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Uva-DARE (Digital Academic Repository) UvA-DARE (Digital Academic Repository) The DAZ genes and impaired spermatogenesis de Vries, J.W.A. Publication date 2002 Link to publication Citation for published version (APA): de Vries, J. W. A. (2002). The DAZ genes and impaired spermatogenesis. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:29 Sep 2021 Chapterr 3 FOURR DAZ GENES IN TWO CLUSTERS FOUND IN THE AZFC REGION OF THEE HUMAN Y CHROMOSOME Richaa Saxena, Jan W.A. de Vries,* Sjoerd Repping,* Raaji K. Alagappan,, Helen Skaletsky, Laura G. Brown, Peter Ma/ Ellson Chen/ Jann M.N. Hoovers/ and David C. Page1 Howardd Hughes Medical Institute, Whitehead Institute, and Department of Biology,, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, Massachusettss 02142; ^Centerr for Reproductive Medicine, Department of Gynecology and Obstetrics, ^Departmentt of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands; ; 1Celeraa Genomics, Foster City, California 94404 GENOMICSS 67, 256-267 (2000) Chapterr 3 ABSTRACT T Thee DAZ genes are candidate fertility factors that lie within the human Y chromosome'ss AZFc region, whose deletion is a common cause of spermatogenic failure.. The number of DAZ genes has been difficult to determine, in part because thee nucleotide sequences of the DAZ genes are nearly identical. Here, fluorescencee in situ hybridization and characterization of BAC clones revealed fourr full-length DAZ genes on the human Y chromosome. They exist in two clusters,, each comprising an inverted pair of DAZ genes (3' <- 5'::5' -> 3'). Analysiss of genomic sequences and testicular transcripts suggested that three or fourr DAZ genes are translated. Each gene contains at least seven tandem copies of aa previously described, 2.4-kb repeat unit that encodes 24 amino acids. In addition,, two DAZ genes contain tandem copies of a 10.8-kb repeat unit that encodess the RNA binding domain, which appears to be multimerized in some DAZZ proteins. Combiningg our present results with previous studies, we can reconstruct severall steps in the evolution of the DAZ genes on the Y chromosome. In the ancestrall Y-chromosomal DAZ gene, amplification of both intragenic repeats begann before the human and cynomolgus (Old World) monkey lineages diverged. Duringg subsequent evolution, an inverted duplication of this modified gene occurred.. Finally, the resulting two-gene cluster was duplicated, generating the two-cluster/fourr gene arrangement found on modern human Y chromosomes. 34 4 Fourr DAZ genes found INTRODUCTION N Approximatelyy 2% of men are infertile because they produce few or no spermm (1,2). The most common known molecular cause of such spermatogenic failuree is deletion of the AZFc region on the long arm of the human Y chromosomee (3-5). Although one or more spermatogenesis genes must lie within thee AZFc region, the identity of the critical factor(s) is still uncertain because no pointt mutations or internal deletions in candidate genes have been identified. Candidatee genes within this region include DAZ, BPY2, RBMY, and CDY1 (4,6,7,). Thee DAZ {Deleted in Azoospermia) genes, which encode putative RNA- bindingg proteins, are strong AZFc candidates. The DAZ genes are located exclusivelyy within the AZFc region and are transcribed only in testicular germ cellss (4,8,9). In model organisms, genetic studies have demonstrated that DAZ homologss play essential roles in germ cell development (10-12). In mice, disruptionn of the DAZl gene leads to germ cell loss before birth, rendering both maless and females infertile (11). In Drosophila, males mutant for the DAZ homologg boule are infertile with germ cell arrest at the G2/M transition into meiosiss I (10). Thee precise number of DAZ genes in the AZFc region has been difficult to determine.. Initially, only one DAZ gene was thought to exist within the AZFc regionn (4). We later reported that DAZ cosmids derived from a single individual differedd slightly in DNA sequence, providing evidence for at least two distinct DAZDAZ genes (8). Glaser et a/. (13) found evidence of multiple DAZ genes on Yq by fluorescencee in situ hybridization (FISH). By Southern blotting and long-range restrictionn mapping, Yen and colleagues obtained evidence of at least three DAZ geness on the Y chromosome (7,14). Most recently, using fiber-FISH, Glaser et al. (15)) observed what they interpreted to be seven DAZ genes or pseudogenes on Yq. Howw many of the DAZ genes on the Y chromosome are functional? Are somee of them pseudogenes? Genes on Y chromosomes are often subject to Chapterr 3 degenerationn during evolution (16-18). Repetitive gene families on the human Y chromosomee may include both functional and corrupted gene copies. For example,, RBMY is present in at least 10 copies throughout the Y chromosome, but onlyy a few copies appear to be transcribed and functional (19). Similarly, the TSPY genee family on the human Y chromosome consists of a mixture of active and silent genee copies (20). By analogy, one might anticipate that the Y-linked DAZ genes wouldd include some transcriptionally active and some decayed family members. Yenn and colleagues found a variety of DAZ transcripts in single individuals. These findingss raise the possibility that multiple DAZ genes are expressed, but the transcriptss could also have arisen by alternative splicing of a single gene (14). If onlyy one DAZ gene was shown to be expressed, then one might search that gene forr point mutations in men with spermatogenic failure to identify a critical role in spermatogenesis.. If multiple DAZ genes were expressed, it would be less likely thatt spermatogenic failure would be caused by DAZ point mutations. Wee sought to build upon previous studies and to address several questions. Exactlyy how many DAZ genes with an intact genomic structure are present on humann Y chromosomes? How many of these genes are transcribed and translated? Howw are the genes arranged, and how do they differ from each other? What can bee inferred about the pathway by which the DAZ genes evolved on the human Y chromosome? ? MATERIALSS AND METHODS COSMIDS. Wee used three sequenced DAZ cosmids in these studies. Cosmid 18E8 (8) hass an insert of 42,791 bp, corresponding to nucleotides 670 through 43,460 in thee recently sequenced BAC RP11-290O3 (GenBank Accession No. AC010089). 36 6 Fourr DAZ genes found Ass shown in Fig. 1, cosmid 18E8 encompasses the 5' portions of two neighboring DAZDAZ genes. Cosmid 63C9 (8) (GenBank Accession No. AC000021) contains exons 22 through 11 and thus almost an entire DAZ gene. Cosmid 46A6 (8) (GenBank Accessionn No. AC000022) derives from the 3' portion of DAZ; it contains exons 8 throughh 11 as well as 35 kb downstream of the gene. FLUORESCENCEE IN SITU HYBRIDIZATION. Onee or two-color FISH was performed according to standard procedures (21).. Probes were labeled with biotin or digoxigenin, hybridized to target DNA, andd detected by avidin or anti-digoxigenin antibodies conjugated to fluorochromes Cy33 (red) or fluorescein (green). Extendedd chromatin fibers from spermatozoa were prepared as described previouslyy (22) with minor modifications. Sperm were isolated by density centrifugationn on a 70% Percoll gradient, washed twice in phosphate-buffered salinee (PBS), resuspended in a 3:1 mixture of methanol : acetic acid to 107 sperm/ml,, allowed to fix for 1 h at , and dropped onto glass slides. After beingg blow-dried, slides were incubated in extraction solution (0.125% SDS, 0.2 MM NaOH) for 5 min at . The solution was removed, and new extraction solutionn was pipetted onto one end of the slide and smeared out using a coverslip. Thiss procedure was repeated using fixative (3:1 methanol : acetic acid). The slides weree dehydrated and kept at room temperature prior to hybridization. Extendedd chromatin fibers from lymphocytes were prepared using SDS/EDTAA extraction (23). BACs. DAZDAZ BACs were isolated from human male genomic libraries prepared at thee California Institute of Technology (24). We probed high-density library filters (Researchh Genetics) using radiolabeled PCR products corresponding to DAZ STS's. AA total of 16 DAZ BACs were identified. Three BACs (prefixed with CTA) derive Chapterr 3 fromm the DNA of one male donor. The remaining 13 BACs (prefixed with CTB) derivee from a second, unrelated male donor. BAC DNA was isolated using alkaline lysiss and column chromatography (Qiagen) using preheated elution buffer. PULSED-FIELDD GEL ELECTROPHORESIS. DAZDAZ BACs were sized by pulsed-field gel electrophoresis in 1% agarose usingg a Bio-Rad CHEF DRII system. Electrophoresis was performed for 26 h at CC and 1 79 V with ramped switch times of 5 to 20 s. Estimated BAC sizes (includingg vector sequences) were as follows: CTA-50D17, 240 kb; CTA- 132B16, 1222 kb; CTA-148114, 110 kb; CTB-235111, 165 kb; CTB-263M7, 130 kb; CTB- 293A20,, 170 kb; CTB-315F14, 140 kb; CTB-327P21, 130 kb; CTB-352E14, 200 kb;; CTB-374C1, 100 kb; CTB-387E18, 138 kb; CTB-415B11, 160 kb; CTB-482K23, 1755 kb; CTB-492016, 200 kb; CTB-530K16, 150 kb; and CTB-546E5, 135 kb.
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