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Determination of sex ? Dr. habil. Kőhidai László Dept. Genetics, Cell- & Immunobiology, Semmelweis University 2014.

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Presentation on theme: "Determination of sex ? Dr. habil. Kőhidai László Dept. Genetics, Cell- & Immunobiology, Semmelweis University 2014."— Presentation transcript:

1 Determination of sex ? Dr. habil. Kőhidai László Dept. Genetics, Cell- & Immunobiology, Semmelweis University 2014.

2  Determination of sex  Characterization of sex chrs  Main types of sex chrs linked inheritance inheritance  Pathological forms

3 Main determining factors of sex  Environmental factors - size of body (marine worms) - temperature (reptiles)  Genetical - allelic + environment (wasps) - chromosomal Ratio of X chrs and autosomes autonomic e.g. Drosophila not autonomic e.g. human

4 General characteristics of X chromosome  5% of haploide genome  House-keeping and specialized genes  conserved sequences  it does NOT code sex determining factor  one of X chrs gets inactive in female (1961)

5 General characteristics of Y chromosome  It was a homologue pair of X chrs in a previous phase of phyligeny phase of phyligeny  Phenotype of somatic cells is determined by the testicular hormones testicular hormones  Y chrs acts on testis developement by TDF  SRY gene product = TDF (1991)  SRY codes a Zn-fingered transcription factor  SRY is expressed ONLY in: - gonadal tissues - gonadal tissues - at the development of testis - presence of gonocytes is not a - presence of gonocytes is not aprerequisite

6 X chrs has a homologue NO homologue of X chrs HousekeepingTestis Other places Y chrs.

7 Known genes of Y chromosome  SRY – sex region of X (see below)  ZFY – code of a Zn-fingered protein  AZY – responsible for development of sperm (AZ=azospermia)  H-Y – cell surface antigene, present on each cell of males  MSY – long palindromic sequences on the q arm of Y chrs ? !

8 Genes of early sex differentiation  SF-1 ‘Steroidogenic’ factor, nuclear receptor which regulates expression of steroid hydroxylases  WT1Wilm’s tumor locus determined chrs 11p13  SOX9‘SRY-releated HMG-box’, chrs 17q about 14 genes  MISproduct of Sertoli-cells; chrs. 19p13.3 regulatory domaine which binds F-1, its promoter binds SRY  DSS‘Dosage Sensitive Sex reversal’, Duplication on chrs Xp21.2-p22.2  DAX-1 nuklear hormone receptor, expressed: testis and adrenal gland  SRY‘Sex-determining region product of Y gene, transcription factor

9 SRY gene  Yp 11.3  only one, 850 bp exon  highly conserved  79 amino acid containing HMG box ( ‘Highly Mobile Group of proteins)

10 Bipotencialgonade Ovary TestisFollicularcellsThecacells Sertoli-cells Leydigcells Follicle AMH Testosteron SRYSOX9 DAX1WNT4 SF1 SF1 SF1WT1LHX9 Estrogen

11 Gonades Genotype Phenotype Testis Male Female Female Ovary Gonadedisgenesis DAX1 SRY SRY DAX1 DAX1 inactiveDAX1 2 copies DAX1 Ref.: Genetics Review Group (1995)

12 Sexually not differentiated Male Female Ref.:Langman (1981)

13 Week 4 Week 6 Week 8 Week 8 Week 8 Testis Ovary Ref.:Langman (1981)

14 Week 16 Week 20 TestisOvary Ref.:Langman (1981)

15 XChromosome YChromosome SRYSF1SOX9TESTIS DAX1 WNT1 OVARY Ref.: Aberger F.

16 Promoter Amh Sox9 Amh Sox9 SF1Wt-1 Amh Sox9 SF1Wt-1Gata Ref.: Arango et al. (1999)

17 Evolution of huma sex chromosomes (1) Sex chrs. Developes SRY (NRY) blocks Recombination Mill.year Az NRY expansion (RBMY, RPS4Y) Mill year NRY expansion (SMCY, UBE1Y) Mill year recomb.Non-recomb. X-chrs. spec. XY egg layer mammals mammals XYMarsupials Autosomebirds

18 recomb. not rekomb. X-chrs. spec. Translocation expansion expansion to PARp to PARp Myr NRYexpansion(CASKP,DBY) NRYexpansion(AMELY,KALP) Myr X-Y translocatio n PCDHY 3-4 Myr XY Not human anthropoids XYNon-anthropoidmammals XYHomosapiens Protocadherin X/Y Evolution of huma sex chromosomes (1)

19 Y kromoszóma X kromoszóma Ember Ember Macska Macska Conserved loci in mammalian X and Y chrs X and Y chrs

20 Testicular feminisation Genotype: XY Testosteron in sera is normal Testis in the abdominal cavity Feminine statue Reasons: - error of differentiation after testosteron action? after testosteron action? - testosteron can influence development of Wolff-tubule at differentiation? Reason: MUTATION OF TESTOSTERON RECEPTOR

21 REASON: Xq11-12 mutation – androgenic receptor Inactive gene gene Enhancer Promoter Start Hormone-Reccomplex Active Activatedenhancer Promoter mRNS synthesis

22 Hermaphroditism True hermaphroditism - Both gonads (ovary and testis) or its tissue is present in the body - Male OR female external sexual organs are dominant - Forms 46XX – SRY translocation or 46XXY – loss of Y chrs 46XY – point mutation of Y chrs 46XX/46XY mosaicism (Hermaphroditism is frequent in invertebrates and plants)

23 Hermaphroditism Pseudo hermaphroditism - Gonad of one sex and the opposite external sex organs - Ph masculinus Mixed gonad dysgenesis (45X/46XY – gonadal streak/testis) Testicular feminisation (46XY – pointmutation of Y chrs – testis releases estrogen; ligand is not bind by receptors) - Ph femininus Adrenogenital syndrome (androgen threatments can induce it)

24 Form of „gene dose compensation” Only 1 X chrs is active when there are X chrs’ in excess number n Barr = n X – 1 n Barr = n X – 1 X recessive mutations: some cells in female are „functional hemizygotes” – this may result disease An other form of gene dose compensation: differences in activity of X chrs in the two sex Inactive X chromosome

25 Barr-bodies ‘Drumstick’ ‘Drumstick’ XY XX

26 Inactivation of X chromosome (1) Xist expression - inhibitor factor Inhibitor factor LINE helps in sreading the effect Xist RNA coats the chromosome

27 Transcriptional „silencing” „silencing” Timing of asynchron replication Increased macroH2A Hypoacethylated: H3; H4 H3; H4 X kromoszóma inaktiválódása (2)

28 Xist transcription in embryonic stem cells Xist is active on both X chrs’ Inactive X chrs is covered by RNA Only the inactive, „RNA-coated” Xchrs is detectable

29 XX XY > XYX= Mary F. Lyon

30 Inactivation of X chromosome  Takes place randomly in the early phase of development in healthy female development in healthy female  The same X chrs gets inactive in the offspring generations of cells generations of cells  A product of Xq13 (Xist) is significant in the process  Virtually all genes of X chr turn into inactive phase (except genes responsible for inactivation) (except genes responsible for inactivation)  Female are mosaic for inactive X chrs as maternal and paternal X chrs get inactive, too and paternal X chrs get inactive, too Male: constitutional hemizygotes Female: functional hemizygotes

31

32 PAR regions PAR = pseudo autoszomal region  Never gets inactive  Telomeric position on the two sex chromosomes  PAR1 – 2.6 Mb; PAR2 – 320 kb  Provide choice for partial meiotic pairing of X-Y chrs  „Obligatory crossing over” in PAR1 (e.g. Xg blood group, IL-3 receptor) IL-3 receptor)

33 Frequent problems resulting disfunctions in sexual differentiation  mutations of SRY  disturbed biosynthesis of androgens  mutations of androgen receptor  errors of AMH  XY/XO mosaicism  Wnt and WT-1 mutations (differentiation of gononephrotom)

34  Sex limited inheritance The trait is present in the genotype of both sex, however it is expressed only in one sex E.g. hair, menstruation, pelvic parameters

35  Incomplet sex restriction Crossing over between pseudoautosomal regions of X and Y chrs. XX XY XYXYXX XX

36  Sex controlled inheritance The trait is expressed in both sex, however its degree is different Normal features: Deepness of sound Baldness BB + B + B + Male-baldness (androgenes) Female– normal Male and Female - baldness Diseases: gout 80% M Cleft lip/palate Anencephaly - F Spina bifida


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