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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 17q24.3-25.1 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 290-350 Mill.year Az NRY expansion (RBMY, RPS4Y) 230-300 Mill year NRY expansion (SMCY, UBE1Y) 130-170 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 80-130 Myr NRYexpansion(CASKP,DBY) NRYexpansion(AMELY,KALP) 30-50 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


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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