DOCSLIB.ORG

Loss of Sequences 3' to the Testis-Determining Gene, SRY, Including the Y Pseudoautosomal Boundary Associated with Partial Testicular Determination K

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Loss of Sequences 3' to the Testis-Determining Gene, SRY, Including the Y Pseudoautosomal Boundary Associated with Partial Testicular Determination K Proc. Natl. Acad. Sci. USA Vol. 93, pp. 8590-8594, August 1996 Medical Sciences Loss of sequences 3' to the testis-determining gene, SRY, including the Y pseudoautosomal boundary associated with partial testicular determination K. MCELREAVEY*t, E. VILAIN*, S. BARBAUX*, J. S. FUQUAt, P. Y. FECHNERt, N. SOULEYREAU*, M. Doco-FENZY§, R. GABRIEL§, C. QUEREUX§, M. FELLOUS*, AND G. D. BERKOVITZt *Immunogenetique Humaine, Institut Pasteur, 75724 Paris, Cedex 15, France; tDivision of Pediatric Endocrinology, The Johns Hopkins University School of Medicine, 600 North Wolf Street, Baltimore, MD 21205-3311; and §H6pital Maison Blanche, 45 Rue Cognacq-Jay, 51092 Reims, France Communicated by Jean Dausset, Human Polymorphism Study Center, Paris, France, May 1, 1996 (received for review February 8, 1996) ABSTRACT The condition termed 46,XY complete go- In the first 5 weeks of gestation, the human fetus develops nadal dysgenesis is characterized by a completely female various bipotential and neutral sex structures, such as the phenotype and streak gonads. In contrast, subjects with 46,XY bipotential gonads, neutral external genitalia, and paired partial gonadal dysgenesis and those with embryonic testic- internal sex ducts. In the presence of SRY the bipotential ular regression sequence usually present ambiguous genitalia gonads become testes and male sex differentiation occurs. In and a mix of Mullerian and Wolffian structures. In 46,XY 46,XX individuals, in the absence of SRY, the fetal gonads partial gonadal dysgenesis gonadal histology shows evidence develop as ovaries. In rare individuals with a 46,XY karyotype, of incomplete testis determination. In 46,XY embryonic tes- there may be an abnormality in testis determination or in the ticular regression sequence there is lack of gonadal tissue on early steps of testis differentiation. The conditions that result both sides. Various lines of evidence suggest that embryonic are referred to as 46,XY gonadal dysgenesis and are further testicular regression sequence is a variant form of 46,XY classified as 46,XY complete (or pure) gonadal dysgenesis, gonadal dysgenesis. The sex-determining region Y chromo- 46,XY partial gonadal dysgenesis, and embryonic testicular some gene (SRY) encodes sequences for the testis-determining regression sequence (6-8). factor. To date germ-line mutations in SRYhave been reported The 46,XY complete gonadal dysgenesis is characterized by in "20%v of subjects with 46,XY complete gonadal dysgenesis. female external genitalia and well-developed Mullerian struc- However no germ-line mutations ofSRY have tures. The gonad consists of fibrous ovarian-like stroma with been reported in no evidence of testicular differentiation. The 46,XY partial subjects with the partial forms. We studied 20 subjects who gonadal dysgenesis is characterized by partial testis determi- presented either 46,XY partial gonadal dysgenesis or 46,XY nation in an individual with a normal XY karyotype. Partially embryonic testicular regression sequence. We examined the developed internal ducts usually consist of a mixture of Wolf- SRY gene and the minimum region of Y-specific DNA known fian (epididymus, vas deferens, and seminal vesicle) and to confer a male phenotype. The SRY-open reading frame Mullerian ducts (fallopian tube, uterus, and upper third of the (ORF) was normal in all subjects. However a de novo inter- vagina). Affected individuals exhibit varying degrees of mas- stitial deletion 3' to the SRY-ORF was found in one subject. culinization of the external genitalia. Embryonic testicular Although it is possible that the deletion was unrelated to the regression sequence can also be regarded as part of the clinical subject's phenotype, we propose that the deletion was respon- spectrum of 46,XY gonadal dysgenesis. Gonad tissue is absent sible for the abnormal gonadal development by diminishing on one or both sides. Affected individuals have a 46,XY expression ofSRY. We suggest that the deletion resulted either karyotype and usually present a mix of Wolffian and Mullerian in the loss of sequences necessary for normal SRY expression tissue and ambiguous genitalia. Various evidence supports the or in a position effect that altered SRY expression. This case claim that the embryonic gonads were functionally abnormal provides further evidence that deletions of the Y chromosome before their loss (8). outside the SRY-ORF can result in either complete or incom- Mutations in the SRY-ORF have been reported in -20% of plete sex reversal. subjects with 46,XY complete gonadal dysgenesis (9-14). The mutations are clustered in sequences encoding the HMG Sex determination in mammals is controlled by the presence or domain of the molecule. By contrast no germ-line mutations absence of a testis-determining factor encoded by a gene in the SRY-ORF have been reported among subjects with termed sex determining region Y (SRY) (1). In humans the partial forms of 46,XY gonadal dysgenesis. As SRY is respon- SRY gene resides in a 35-kb region on the short arm of the Y sible for the primary step in testis determination, mutations in chromosome, referred to as the testis-determining region. This the SRY-ORF could be expected to completely block testis is the smallest region of Y-specific DNA known to induce formation. However, it is conceivable that some cases of46,XY masculinization in XX males partial gonadal dysgenesis might result from mutations in the (2). The SRYgene itself has been SRY-ORF that modified SRY protein function in a subtle mapped to a region 5 kb proximal to the pseudoautosomal fashion. Similarly, a mutation in a putative regulatory element boundary. SRYconsists of a single exon of -700 bp (3, 4). The might result in reduced expression of SRY or an alteration in central one third of the open reading frame (ORF) encodes a the timing of SRY gene expression. To examine these possi- motif that has sequence homology to a conserved region of the bilities we studied 20 subjects who had either 46,XY partial high mobility group (HMG) proteins (5). This motif, termed gonadal dysgenesis or 46,XY embryonic testicular regression the HMG-box, has the capacity to bind to DNA, which is syndrome. We determined the presence of genetic abnormal- consistent with a cell-autonomous signal in the sex- ities in the testis-determining locus on the Y chromosome, determining pathway. including the SRY gene. In all cases the sequence of the SRY The publication costs of this article were defrayed in part by page charge Abbreviations: HMG, high mobility group; PABY, Y pseudoautoso- payment. This article must therefore be hereby marked "advertisement" in mal boundary; PABX, X pseudoautosomal boundary. accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 8590 Downloaded by guest on September 26, 2021 Medical Sciences: McElreavey et aL Proc. Natl. Acad. Sci. USA 93 (1996) 8591 gene was found to be identical to that of a normal male. asymetrically amplified using the primers XES2 and XES7 (12) However one subject with 46,XY partial gonadal dysgenesis and sequenced directly using Sequenase (United States Bio- had a small de novo interstitial deletion 3' to the SRYgene. The chemical) using conditions described by the manufacturer. The results suggest that (i) human sex determination is sensitive to X and Y pseudoautosomal boundaries (PABX and PABY) variations in the activity of the testis-determining gene SRY were amplified using oligonucleotides A and C for the Y and (ii) small interstitial deletions in the Y chromosome may boundary and the oligonucleotides B and C for the X chro- be more common than previously supposed. mosomal boundary, as described (18). Amplification of Y- specific sequences 2 kb proximal to the pseudoautosomal boundary was performed using the primers Y2A, GCATTA- MATERIALS AND METHODS GTGAAGAATTAACT; and Y2B, TCTCATGAAGATTT- Subjects. Table 1 summarizes the clinical description of 20 TTACTC. These primers amplify a 343-bp Y-specific fragment subjects with a 46,XY karyotype and abnormalities of testis under standard conditions. Expression of SRY in peripheral determination. Subjects had 46,XY partial gonadal dysgenesis blood lymphocytes was determined as described elsewhere on the basis of (i) ambiguous external genitalia, (ii) mixture of (13). Paternity was determined by Southern analysis using both Wolffian and Mullerian ducts, and (iii) dysgenetic testis. minisatellite probes (19). Patients who have been described elsewhere are indicated. Blood karyotype analysis excluded mosaicism in all cases, and RESULTS none of the patients presented with Turner stigmata. DNA Analysis. Genomic DNA was prepared from periph- The SRY-ORF was sequenced in each case by using an eral blood lymphocytes. In Southern blot analysis, 15-,ug asymetrically amplified PCR product as a template. In all 20 samples were digested with restriction endonucleases accord- subjects the SRY-ORF sequence was identical to that of a ing to the manufacturer's recommended conditions. Agarose normal male control. To determine if mutations were present gel electrophoresis, transfer to nylon membranes (Hybond N; in the testis-determining region of the Y short arm, Southern Amersham), prehybridization, hybridization to 32P-labeled analysis was performed by using the probes, pY53.3 (SRY), probes, and autoradiography were performed essentially as pO.9, pDP1226, and HfO.2. Southern analysis using the probes described (13, 15). Blots were hybridized with the Y-DNA- pDP1226 and pO.9 failed to detect in all patients any change specific probes pY53.3 (SRY), pO.9, pDP1226, and with the in fragment size from that of a normal male control (data not pseudoautosomal probe HFO.2 (1, 16-18). Hybridization was shown). Southern analysis was performed on StuI digested also performed using probes from 10 kb and 4 kb distal to the DNA using the probe pY53.3 which contains the SRY gene. pseudoautosomal boundary. Primer pairs KPR1OA (GAGT- Hybridization of StuI digested DNA from a normal male CTGAGACTTTTAGAGAG) and KPR1OB (GGGCGGG- control with the probe pY53.3 results in two Y-specific frag- GATATGCCTGTCCTAAGC) amplify a 738-bp fragment ments of 9 and 6 kb (Fig.
Load more

Recommended publications
  • Amphibian Sex Determination and Sex Reversal
    CMLS, Cell. Mol. Life Sci. 55 (1999) 901–909 1420-682X/99/070901-09 $ 1.50+0.20/0 © Birkha¨user Verlag, Basel, 1999 Amphibian sex determination and sex reversal H. Wallace*, G. M. I. Badawy and B. M. N. Wallace School of Biological Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT (UK), Fax +44 121 414 5925, e-mail: [email protected] Abstract. Amphibians employ a genetic mechanism of published studies on crested newts. These newts re- sex determination, according to all available informa- spond conventionally to temperature and hormone tion on sex chromosomes or breeding tests. Sex reversal treatment but provide anomalous results from breeding allows breeding tests to establish which sex is het- tests. It is suggested that both the evolution from tem- erogametic and provides an indication of the mecha- perature dependency to a genetic switch and from ZZ/ nism of sex determination. Cases of spontaneous and ZW to XX/XY are superimposed on a generally experimental sex reversal (by temperature, hormones or uniform mechanism of sex determination in all verte- surgery) are reviewed and illustrated by previously un- brates. Key words. Sex determination; sex reversal; temperature dependence; sex hormone; amphibia; Triturus cristatus. Genetic sex determination insight into its mechanism, by showing how it can be overridden by environmental or hormonal influences. All amphibians that have been tested possess a genetic Third, using irradiated sperm to activate eggs which are mechanism of sex determination. Examples of male then heat-shocked to arrest the second meiotic division heterogamety (XX/XY) or female heterogamety (ZZ/ and thus restore diploidy, which is equivalent to self-fer- ZW) have been found repeatedly in both anurans and tilization of a female or breeding from a neomale (fig.
    [Show full text]
  • History of the Research on Sex Determination
    Review Article ISSN: 2574 -1241 DOI: 10.26717/BJSTR.2020.25.004194 History of The Research on Sex Determination Jacek Z Kubiak1,2, Malgorzata Kloc3-5 and Rafal P Piprek6* 1UnivRennes, CNRS, UMR 6290, IGDR, Cell Cycle Group, F-35000 Rennes, France 2Military Institute of Hygiene and Epidemiology, ZMRiBK, Warsaw, Poland 3The Houston Methodist Research Institute, USA 4Department of Surgery, The Houston Methodist Hospital, USA 5University of Texas, MD Anderson Cancer Center, USA 6Department of Comparative Anatomy, Institute of Zoology and Biomedical Research, Jagiellonian University, Poland *Corresponding author: Rafał P Piprek, Department of Comparative Anatomy, Institute of Zoology and Biomedical Research, Jagiellonian University, Poland ARTICLE INFO Abstract Received: Published: January 28, 2020 Since the beginning of the humanity, people were fascinated by sex and intrigued by February 06, 2020 how the differences between sexes are determined. Ancient philosophers and middle Citation: age scholars proposed numerous fantastic explanations for the origin of sex differences in people and animals. However, only the development of the modern scientific methods Jacek Z Kubiak, Malgorzata Kloc, allowed us to find, on the scientific ground, the right answers to these questions. In this Rafal P Piprek. History of The Research on review article, we describe the history of these discoveries, and which major discoveries allowed the understanding of the origin of sex and molecular and cellular basis of the Sex Determination. Biomed J Sci & Tech Res
    [Show full text]
  • Zfyl Encodes a Nuclear Sequence-Specific DNA Binding
    View metadata, citation and similar papers at core.ac.uk brought to you byCORE provided by Elsevier - Publisher Connector FEBS 15213 FEBS Letters 360 (1995) 315-319 Zfyl encodes a nuclear sequence-specific DNA binding protein Pamela Taylor-Harris, Sally Swift, Alan Ashworth* CRC Centre of Cell and Molecular Biology, Chester Beatty Laboratories, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK Received 19 January 1995; revised version received 3 February 1995 sively to RNA and have functions in RNA storage or processes Abstract Zfyl is a mouse Y chromosomal gene encoding a zinc such as splicing. finger protein which is thought to have some function during In order to analyse the properties of the ZFY family of zinc spermatogenesis. Here we show that, when introduced into tissue finger proteins, we have raised specific antibodies to murine culture cells, Zfyl is targeted to the nucleus. Two independent signals are present within the protein for nuclear localization. Zfyl. These have been used to demonstrate that Zfyl protein This nuclear Zfyl protein is able to bind strongly to DNA-ceHu- localizes to the nucleus of transfected cells and to identify spe- lose and, using site-selection assays, we have identified specific cific DNA binding sites for Zfyl, suggesting a role for this Zfyl DNA binding sites. Taken together these results suggest protein as a transcription factor regulating gene expression that Zfyl is a nuclear-located sequence-specific DNA binding during spermatogenesis. protein which functions during spermatogenesis. Key words: Spermatogenesis; Zinc finger protein; 2. Materials and methods Y chromosome; Nucleus; DNA binding; Transcription factor 2.1.
    [Show full text]
  • Downloaded from Interpro Database (IPR013087)
    bioRxiv preprint doi: https://doi.org/10.1101/637298; this version posted May 15, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Why Do Long Zinc Finger Proteins have Short Motifs? A case study of ZFY and CTCF reveals non-independent recognition of tandem zinc finger proteins. Zheng Zuo1*, Timothy Billings6, Michael Walker6, Petko Petkov6, Polly Fordyce1, 2, 3, 4, Gary D. Stormo5* 1. Department of Genetics, Stanford University, CA, USA 2. Chan Zuckerberg Biohub, San Francisco, CA, USA 3. Department of Bioengineering, Stanford University, CA, USA 4. Stanford CheM-H Institute, Stanford University, CA, USA 5. Department of Genetics, Washington University in St. Louis, MO, USA 6. The Jackson Laboratory, ME, USA Correspondence: [email protected] Summary The human genome has more than 800 C2H2 Zinc Finger-containing genes, and many of them are composed of long tandem arrays of zinc fingers. Current Zinc Finger Protein (ZFP) motif prediction models assume longer finger arrays correspond to longer DNA-binding motifs and higher specificity. However, recent experimental efforts to identify ZFP binding sites in vivo contradict this assumption with many having short reported motifs. Using Zinc Finger Y (ZFY), which has 13 ZFs, we quantitatively characterize its DNA binding specificity with several complementary methods, including Affinity-seq, HT-SELEX, Spec-seq and fluorescence anisotropy. Besides the previously identified core motif GGCCT recognized by fingers 12-13, we find a novel secondary irregular motif recognized by accessory fingers.
    [Show full text]
  • A Genetic Method for Sex Identification of Raccoons (Procyon Lotor) with Using the ZFX and ZFY Genes
    NOTE Wildlife Science A Genetic Method for Sex Identification of Raccoons (Procyon lotor) with Using the ZFX and ZFY Genes Minami W. OKUYAMA1), Michito SHIMOZURU1) and Toshio TSUBOTA1)* 1)Laboratory of Wildlife Biology and Medicine, Graduate School of Veterinary Medicine, Hokkaido University, Kita18, Nichi9, Kita-ku, Sapporo, Hokkaido 060–0818, Japan (Received 19 November 2013/Accepted 2 January 2014/Published online in J-STAGE 23 January 2014) ABSTRACT. A genetic method for sex determination in raccoons was developed based on nucleotide differences of the zinc finger protein genes ZFX and ZFY. Four novel internal primers specific for ZFX or ZFY were designed. PCR amplification using two primer sets followed by agarose gel electrophoresis enabled sex determination. 141-bp and 447-bp bands were in both sex, and 346-bp band was specific only in male with primer set I. 345-bp and 447-bp bands were in both sex, and 141-bp band was specific only in male with primer set II, which could distinguish raccoon’s electrophoresis pattern from three native carnivores in Hokkaido. This method will be useful for conservation genetics studies or biological analyses of raccoons. KEY WORDS: PCR, raccoons, sex identification, ZFX and ZFY genes. doi: 10.1292/jvms.13-0577; J. Vet. Med. Sci. 76(5): 773–775, 2014 Sex is one of the most important pieces of information between ZFX and ZFY in raccoons and to establish a new about an animal, as it is related to physiology, behavior and genetic method for sex determination of raccoons. reproduction. Thus, developing methods for sex identifica- Hair or whisker samples were collected from the carcasses tion are essential in many fields of study, including zoology of feral raccoons that were euthanized for eradication control and ecology.
    [Show full text]
  • Multiple Congenital Genitourinary Anomalies in a Polled Goat
    Multiple Congenital Genitourinary Anomalies in a Polled Goat WILLIAM W. KING, DVM, PHD, DIPLOMATE, ACLAM,1,2* MELVIN E. YOUNG,1 AND M. EUGENE FOX, DVM3 A 1-day-old, Toggenburg/Nubian crossbred goat of polled parentage was referred for necropsy because of a large (diameter, 5 cm) bladder-like mass protruding from the perineal midline and difficult urination. Differential diagnoses included cutaneous cyst, ectopic urinary bladder, and urethral diverticulum/dilatation. Several genitourinary aberrations were noted. A second, smaller (diameter, 1 cm), more distal cystic structure was adjacent to an ambiguous prepuce. Testicles were discovered within a con- stricted, subcutaneous space near the inguinal canals. A rudimentary penis was located dorsal to the penile urethra with no appreciable urethral process. A tiny external urethral orifice was discerned only after liquid was injected into the lumen of the cystic structures, confirming their identity as urethral dilatations. The dilatations were separated by a constricting band of fibrous tissue. No other significant findings were detected. This case illustrates a combination of congenital anomalies including bilateral cryptorchidism with scrotal absence, segmental urethral hypoplasia, and urethral dilatation, most likely associated with the intersex condition seen in polled breeds. The continued production and use of small ruminants as animal models demands the prompt recognition of congenital anomalies. This case also exemplifies the precautions required when breeding goats with polled ancestry. The domestic goat (Capra hircus) has historically served and Nubian/Toggenburg sire. The owner reported that the doe had continues to play an important role in biomedical research (1). completed a normal gestation period on a diet of natural grass/ Many small breeds are available, facilitating common labora- alfalfa hay and water.
    [Show full text]
  • Normal Structure and Expression of Zfy Genes in XY Female Mice Mutant in Tdy
    Development 109, 647-653 (1990) 647 Printed in Great Britain ©The Company of Biologists Limited 1990 Normal structure and expression of Zfy genes in XY female mice mutant in Tdy JOHN GUBBAY1, PETER KOOPMAN1, JEROME COLLIGNON1, PAUL BURGOYNE2 and ROBIN LOVELL-BADGE1* [ Laboratory of Eukaryotic Molecular Genetics, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW71AA, UK 2MRC Mammalian Development Unit, Wolfson House, 4 Stephenson Way, London NWI 2HE, UK •To whom correspondence should be addressed Summary Zfy-1 and Zfy-2 are candidate genes for Tdy, the testis- show a normal structure and expression pattern in mice determining gene in mice. We have analysed these genes with a Y chromosome known to carry a mutation in Tdy in a line of XY female mice that have been shown to be and that mutant embryos develop into females despite mutated in Tdy. We have used Southern blot analysis to Zfy-1 expression, strongly supports other recent evi- show that the Zfy genes have not undergone any major dence that Zfy genes are not directly involved in primary structural alterations, and have also demonstrated that testis determination. both genes are transcribed normally from the mutant Y chromosome (¥) in both adult XY¥ testis and X¥ Key words: sex determination, Tdy, Zfy, zinc finger genes, female embryonic gonads. The fact that these genes polymerase chain reaction, gene expression. Introduction conservation and cell autonomous action of the testis- determining gene (Burgoyne et al. 1988). Sex determination in mammals is dependent upon the However, theories of the mode of action of ZFY in action of a Y-linked testis-determining gene termed testis determination have to take into account the TDF in humans and Tdy in mice (Goodfellow and presence of a highly homologous gene (ZFX) present Darling, 1988; McLaren, 1988).
    [Show full text]
  • Genome Editing Reveals Dmrt1 As an Essential Male Sex-Determining
    www.nature.com/scientificreports OPEN Genome editing reveals dmrt1 as an essential male sex-determining gene in Chinese tongue sole Received: 13 October 2016 Accepted: 06 January 2017 (Cynoglossus semilaevis) Published: 16 February 2017 Zhongkai Cui1,2,3,*, Yun Liu4,5,*, Wenwen Wang1, Qian Wang1, Ning Zhang1, Fan Lin1, Na Wang1,2, Changwei Shao1,2, Zhongdian Dong1, Yangzhen Li1,2, Yingming Yang1, Mengzhu Hu1, Hailong Li1, Fengtao Gao1, Zhanfei Wei1, Liang Meng1, Yang Liu1,2, Min Wei1,2, Ying Zhu1,2, Hua Guo1,2, Christopher H. K. Cheng4,5,†, Manfred Schartl6,7,† & Songlin Chen1,2,† Chinese tongue sole is a marine fish with ZW sex determination. Genome sequencing suggested that the Z-linked dmrt1 is a putative male determination gene, but direct genetic evidence is still lacking. Here we show that TALEN of dmrt1 efficiently induced mutations of this gene. The ZZdmrt1 mutant fish developed ovary-like testis, and the spermatogenesis was disrupted. The female-related genes foxl2 and cyp19a1a were significantly increased in the gonad of the ZZdmrt1 mutant. Conversely, the male-related genes Sox9a and Amh were significantly decreased. Thedmrt1 deficient ZZ fish grew much faster than ZZ male control. Notably, we obtained an intersex ZW fish with a testis on one side and an ovary on the other side. This fish was chimeric for admrt1 mutation in the ovary, and wild-type dmrt1 in the testis. Our data provide the first functional evidence thatdmrt1 is a male determining gene in tongue sole. Sex-determining (SD) genes are located on the sex chromosomes to initiate a series of signaling pathways of sex related events to induce the development of bipotential primordial gonads into testes or ovaries.
    [Show full text]
  • Prenatal Sex Differences in the Human Brain
    Molecular Psychiatry (2009) 14, 988–991 & 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00 www.nature.com/mp LETTERS TO THE EDITOR Prenatal sex differences in the human brain Molecular Psychiatry (2009) 14, 988–989. doi:10.1038/ development. These genes are not only expressed in mp.2009.79 the brain before birth but some of them are also known to have sex differences in adult brain,1,4 whereas others are expressed during infancy, but The presence of genetic sex differences in the adult reduced later on during their lifetime.5 human brain is now recognized.1 We hypothesized Intriguingly, SRY, a well-known determinant of that the basis of this sex bias is already established in testicle development during midgestation,6 showed the brain before birth. Here, we show that several no evidence of expression in any of the brain regions genes encoded in the Y-chromosome are expressed in analyzed (Figure 1b, and Supplementary Figure 1), many regions of the male prenatal brain, likely having suggesting that the main somatic sex determinants functional consequences for sex bias during human may be different for the brain and gonads during brain development. human gestation. The marked sex differences in age at onset, In humans, all 11 genes described here are encoded prevalence and symptoms for numerous neuropsy- in the male-specific region of the Y-chromosome,7 chiatric disorders2 indicate the importance to study with RPS4Y1 and ZFY located in the p-arm very close the emergence of a sex bias during human brain to SRY and most of the remaining genes located in the development.
    [Show full text]
  • Quantitative Analysis of Y-Chromosome Gene Expression Across 36 Human Tissues 6 7 8 9 Alexander K
    Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press 1 2 3 4 5 Quantitative analysis of Y-Chromosome gene expression across 36 human tissues 6 7 8 9 Alexander K. Godfrey1,2, Sahin Naqvi1,2, Lukáš Chmátal1, Joel M. Chick3, 10 Richard N. Mitchell4, Steven P. Gygi3, Helen Skaletsky1,5, David C. Page1,2,5* 11 12 13 1 Whitehead Institute, Cambridge, MA, USA 14 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA 15 3 Department of Cell Biology, Harvard Medical School, Boston, MA, USA 16 4 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 17 5 Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA, USA 18 19 20 21 *corresponding author: 22 Email: [email protected] 23 24 25 Running title: 26 Human Y-Chromosome gene expression in 36 tissues 27 28 29 Keywords: 30 Y Chromosome, sex chromosomes, sex differences, EIF1AY, EIF1AX 31 Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press 32 ABSTRACT 33 Little is known about how human Y-Chromosome gene expression directly contributes to 34 differences between XX (female) and XY (male) individuals in non-reproductive tissues. Here, 35 we analyzed quantitative profiles of Y-Chromosome gene expression across 36 human tissues 36 from hundreds of individuals. Although it is often said that Y-Chromosome genes are lowly 37 expressed outside the testis, we report many instances of elevated Y-Chromosome gene 38 expression in a non-reproductive tissue.
    [Show full text]
  • Genetics of Azoospermia
    International Journal of Molecular Sciences Review Genetics of Azoospermia Francesca Cioppi , Viktoria Rosta and Csilla Krausz * Department of Biochemical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; francesca.cioppi@unifi.it (F.C.); viktoria.rosta@unifi.it (V.R.) * Correspondence: csilla.krausz@unifi.it Abstract: Azoospermia affects 1% of men, and it can be due to: (i) hypothalamic-pituitary dysfunction, (ii) primary quantitative spermatogenic disturbances, (iii) urogenital duct obstruction. Known genetic factors contribute to all these categories, and genetic testing is part of the routine diagnostic workup of azoospermic men. The diagnostic yield of genetic tests in azoospermia is different in the different etiological categories, with the highest in Congenital Bilateral Absence of Vas Deferens (90%) and the lowest in Non-Obstructive Azoospermia (NOA) due to primary testicular failure (~30%). Whole- Exome Sequencing allowed the discovery of an increasing number of monogenic defects of NOA with a current list of 38 candidate genes. These genes are of potential clinical relevance for future gene panel-based screening. We classified these genes according to the associated-testicular histology underlying the NOA phenotype. The validation and the discovery of novel NOA genes will radically improve patient management. Interestingly, approximately 37% of candidate genes are shared in human male and female gonadal failure, implying that genetic counselling should be extended also to female family members of NOA patients. Keywords: azoospermia; infertility; genetics; exome; NGS; NOA; Klinefelter syndrome; Y chromosome microdeletions; CBAVD; congenital hypogonadotropic hypogonadism Citation: Cioppi, F.; Rosta, V.; Krausz, C. Genetics of Azoospermia. 1. Introduction Int. J. Mol. Sci.
    [Show full text]
  • Distinct Prophase Arrest Mechanisms in Human Male Meiosis
    bioRxiv preprint doi: https://doi.org/10.1101/195321; this version posted September 28, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Distinct prophase arrest mechanisms in human male meiosis Sabrina Z. Jan1, Aldo Jongejan2, Cindy M. Korver1, Saskia K.M. van Daalen1, Ans M.M. van Pelt1, Sjoerd Repping1 and Geert Hamer1,* 1 Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 2 Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center Amsterdam, The Netherlands * Correspondence: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/195321; this version posted September 28, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. To prevent chromosomal aberrations to be transmitted to the offspring, strict meiotic checkpoints are in place to remove aberrant spermatocytes. However, in about 1% of all males these checkpoints cause complete meiotic arrest leading to azoospermia and subsequent infertility. We here unravel two clearly distinct meiotic arrest mechanisms that act during the prophase of human male meiosis. Type I arrested spermatocytes display severe asynapsis of the homologous chromosomes, disturbed XY-body formation and increased expression of the Y-chromosome encoded gene ZFY and seem to activate a DNA damage pathway leading to induction of p63 mediated spermatocyte elimination. Type II arrested spermatocytes display normal chromosome synapsis, normal XY-body morphology and meiotic crossover formation but have a lowered expression of several cell cycle regulating genes and fail to properly silence the X-chromosome encoded gene ZFX.
    [Show full text]