seminiferous tubules. Two SCOS phenotypes have been described: SCOS I, where none of the tubules in a histological section contains germ cells; and SCOS II, where some of the tubules are devoid of germ cells and others contain reduced numbers (Ref. 8). The SCOS I phenotype is likely to arise from a primary defect in early spermatogenesis, whereas the SCOS II phenotype is believed to develop at a later stage of differentiation as a secondary effect of a primary defect that affects spermatogenesis.

Deletions of the AZFb region are associated with azoospermia, oligozoospermia and normozoospermia (normal spermatogenesis; Refs 8, 9, 15). Azoospermia is accompanied not only by SCOS, but also by the arrest of meiosis and maturation at the spermatocyte and spermatid stages of male germ-cell differentiation.

Deletions of the AZFc interval are associated with azoospermia, severe-to-mild oligozoospermia and the production of insufficient mature sperm to enable reproduction (Refs 8, 16, 17). As for deletions of AZFb, the azoospermia reflects a spectrum of spermatogenic phenotypes from SCOS to meiotic and maturation arrest.

From these genotype–phenotype correlations, it is evident that similar or identical deletions in patients can cause different impairments in spermatogenesis. There could be several explanations for this phenotypic variation. First, it is notoriously difficult to map the Y chromosome because of the accumulation on this chromosome of amplified families of DNA sequences. It is, therefore, difficult to be sure that a marker has only one location on the chromosome. Clearly, this could lead to errors when deletions are scored: what might appear to be similar deletions could, in fact, be different. Second, variation between individuals might reflect the modification of phenotype as a consequence of X–Y mosaicism in the germline, resulting in some germ cells possessing an intact Y chromosome. Such mosaicism might not be present in the lymphocytes that are used to prepare DNA from these patients. Third, variation in phenotype could also reflect the presence, within the genetic background of the individual, of alleles of modifying genes that are able to compensate for the loss of function of Y-chromosome-linked genes.

The Y chromosome has been mapped in considerable detail, using a combination of deletion-mapping studies that define specific intervals, and a series of overlapping yeast artificial chromosome (YAC), P1-derived artificial chromosome (PAC) and bacterial artificial chromosome (BAC) clones that cover the entire active, euchromatic DNA (Refs 18, 19, 20). This has enabled a detailed search for candidate genes within the clones covering the key intervals that are associated with the disease phenotypes. A great deal of effort has been placed on the identification of candidate genes that map to the AZFa, AZFb and AZFc intervals; these mapped genes are considered below in historical order.

Antibodies to RBM show that, in human testes, the protein is localised to the nucleus, confined to germ cells and is present at all stages of spermatogenesis except in elongating spermatids (Ref. 26). The analysis of RBM protein in testicular sections from infertile men indicated a correlation between active protein expression and the presence of the AZFb region, particularly interval 6B on the Y chromosome deletion map (Ref. 26; see Fig. 3; fig003nac). This is an important result because it suggests that the key RBM genes lie in the AZFb interval and that other RBM loci on the human Y chromosome do not encode proteins that are essential for spermatogenesis. In the mouse, Rbmy transcripts were also shown to have a pattern of expression that is specific to germ cells. However, unlike the human gene(s), expression is switched off in pachytene spermatocytes and can be detected in elongating spermatids (Ref. 27).

It is likely that RBMY1 functions as an RNA-binding protein and its location in the nucleus in association with splicing factors (Ref. 28) implies that it might have a role in RNA metabolism, perhaps in RNA processing. Post-transcriptional and post-translational control is important in spermatogenesis (for review, see Ref. 29), especially during post-meiotic stages, where transcriptional activity has almost ceased. RBMY1 is present throughout most of spermatogenesis, indicating that the protein has a role at many stages. However, because AZFb deletions abolish the expression of RBMY1 and cause meiotic arrest, this protein does not appear to be essential for germ cells to reach meiosis but does seem to be necessary for them to pass successfully to the haploid state. In mice, the deletion of Rbmy is associated with maturation defects, indicating that the protein might be essential for the post-meiotic maturation of germ cells and that it could be required for post-transcriptional control (Ref. 27).

Comparative analysis of RBM and related genes in different eutherian mammals and marsupials has revealed details of the evolution of this family of genes (Ref. 30). The original data indicated that the Y-borne genes arose by the translocation of an ancestral, autosomal HnRNP G gene onto the Y chromosome; this was followed by independent amplification events in different species. Two amplification events can be distinguished: (1) an internal amplification of the exon that encodes the SRGY box in humans, giving rise to four tandem repeats; and (2) amplification of the whole gene, leading to the multicopy family. In mice, the Rbm gene on the Y chromosome has been amplied, but not the SRGY box. In some marsupials, it appears that the gene has been amplified on the Y chromosome, but that there is a single copy of the SRGY box. Because different members of the human gene family contain the four, tandem SRGY-box repeats, these findings suggest that the amplification of the SRGY box occurred after the divergence of the human and mouse lineages and before amplification of the gene on the Y chromosome. That RBMY1 genes have an important function is suggested by the fact that they are conserved on the Y chromosome of both eutherian mammals and marsupials. This finding is consistent with these genes having a role in an essential function such as spermatogenesis.

The fact that the RBMY1 genes are a multicopy family makes it difficult to provide direct genetic and functional evidence that they are critical to spermatogenesis. There is strong, indirect evidence to support their involvement in germ-cell differentiation, based primarily on the correlation between the AZFb interval and expression of the gene encoding the RBMY1 protein in germ cells. Figure 3 (fig003nac) shows the region of the Y chromosome in which AZFb deletions have been mapped and the genes that are mapped in this interval. Several questions arise when attempting to correlate genotype to phenotype. How many RBM genes are involved in the critical deletions that abolish RBM protein production? What contribution (if any) do other genes mapped to the AZFb interval make to spermatogenic phenotypes that are associated with this region? What other genes are encompassed by the AZFb interval? Two X–Y homologous genes that are expressed ubiquitously have been mapped to the AZFb region: SMCY, which encodes a protein that has male-specific H-Y antigen epitopes (Ref. 33); and EIF1AY, which encodes a translation initiation factor (Ref. 34). Two other transcripts, TTY2 and PRY, both members of gene families that are amplified on the Y chromosome, have also been assigned to the AZFb interval (Ref. 34). No functional open reading frames are present in TTY2 transcripts; PRY is related to PTP-BL, which encodes a protein tyrosine phosphatase.

How can these questions be resolved? Refined deletion mapping using a larger group of patients is one approach to isolate single genes within critical intervals. Mutation analysis in non-deletion cases of male infertility would provide direct genetic evidence of the role of a gene in an associated phenotype. This is more complex in multicopy gene families because it requires the analysis of all family members. In the case of RBM genes, analysis could be restricted to genes mapping to the critical region that is required for protein expression. Functional analysis using mouse models is another approach, whereby different strategies can be used to inactivate the relevant genes and to observe the phenotypic consequences, or to attempt phenotypic rescue by introducing functional genes into a mouse in which the Rbmy genes have been deleted.

DAZ is expressed specifically in testes (Refs 17, 37) and is closely related to a fertility gene, named boule, in Drosophila (Ref. 38). Mutations that disrupt the function of the boule gene cause azoospermia. Thus, it seems reasonable to expect that DAZ could be involved in the AZFc phenotype(s), although it is not necessarily the only gene. The protein encoded by DAZ is found mainly in post-meiotic germ cells (late spermatids and sperm; Ref. 39) and this might indicate that is has a role in post-transcriptional control during the transcriptionally inactive stages of germ-cell differentiation.

An autosomal homologue of DAZ that contains a single DAZ repeat has been described in both humans and mice, but no DAZ-related sequences have been found on the mouse Y chromosome. The human gene (named DAZLA), which maps to chromosome 3p24, is expressed specifically in the testes and, at lower levels (detectable by RT-PCR), in the ovaries (Refs 35, 40, 41, 42). This observation has prompted the suggestion that the DAZLA gene might be involved in autosomal recessive forms of male infertility. The mouse gene (named Dazla for DAZ like, autosomal) maps to chromosome 17 and is also expressed in male germ cells and the female gonads (Refs 43, 44) but, unlike Rbm, is located in the cytoplasm rather than in the nucleus (Ref. 45). The temporal pattern of Dazla expression indicates that it is present throughout spermatogenesis and, thus, might be critical for all stages of germ-cell differentiation. Reijo and colleagues (Ref. 44) suggested that this might explain the range of phenotypes that is associated with AZFc deletions; however, it is not yet known if the transcript from the human Y chromosome has the same pattern of expression and, thus, it is premature to extrapolate from observations made for the mouse autosomal gene. Disruption of the mouse Dazla gene has provided functional evidence that the gene plays a critical role in the production of both male and female germ cells (Ref. 45). The loss of Dazla function completely abolishes gamete production, demonstrating that it is essential for successful gametogenesis.

As mentioned previously, the DAZ gene family differs from the RBM gene family, in that no DAZ genes have been found on the Y chromosome of mice or any non-primate species studied (Refs 35, 42, 43). Furthermore, there is no evidence of the existence of homologous sequences on the X chromosome in humans and mice. DAZ sequences are relatively recent arrivals to the Y chromosome, having appeared on the non-recombining region of the primate Y chromosome after the divergence of the New World monkeys but before the splitting of the lineage that gave rise to Old World monkeys. It has been suggested that this occurred by direct transposition from the autosomal locus to the non-recombining part of the Y chromosome, and subsequent amplification (Ref. 35). Thus, this amplified gene family has a very different evolutionary history to that of the RBM gene family. Two points are worth noting in relation to this finding. First, Lahn and Page (Ref. 34) have suggested that amplified genes on the Y chromosome were recruited from an autosomal homologue. However, the DAZ and RBM gene families illustrate that this is not the case, and that a second class of Y-chromosome-linked, amplified gene family can arise from an ancestral homologue of the X chromosome. This might also be the case for other Y-linked, amplified gene families. Second, genes that are homologous between the X and Y chromosomes, not just Y-specific genes, must be considered as candidates that might be involved in the regulation of spermatogenesis.

Although the DAZ gene would appear to be involved in the AZFc phenotype, efforts to confirm this are dogged by the same problems that confront a functional analysis of the RBM genes. No discrete mutations have been found in DAZ genes that are associated with infertility, and the existence of a gene family hinders efforts to establish such genetic evidence. The picture becomes even more complex as a consequence of new data showing that the DAZ gene family is not the only one to map to the AZFc region (Ref. 34). A recent map of this region is summarised in Figure 4 (fig004nac), which shows that AZFc deletions occur in at least three other gene families: BPY2 transcripts encode a basic protein of unknown function, PRY is mentioned above, and CDY contains a chromodomain (chromatin-binding domain) and a potential CoA-substrate catalytic domain. Members of the CDY1 gene family might modify chromatin during spermatogenesis. Stuppia and colleagues (Ref. 46) have reported deletions of the AZFc region that cause infertility. These do not involve the deletion of DAZ genes but might remove other genes, such as CDY1 and BPY1. This finding suggests that, in addition to DAZ, other loci in the AZFc interval contribute to fertility, and this might partially explain the diverse phenotypes that are associated with different deletions.

Despite their distinct evolutionary histories, the parallels between RBM and DAZ genes are striking: both genes encode RNA-binding proteins and are likely to be involved in RNA metabolism; both genes have undergone internal amplification of a single repeat motif in primates; both genes have undergone gene amplification to give rise to a Y-linked multicopy family; and, finally, both genes are expressed in a testis-specific manner.

Our present knowledge of the map of the AZFa region is summarised in Figure 5 (fig005nac), which shows the location of key deletion breakpoints in four infertile patients (Ref. 48) and the relationship of this region to homologous regions of the X chromosome. The position of the breakpoints indicates the involvement of the DFFRY and DBY genes in the AZFa phenotype. Of the four patients, one (SAYER) has a milder oligozoospermic phenotype. This patient has a deleted DFFRY gene and a transcriptionally active DBY gene (Ref. 48), whereas both these genes are deleted in the other three, suggesting that the more-severe SCOS phenotype is produced only if both of these genes are deleted. More patients must be studied to investigate this possibility, particularly cases where there is genetic evidence of point mutations affecting both genes. A recent study of 500 infertile men described one case of a deletion of 4 base pairs in the DFFRY gene that affected a splice donor site in intron 7 and led to premature termination of the polypeptide chain (Ref. 54). This patient’s phenotype was similar to that of SAYER, supporting the theory that the DFFRY and DBY genes might act synergistically to enable full fertility. None of the 500 patients studied by Sun and colleagues (Ref. 54) showed evidence of mutations in the DBY gene.

In 1931, Fisher argued that, what he termed, male-benefit genes would accumulate on the Y chromosome (Ref. 59). Where this provided a reproductive advantage to the male, selection would have acted to maintain these genes in a genetically isolated region of the genome, thus favouring the suppression of recombination for most of the length of the Y chromosome and the transmission of an unchanged chromosome in the male line. Such genes are not necessarily concerned exclusively, or directly, with the production of germ cells; they could also encode genetic functions that enhance the reproductive performance of the male, such as size and attractiveness to a mate. Muller and Charlesworth have both argued that the rapid degeneration of genes in the non-recombining region of the Y chromosome follows from the failure to reconstruct defective genes through recombination (Refs 60, 61). Thus, once established, deleterious mutations in genes on the Y chromosome become fixed irreversibly in the male population (known as Muller’s Ratchet) and will accumulate, leading to the degeneration of most of the genes on the Y chromosome. Rice demonstrated this process elegantly in a Drosophila model system in which the removal of a chromosomal segment from the recombination system caused the rapid degeneration of genes contained within it (Ref. 62).

These unique features perhaps partially explain why the genes on the Y chromosome have become amplified. Thus, the selection of multiple copies of a Y-linked gene that is critical for spermatogenesis might be favoured because it increases the amount of the protein product which, owing to the accumulation of deleterious mutations, is produced in insufficient amounts. In contrast, the absence of pairing and recombination for members of an amplified gene family producing an altered gene product might reduce selection against the gene and lead to its retention. Other selective pressures favouring the amplification of genes that are involved in spermatogenesis might also arise from the need to produce large amounts of protein or a combination of variant proteins that act synergistically to ensure efficient gametogenesis.

There are two main clinical implications of this work. First, a description of the genes that cause some cases of infertility provides the basis for diagnosis at the molecular level. Thus, patients can be screened for deletions of the Y chromosome to establish the causative lesion. Second, an understanding of the structure and function of the genes involved in male infertility and with which genes they interact will facilitate the development of potential therapies. Based on an understanding of the biochemical function(s) and pathways with which these genes are involved, it may be possible to develop drugs that permit spermatogenesis to proceed normally.

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