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Male Infertility and the Y Chromosome

1999; Elsevier BV; Volume: 64; Issue: 4 Linguagem: Inglês

10.1086/302351

1537-6605

Ken McElreavey, Csilla Krausz,

Sperm and Testicular Function

Although it has been established since the 1970s that deletions of the long arm of the Y chromosome are associated with spermatogenic failure, only in the last few years have these regions been described at the molecular level. In parallel, Y-linked genes and gene families that may explain the phenotypes of men carrying these deletions have been identified. The first association between spermatogenic failure and an underlying genetic cause was demonstrated by Tiepolo and Zuffardi (Tiepolo and Zuffardi, 1976Tiepolo L Zuffardi O Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm.Hum Genet. 1976; 34: 119-124Crossref PubMed Scopus (800) Google Scholar) in a report of six azoospermic patients carrying microscopically detectable deletions of the distal portion of Yq. In four patients, the deletion was de novo—that is, their fathers were tested and were found to carry intact Y chromosomes. On this basis, Tiepolo and Zuffardi (Tiepolo and Zuffardi, 1976Tiepolo L Zuffardi O Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm.Hum Genet. 1976; 34: 119-124Crossref PubMed Scopus (800) Google Scholar) proposed the existence of a spermatogenesis factor, called the "azoospermia factor" (AZF), encoded by a gene on distal Yq. However, the assumption that AZF represented a single Y-linked gene was overturned when Vogt et al. (Vogt et al., 1996Vogt PH Edelmann A Kirsch S Henegariu O Hirschmann P Kiesewetter F Kohn FM et al.Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11.Hum Mol Genet. 1996; 5: 933-943Crossref PubMed Scopus (1058) Google Scholar) observed that Y chromosome microdeletions follow a certain deletion pattern, with three recurrently deleted nonoverlapping subregions in proximal, middle, and distal Yq11, designated "AZFa," "AZFb," and "AZFc," respectively. In addition, it became clear that these deletions were not exclusively associated with azoospermia (Reijo et al. Reijo et al., 1996aReijo R Alagappan RK Patrizio P Page D Severe oligospermia resulting from deletions of azoospermia factor gene on Y chromosome.Lancet. 1996a; 347: 1290-1293Abstract PubMed Scopus (397) Google Scholar). Deletions are associated with a wide range of histological profiles, from Sertoli cell–only syndrome (SCOS) to spermatogenic arrest (SGA) and severe hypospermatogenesis. The physical size of these regions has been estimated to be 1–3 Mb for AZFa and AZFb and ∼1.4 Mb for AZFc. Recent studies have shown that ∼10%–15% of azoospermic and ∼5%-10% of severely oligozoospermic men have Yq microdeletions. However, despite these advances, there are still many unanswered questions, which are the subject of this review. Several combined clinical and molecular studies have sought (1) to define recurrently deleted regions of Yq, (2) to determine the incidence of microdeletions among azoospermic and oligozoospermic men, and (3) to correlate the size and position of the deletions that cause the infertile phenotype. The reported incidence of microdeletions in infertile men varies enormously between studies, within the range 1%–55% (Reijo et al. Reijo et al., 1995Reijo R Lee TY Salo P Alagappan R Brown LG Rosenberg M Rozen S et al.Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene.Nat Genet. 1995; 10: 383-393Crossref PubMed Scopus (1070) Google Scholar; Quereshi et al. Quereshi et al., 1996Quereshi SJ Ross AR Ma K Cooke HJ Intyre MAM Chandley AC Hargreave TB PCR screening for Y chromosome microdeletions: a first step towards the diagnosis of genetically determined spermatogenic failure in men.Mol Hum Reprod. 1996; 2: 775-779Crossref PubMed Scopus (155) Google Scholar; Stuppia et al. Stuppia et al., 1996Stuppia L Mastroprimiano G Calabrese G Peila R Tenaglia R Palka G Microdeletions in interval 6 of the Y chromosome detected by STS-PCR in 6 of 33 patients with idiopathic oligo- and azoospermia.Cytogenet Cell Genet. 1996; 72: 155-158Crossref PubMed Scopus (106) Google Scholar, Stuppia et al., 1997Stuppia L Gatta V Mastroprimiano G Pompetti F Calabrese G Guanciali Franchi P Morizio E et al.Clustering of Y chromosome deletions in subinterval E of interval 6 supports the existence of an oligozoospermia critical region outside the DAZ gene.J Med Genet. 1997; 34: 881-883Crossref PubMed Scopus (31) Google Scholar; Foresta et al. Foresta et al., 1997Foresta C Ferlin A Garolla A Rossato M Barbaux S Bortoli A Y-chromosome deletions in idiopathic severe testiculopathies.J Clin Endocrinol Metab. 1997; 82: 1075-1080Crossref PubMed Scopus (145) Google Scholar, Foresta et al., 1998Foresta C Ferlin A Garolla A Moro E Pistorello M Barbaux S Rossato M High frequency of well-defined Y-chromosome deletions in idiopathic Sertoli cell-only syndrome.Hum Reprod. 1998; 13: 302-307Crossref PubMed Scopus (195) Google Scholar; Pryor et al. Pryor et al., 1997Pryor JL Kent-First M Muallem A Van Bergen AH Nolten WE Meisner L Roberts KP Microdeletions in the Y chromosome of infertile men.N Engl J Med. 1997; 336: 534-539Crossref PubMed Scopus (452) Google Scholar; Simoni et al. Simoni et al., 1997Simoni M Gromoll J Dworniczak B Rolf C Abshagen K Kamischke A Carani C et al.Screening for deletions of the Y chromosome involving the DAZ (deleted in azoospermia) gene in azoospermia and severe oligozoospermia.Fertil Steril. 1997; 67: 542-547Abstract Full Text PDF PubMed Scopus (196) Google Scholar; Van der Vent et al. Van der Vent et al., 1997Van der Vent K Montag M Peshka B Leygraaf J Schwanitz G Haidl G Krebs D et al.Combined cytogenetic and Y chromosome microdeletion screening in males undergoing intracytoplasmic sperm injection.Mol Hum Reprod. 1997; 3: 699-704Crossref PubMed Scopus (137) Google Scholar), but study design probably accounts for much of this variation. Study populations have included azoospermic patients, azoospermic and oligozoospermic patients, or azoospermic/oligozoospermic and infertile normospermic patients. Most clinical studies "select" individuals with idiopathic azoospermia or oligozoospermia, although others include "unselected" infertile men with known or unknown causes of infertility. Unfortunately, however, there is no general agreement on what constitutes idiopathic infertility. Varicocele and history of cryptorchidism are considered idiopathic in some studies and nonidiopathic in others. Variation in reported deletion frequency also seems to be affected by the number of patients in the study; in general, studies with low patient numbers report a higher deletion frequency, perhaps because these studies select patients more stringently. Another variable that may also affect Yq deletion frequency is marker density or the position of markers. Despite these caveats, it is possible that differences in deletion frequency and/or localization, between studies, may reflect genuine geographic or ethnic differences, perhaps related to a particular Y chromosome haplogroup, the genetic background, or environmental influences. Vogt et al. (Vogt et al., 1996Vogt PH Edelmann A Kirsch S Henegariu O Hirschmann P Kiesewetter F Kohn FM et al.Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11.Hum Mol Genet. 1996; 5: 933-943Crossref PubMed Scopus (1058) Google Scholar) originally proposed that AZFa deletions result in type I SCOS, in which no spermatogonia develop, whereas deletions in AZFb cause SGA, usually at the spermatocyte stage, and deletions in AZFc are associated with a more variable phenotype, ranging from type II SCOS (absence of germ cells in most testis tubules) to hypospermatogenesis (presence of all germ-cell types, albeit in reduced numbers). In general, subsequent studies have supported these findings, but there have been exceptions: both AZFa and AZFb deletions have been reported in oligozoospermic men, and we have found oligozoospermia associated with AZFb deletions (authors' unpublished data). Another problem in the definition of genotype/phenotype correlations is the variability of the phenotype in the same man, over time. In one study, an individual with an AZFc deletion showed a progressive decrease in sperm concentration, from severe oligozoospermia to azoospermia, over 30 mo (Girardi et al. Girardi et al., 1997Girardi SK Mielnik A Schlegel PN Submicroscopic deletions in the Y chromosome of infertile men.Hum Reprod. 1997; 12: 1635-1641Crossref PubMed Scopus (171) Google Scholar). Nevertheless, some patterns have emerged from a survey of the clinical literature on these deletions. First, microdeletions are found almost exclusively in males affected by azoospermia or severe oligozoospermia or, occasionally, in patients with other abnormal andrological findings. Second, a higher frequency of Yq deletions is found in azoospermic men, compared with oligozoospermic men, and in men with well-defined idiopathic infertility, compared with men for whom the etiology of the infertility is known. Third, large deletions generally are associated with more-severe spermatogenic defects. Finally, AZFa deletions, which are relatively uncommon (frequency of 1%–5%), generally are associated with SCOS type I, whereas AZFc and AZFc+AZFb deletions, the most frequent form of these lesions, may be associated with a variety of spermatogenesis defects, including oligozoospermia. The relatively high frequency of de novo Y deletions indicates that the Y chromosome is susceptible to the spontaneous loss of genetic material. The instability of the Y chromosome may be related to the high frequency of repetitive elements clustered along the length of the chromosome, and deletions may occur through aberrant recombination events (between areas of homologous or similar sequence repeats, between the X and Y chromosomes, or by Y chromosome unbalanced sister-chromatid exchange) or by slippage during DNA replication. There also may be particular Y chromosome sequences that promote deletion of the AZF regions; consequently, some individuals may be more susceptible to de novo deletions than are others. Indeed, Jobling et al. (Jobling et al., 1998Jobling MA Williams G Schiebel K Pandya A McElreavey K Salas L Rappold GA et al.A selective difference between human Y-chromosomal DNA haplotypes.Curr Biol. 1998; 8: 1391-1394Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar) defined one Y chromosome haplotype that is susceptible to aberrant X/Y exchange during male meiosis, leading to Y-positive 46,XX maleness and infertility. Advanced paternal age also might promote the loss of Y sequences, although this hypothesis needs to be examined by correlation of deletion incidence with the age of the father at conception. Paternal age effects have been described in Marfan syndrome, neurofibromatosis, and Apert syndrome. However, in most of these cases, the mutations are 1-bp substitutions, rather than deletions. Several genes and gene families have been identified on the long arm of the Y chromosome (Lahn and Page Lahn and Page, 1997Lahn BT Page D Functional coherence of the human Y chromosome.Science. 1997; 278: 675-680Crossref PubMed Scopus (686) Google Scholar; also see Lau Lau, 1999Lau Y-FC Gonadoblastoma, testicular and prostate cancers, and the TSPY gene.Am J Hum Genet. 1999; 64 (in this issue): 921-927Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar [in this issue]). Some of these genes fall within AZF deletion intervals and therefore may underlie the observed deletion phenotypes (tables 1 and 2). These genes can be divided into those that may be involved in cellular "housekeeping" activities and those that are expressed solely in the testis. The former group (table 1) includes Drosophila fats facets related Y (DFFRY), dead box Y (DBY), ubiquitous tetratricopeptide repeat (TPR) motif Y (UTY), the eukaryotic translation-initiation–factor 1A Y isoform (eIF-1AY), selected mouse cDNA on the Y (SMCY), and the thymosin β4 Y isoform (Tβ4Y). These ubiquitously expressed genes each exist in a single copy on the Y chromosome, and each possesses a closely related X-linked homologue that escapes X inactivation. The testis-specific group (table 2) includes the RNA-binding–motif Y chromosome gene (RBMY) and its relatives, deleted in azoospermia (DAZ), chromodomain Y (CDY), XK-related Y (XKRY), protein-tyrosine phosphatase BAS-like (PTP-BL)–related Y (PRY), and the genes for basic proteins Y1 and Y2 (BPY1 and BPY2). These genes are present in multiple copies on the Y and do not appear to have X homologues.Table 1Ubiquitously Expressed Housekeeping Genes That Map to AZF-Deleted Regions and That Have Been Implicated in Male InfertilityGene SymbolGene NameComment(s)X-Linked HomologueAmino Acid Identity (%)DFFRYDrosophila fats facets related YHomologous to Drosophila deubiquinating enzyme (Brown et al. Brown et al., 1998Brown GM Furlong RA Sargent CA Erickson RP Longepied G Mitchell M Jones MH et al.Characterisation of the coding sequence and fine mapping of the human DFFRY gene and comparative expression analysis and mapping to the Sxrb interval of the mouse Y chromosome of the Dffry gene.Hum Mol Genet. 1998; 7: 97-107Crossref PubMed Scopus (182) Google Scholar)DFFRX91DBYDead box YContains a DEAD (amino acid sequence Asp-Glu-Ala-Asp) box motif; may function as an RNA helicase (Linder et al. Linder et al., 1989Linder P Lasko PF Ashburner M Leroy P Nielsen PJ Nishi K Schnier J et al.Birth of the D-E-A-D box.Nature. 1989; 337: 121-122Crossref PubMed Scopus (598) Google Scholar)DBX91Tβ4YThymosin β4 YMay be involved in actin sequestration (Gondo et al. Gondo et al., 1987Gondo H Kudo J White JW Barr C Selvanayagam P Saunders GF Differential expression of the human thymosin-beta 4 gene in lymphocytes, macrophages, and granulocytes.J Immunol. 1987; 139: 3840-3848PubMed Google Scholar)Tβ4X93UTYUbiquitous TPR motif YContains 10 tandem TPR motifs that may be involved in protein-protein interactions (Greenfield et al. Greenfield et al., 1996Greenfield A Scott D Pennisi D An H-YDb epitope is encoded by a novel mouse Y chromosome gene.Nat Genet. 1996; 14: 474-478Crossref PubMed Scopus (158) Google Scholar)UTX85SMCYSelected mouse cDNA on the YEncodes an H-Y antigen epitope (Agulnik et al. Agulnik et al., 1994aAgulnik AI Mitchell MJ Lerner JL Woods DR Bishop CE A mouse Y chromosome gene encoded by a region essential for spermatogenesis and expression of male-specific histocompatibility antigens.Hum Mol Genet. 1994a; 3: 873-878Crossref PubMed Scopus (115) Google Scholar,Agulnik et al., 1994bAgulnik AI Mitchell MJ Mattei MG Borsani G Avner PA Lerner JL Bishop CE A novel X gene with a widely transcribed Y homologue escapes X inactivation in mouse and human.Hum Mol Genet. 1994b; 3: 879-884Crossref PubMed Scopus (152) Google Scholar)SMCX84eIF-1AYEukaryotic translation-initiation–factor 1AEukaryotic translation-intiation factor (Pestova et al. Pestova et al., 1998Pestova TV Borukhov SI Hellen CTU Eukaryotic ribosomes require initiation factors 1 and 1A to locate initiation codons.Nature. 1998; 394: 854-859Crossref PubMed Scopus (304) Google Scholar).eIF1-1AX98Note.—These genes are present in a single copy on the Y, but they all have X homologues that escape X inactivation. In all cases, the degree of sequence identity between the X and Y homologues is ≥84%. Open table in a new tab Table 2Genes and Gene Families with Expression Restricted to the Testis and That Map to the AZF-Deleted Regions of the Y chromosomeGene SymbolGene NameComment(s)X-Linked or Autosomal HomologueRBMYRNA-binding–motif YSubfamilies include RBMY1 and RBMY2; RBMY1 may be functional and is predicted to bind RNARBMY may be an ancestral hnRNPG geneDAZDeleted in azoospermiaPredicted to bind RNA, as Xenopus Dazl does in vitroDAZL1 chromosome 3p25XKRYXK-related YSimilar to XK, a putative membrane-transport protein (Ho et al. Ho et al., 1994Ho M Chelly J Carter N Danek A Crocker P Monaco AP Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein.Cell. 1994; 77: 869-880Abstract Full Text PDF PubMed Scopus (220) Google Scholar)None knownCDYChromodomain YContains chromodomain (James and Elgin James and Elgin, 1986James TC Elgin SC Identification of a nonhistone chromosomal protein associated with heterochromatin in Drosophila melanogaster and its gene.Mol Cell Biol. 1986; 6: 3862-3872Crossref PubMed Scopus (462) Google Scholar); may be involved in chromatid modification during spermatogenesisNone knownPRYPTP-BL–related YSimilar to PTP-BL, a putative membrane-transport protein (Hendriks et al. Hendriks et al., 1995Hendriks W Schepens J Bachner D Rijss J Zeeuwen P Zechner U Hameister H et al.Molecular cloning of a mouse epithelial protein-tyrosin phosphatase with similarities to submembranous proteins.J Cell Biochem. 1995; 59: 418-430Crossref PubMed Scopus (47) Google Scholar)None knownBPY1Basic protein Y1Basic protein of unknown functionNone knownBPY2Basic protein Y2Basic protein of unknown functionNone knownNote.—Table modified from the report by Lahn and Page (Lahn and Page, 1997Lahn BT Page D Functional coherence of the human Y chromosome.Science. 1997; 278: 675-680Crossref PubMed Scopus (686) Google Scholar). Open table in a new tab Note.— These genes are present in a single copy on the Y, but they all have X homologues that escape X inactivation. In all cases, the degree of sequence identity between the X and Y homologues is ≥84%. Note.— Table modified from the report by Lahn and Page (Lahn and Page, 1997Lahn BT Page D Functional coherence of the human Y chromosome.Science. 1997; 278: 675-680Crossref PubMed Scopus (686) Google Scholar). DFFRY, DBY, and UTY all fall within the AZFa deletion interval; therefore, one or more of these genes may be implicated in SCOS or other male-fertility disorders. AZFb includes copies of CDY and XKRY, as well as of SMCY, eIF-1AY, and RBMY. Although sequences related to RBMY are found throughout the Y chromosome, functional copies appear to be restricted to AZFb, since deletions of distal AZFb lead to the absence of RBMY epitopes in testicular sections (Elliott et al. Elliott et al., 1997Elliott DJ Millar MR Oghene K Ross A Kiesewetter F Pryor J McIntyre M et al.Expression of RBM in the nuclei of human germ cells is dependent on a critical region of the Y chromosome long arm.Proc Natl Acad Sci USA. 1997; 94: 3848-3853Crossref PubMed Scopus (228) Google Scholar). A number of transcripts are found within AZFc. At least six copies of DAZ are found in this region (Saxena et al. Saxena et al., 1996Saxena R Brown LG Hawkins T Alagappan RK Skaletsky H Reeve MP Reijo R et al.The DAZ gene cluster on the human Y chromosome arose from an autosomal gene that was transposed, repeatedly amplified and pruned.Nat Genet. 1996; 14: 292-299Crossref PubMed Scopus (373) Google Scholar; Yen et al. Yen et al., 1997Yen PH Chai NN Salido EC The human DAZ genes, a putative male infertility factor on the Y chromosome, are highly polymorphic in the DAZ repeat regions.Mamm Genome. 1997; 8: 756-759Crossref PubMed Scopus (73) Google Scholar), as are multiple copies of PRY, BPY2, CDY, and XKRY. Any of these genes may contribute to the AZFc-deletion phenotype, and most AZFc deletions probably remove all these genes. Individuals with AZFc deletions can present with oligozoospermia, and some even father children; hence, it is clear that these genes are not essential for spermatogenesis. At present, we know very little about the biochemistry or biology of Y-encoded proteins. Only RBMY and DAZ have been studied extensively. More than 30 RBMY genes and pseudogenes occur over both arms of the Y chromosome (Ma et al. Ma et al., 1993Ma K Inglis JD Sharkey A Bickmore WA Hill RE Prosser EJ Speed RM et al.A Y chromosome gene family with RNA-binding protein homology: candidates for the azoospermia factor AZF controlling spermatogenesis.Cell. 1993; 75: 1287-1295Abstract Full Text PDF PubMed Scopus (478) Google Scholar; Prosser et al. Prosser et al., 1996Prosser J Inglis JD Condie A Ma K Kerr S Thakrar R Taylor K et al.Degeneracy in human multi-copy RBM (YRRM), a candidate spermatogenesis gene.Mamm Genome. 1996; 7: 835-842Crossref PubMed Scopus (50) Google Scholar; Chai et al. Chai et al., 1997Chai NN Salido EC Yen PH Multiple functional copies of the RBM gene family, a spermatogenesis candidate on the human Y chromosome.Genomics. 1997; 45: 355-361Crossref PubMed Scopus (78) Google Scholar), and these sequences can be divided into several subfamilies. The RBMY1 subfamily has at least seven members, all of which appear to be clustered in the AZFb region (Prosser et al. Prosser et al., 1996Prosser J Inglis JD Condie A Ma K Kerr S Thakrar R Taylor K et al.Degeneracy in human multi-copy RBM (YRRM), a candidate spermatogenesis gene.Mamm Genome. 1996; 7: 835-842Crossref PubMed Scopus (50) Google Scholar; Chai et al. Chai et al., 1997Chai NN Salido EC Yen PH Multiple functional copies of the RBM gene family, a spermatogenesis candidate on the human Y chromosome.Genomics. 1997; 45: 355-361Crossref PubMed Scopus (78) Google Scholar, Chai et al., 1998Chai NN Zhou H Hernandez J Najmabadi H Bhasin S Yen PH Structure and organization of the RBMY genes on the human Y chromosome: transposition and amplification of an ancestral autosomal hnRNPG gene.Genomics. 1998; 49: 283-289Crossref PubMed Scopus (48) Google Scholar). These genes encode germ-cell specific nuclear proteins that contain an RNA-binding motif (RBM), as well as four copies of an SRGY (Serine-Arginine-Glycine-Tryosine motif) repeat. RBMY2 genes share 88% homology with RBMY1 genes and encode an RBM and a single SRGY repeat. The RBMY1 sequence is 67% similar to the autosomally expressed hnRNPG (ribonucleoprotein G) protein, a nuclear glycoprotein with RNA-binding activities but with no known biological function (Soulard et al. Soulard et al., 1993Soulard M Valle VD Siomi M Pinol-Roma S Codogno P Bauvy C Bellini M et al.hnRNPG: sequence and characterization of a glycosylated RNA-binding protein.Nucleic Acids Res. 1993; 21: 4210-4217Crossref PubMed Scopus (132) Google Scholar). RBMY1 genes may derive from an hnRNPG gene that translocated to the Y chromosome and subsequently was amplified (Delbridge et al. Delbridge et al., 1997Delbridge ML Harry JL Toder R O'Neill RJ Ma K Chandley AC Graves JA A human candidate spermatogenesis gene, RBM1, is conserved and amplified on the marsupial Y chromosome.Nat Genet. 1997; 15: 131-136Crossref PubMed Scopus (97) Google Scholar). In humans, RBMY1 can be detected by immunostaining of pachytene spermatocytes, an interesting observation in view of the SGA often seen in association with AZFb deletions (Elliott et al. Elliott et al., 1997Elliott DJ Millar MR Oghene K Ross A Kiesewetter F Pryor J McIntyre M et al.Expression of RBM in the nuclei of human germ cells is dependent on a critical region of the Y chromosome long arm.Proc Natl Acad Sci USA. 1997; 94: 3848-3853Crossref PubMed Scopus (228) Google Scholar, Elliott et al., 1998Elliott DJ Oghene K Makarov G Makarova Hargreave TB Chandley AC Eperon IC et al.Dynamic changes in the subnuclear organisation of pre-mRNA splicing proteins and RBM during germ cell development.J Cell Sci. 1998; 111: 1255-1265PubMed Google Scholar). In spermatocytes, RBMY1 colocalizes with pre–mRNA-splicing components in a discrete area of the nucleus, but, by late meiosis, it is found diffusely throughout the nucleoplasm of round spermatids. Hence, RBMY1 may play distinct roles during different phases of spermatogenesis. Like RBMY, DAZ encodes a testis-specific protein that has a single RBM and a series of 8–24 copies of a 24–amino-acid unit termed the "DAZ repeat" (Reijo et al. Reijo et al., 1995Reijo R Lee TY Salo P Alagappan R Brown LG Rosenberg M Rozen S et al.Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene.Nat Genet. 1995; 10: 383-393Crossref PubMed Scopus (1070) Google Scholar; Yen et al. Yen et al., 1997Yen PH Chai NN Salido EC The human DAZ genes, a putative male infertility factor on the Y chromosome, are highly polymorphic in the DAZ repeat regions.Mamm Genome. 1997; 8: 756-759Crossref PubMed Scopus (73) Google Scholar). The biological function of this motif is unknown, and DAZ genes differ substantially in the sequence and organization of these repeats (Yen et al. Yen et al., 1997Yen PH Chai NN Salido EC The human DAZ genes, a putative male infertility factor on the Y chromosome, are highly polymorphic in the DAZ repeat regions.Mamm Genome. 1997; 8: 756-759Crossref PubMed Scopus (73) Google Scholar). DAZ is homologous to an autosomal gene with a single DAZ repeat, named "DAZL1" (DAZ-like autosomal 1; Saxena et al. Saxena et al., 1996Saxena R Brown LG Hawkins T Alagappan RK Skaletsky H Reeve MP Reijo R et al.The DAZ gene cluster on the human Y chromosome arose from an autosomal gene that was transposed, repeatedly amplified and pruned.Nat Genet. 1996; 14: 292-299Crossref PubMed Scopus (373) Google Scholar; Yen et al. Yen et al., 1996Yen PH Chai NN Salido EC The human autosomal gene DAZLA: testis specificity and a candidate for male infertility.Hum Mol Genet. 1996; 5: 2011-2013Crossref Scopus (136) Google Scholar), and the Y-linked DAZ probably originated from the translocation and amplification of this ancestral autosomal gene. Mice lack the Y-located DAZ gene, but they do carry a single autosomal Dazl1 gene (Cooke et al. Cooke et al., 1996Cooke HJ Lee M Kerr S Ruggiu M A murine homologue of the human DAZ gene is autosomal and expressed only in male and female gonads.Hum Mol Genet. 1996; 5: 513-516Crossref PubMed Scopus (192) Google Scholar; Reijo et al. Reijo et al., 1996bReijo R Seligman J Dinulos MB Jaffe T Brown LG Disteche CM Page DC Mouse autosomal homolog of DAZ, a candidate male sterility gene in humans is expressed in male germ cells before and after puberty.Genomics. 1996b; 35: 346-352Crossref PubMed Scopus (125) Google Scholar). Immunostaining has revealed human DAZ in the innermost layer of male germ-cell epithelium and in the tails of spermatozoa (Habermann et al. Habermann et al., 1998Habermann B Mi HF Edelmann A Bohring C Backert IT Kiesewetter F Aumuller G et al.DAZ (deleted in azoospermia) genes encode proteins located in human late spermatids and in sperm tails.Hum Reprod. 1998; 13: 363-369Crossref PubMed Scopus (108) Google Scholar). This observation is consistent with the expression of DAZ transcripts just inside the perimeter of seminiferous tubules in spermatogonia (Menke et al. Menke et al., 1997Menke DB Mutter GL Page DC Expression of DAZ, an azoospermia factor candidate, in human spermatogonia.Am J Hum Genet. 1997; 60: 237-241PubMed Google Scholar). However, some caution must be used when these results are interpreted, since cross-hybridization with DAZL mRNA or protein cannot be excluded. Insights into human DAZ function may come from the analysis of its autosomal homologues in other species. Targeted disruption of Dazl1 in mice leads to a complete absence of gamete production in both testis and ovary, demonstrating that Dazl1 is essential for the development or survival of germ cells (Ruggiu et al. Ruggiu et al., 1997Ruggiu M Speed R Taggart M McKay SJ Kilanowski F Saunders P Dorin J et al.The mouse Dazla gene encodes a cytoplasmic protein essential for gametogenesis.Nature. 1997; 389: 73-77Crossref PubMed Scopus (499) Google Scholar). In Drosophila, mutation of the boule gene, another homologue of DAZL, results in spermatocyte arrest at the G2/M transition and complete azoospermia (Castrillon et al. Castrillon et al., 1993Castrillon DH Gönczy P Alexander S Rawson R Eberhart CG Viswanathan S Dinardo S et al.Toward a molecular genetic analysis of spermatogenesis in Drosophila melanogaster: characterization of male-sterile mutants generated by single P element mutagenesis.Genetics. 1993; 135: 489-505Crossref PubMed Google Scholar; Eberhart et al. Eberhart et al., 1996Eberhart CG Maines JZ Wasserman SA Meiotic cell requirement for a fly homologue of human deleted in azoospermia.Nature. 1996; 381: 783-785Crossref PubMed Scopus (335) Google Scholar). The boule protein occurs in the nucleus of primary spermatocytes until the end of the meiotic prophase, after which it is found in the cytoplasm. In Xenopus, Xdazl is expressed in premeiotic germ cells in adult testis (Houston et al. Houston et al., 1998Houston DW Zhang J Maines JZ Wasserman SA King ML A Xenopus DAZ-like gene encodes an RNA component of germ plasm and is a functional homologue of Drosophila boule.Development. 1998; 125: 171-180PubMed Google Scholar). Interestingly, the Xenopus Xdazl gene can rescue meiotic entry of spermatocytes in Drosophila boule mutants, suggesting functional conservation of the DAZ family over evolutionary time (Houston et al. Houston et al., 1998Houston DW Zhang J Maines JZ Wasserman SA King ML A Xenopus DAZ-like gene encodes an RNA component of germ plasm and is a functional homologue of Drosophila boule.Development. 1998; 125: 171-180PubMed Google Scholar). Xdazl protein has RNA-binding properties in vitro, and perhaps other members of the DAZ family play a role in RNA metabolism during gamete development (Houston et al. Houston et al., 1998Houston DW Zhang J Maines JZ Wasserman SA King ML A Xenopus DAZ-like gene encodes an RNA component of germ plasm and is a functional homologue of Drosophila boule.Development. 1998; 125: 171-180PubMed Google Scholar). Other genes on the long arm of the Y also may be involved in RNA metabolism. DBY is predicted to act as an RNA helicase (Lahn and Page Lahn and Page, 1997Lahn BT Page D Functional coherence of the human Y chromosome.Science. 1997; 278: 675-680Crossref PubMed Scopus (686) Google Scholar), and eIF-1AY encodes an essential translation-initiation factor (Pestova et al. Pestova et al., 1998Pestova TV Borukhov SI Hellen CTU Eukaryotic ribosomes require initiation factors 1 and 1A to locate initiation codons.Nature. 1998; 394: 854-859Crossref PubMed Scopus (304) Google Scholar). During the latter stages of spermatogenesis, transcription terminates and posttranscriptional regulation plays a primary role (see reviews by Braun [Braun, 1998Braun RE Post-transcriptional control of gene expression during spermatogenesis.Semin Cell Dev Biol. 1998; 9: 483-489Crossref PubMed Scopus (126) Google Scholar] and Hecht [Hecht, 1998Hecht NB Molecular mechanism of male germ cell differentiation.Bioessays. 1998; 20: 555-561Crossref PubMed Scopus (369) Google Scholar]). RNA synthesis peaks during the spermatocyte stage, is gradually reduced in subsequent stages, and ceases as round spermatids differentiate into elongated spermatids. Numerous mRNA that are under posttranslational control during spermatogenesis have been identified. It is tempting to speculate that many of the factors encoded by Y-linked genes play key roles in this process. This work was supported by the Institut National de la Santé et de la Recherche Médicale and by the Association pour la Recherche sur la Cancer.