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Determination of sex

?. Determination of sex. Dr. habil . Kőhidai László Dept . Genetics , Cell- & Immunobiology , Semmelweis University 2014. Determination of sex Characterization of sex chrs Main types of sex chrs linked inheritance Pathological forms. Main determining factors of sex.

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Determination of sex

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  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 • 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 • Itwas a homologuepair of X chrsin a previous phase of phyligeny • Phenotype of somaticcells is determinedbythe testicularhormones • Y chrsactsontestisdevelopementby TDF • SRY geneproduct = TDF (1991) • SRY codes a Zn-fingeredtranscriptionfactor • SRY is expressed ONLY in: - gonadaltissues - atthedevelopment of testis - presence of gonocytes is not a prerequisite

  6. Housekeeping Testis Other places X chrs has a homologue NO homologue of X chrs 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 • WT1 Wilm’s tumor locus determined chrs 11p13 • SOX9 ‘SRY-releated HMG-box’, chrs 17q24.3-25.1 about 14 genes • MIS product 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. Follicular cells Ovary DAX1 WNT4 Follicle Theca cells Estrogen SF1 WT1 LHX9 Bipotencial gonade SF1 Sertoli- cells AMH SRY SOX9 Testis SF1 Leydig cells Testosteron

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

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

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

  14. Testis Ovary Week 20 Week 16 Ref.:Langman (1981)

  15. X Chromosome DAX1 Y Chromosome SRY SF1 SOX9 TESTIS WNT1 OVARY Ref.: Aberger F.

  16. Wt-1 Sox9 SF1 Sox9 Amh Wt-1 Promoter Amh SF1 Sox9 Gata Amh Ref.: Arango et al. (1999)

  17. recomb. X-chrs. spec. Non-recomb. Evolution of huma sex chromosomes (1) NRY expansion (SMCY, UBE1Y) 130-170 Mill year Sex chrs. Developes SRY (NRY) blocks Recombination 290-350 Mill.year Az NRY expansion (RBMY, RPS4Y) 230-300 Mill year XY egg layer mammals XY Marsupials Autosome birds

  18. NRY expansion (AMELY, KALP) 30-50 Myr X-Y translocation PCDHY 3-4 Myr NRY expansion (CASKP, DBY) 80-130 Myr Translocation expansion to PARp 80-130 Myr XY Homo sapiens XY Not human anthropoids XY Non-anthropoid mammals recomb. X-chrs. spec. not rekomb. Evolution of huma sex chromosomes (1) Protocadherin X/Y

  19. X kromoszóma Ember Macska Y kromoszóma Ember Macska Conserved loci in mammalian 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? • testosteron can influence development of Wolff-tubule at differentiation? Reason: MUTATION OF TESTOSTERON RECEPTOR

  21. Promoter Enhancer Start Inactive gene Hormone-Rec complex Promoter Active gene mRNS synthesis Activated enhancer REASON: Xq11-12 mutation – androgenic receptor

  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. Inactive X chromosome Form of „gene dose compensation” Only 1 X chrs is active when there are X chrs’ in excess number nBarr = nX – 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

  25. XY XX ‘Drumstick’ Barr-bodies

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

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

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

  29. X XY = XY XX > Mary F. Lyon

  30. Inactivation of X chromosome • Takesplacerandomlyintheearlyphase of developmentinhealthyfemale • The same X chrsgetsinactiveintheoffspring generations of cells • A product of Xq13 (Xist) is significantintheprocess • Virtuallyallgenes of X chrturnintoinactivephase (exceptgenesresponsibleforinactivation) • Femalearemosaicforinactive X chrsasmaternal and paternal X chrsgetinactive, too • Male: constitutionalhemizygotes • Female: functionalhemizygotes

  31. 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)

  32. 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)

  33. 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

  34. X X X X X X X Y Y Y X X • Incomplet sex restriction Crossing over between pseudoautosomal regions of X and Y chrs.

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

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