Presentation on theme: "Determination of sex ? Dr. habil. Kőhidai László"— Presentation transcript:
1 Determination of sex ? Dr. habil. Kőhidai László Dept. Genetics, Cell- & Immunobiology,Semmelweis University2014.
2 Determination of sexCharacterization of sex chrsMain types of sex chrs linkedinheritancePathological forms
3 Main determining factors of sex Environmental factorssize of body (marine worms)temperature (reptiles)Geneticalallelic + environment (wasps)chromosomalRatio of X chrs and autosomesautonomic e.g. Drosophilanot autonomic e.g. human
4 General characteristics of X chromosome 5% of haploide genomeHouse-keeping and specialized genesconserved sequencesit does NOT code sex determining factorone of X chrs gets inactive in female (1961)
5 General characteristics of Y chromosomeIt was a homologue pair of X chrs in a previousphase of phyligenyPhenotype of somatic cells is determined by thetesticular hormonesY chrs acts on testis developement by TDFSRY gene product = TDF (1991)SRY codes a Zn-fingered transcription factorSRY is expressed ONLY in:- gonadal tissues- at the development of testis- presence of gonocytes is not aprerequisite
6 Y chrs. X chrs has NO homologue of X chrs a homologue Housekeeping TestisOther places
7 Known genes of Y chromosome ?!SRY – sex region of X (see below)ZFY – code of a Zn-fingered proteinAZY – responsible for development of sperm (AZ=azospermia)H-Y – cell surface antigene, present on each cell of malesMSY – long palindromic sequences on the q arm of Y chrs
8 Genes of early sex differentiation SF-1 ‘Steroidogenic’ factor, nuclear receptor whichregulates expression of steroid hydroxylasesWT1 Wilm’s tumor locus determined chrs 11p13SOX9 ‘SRY-releated HMG-box’, chrs 17qabout 14 genesMIS product of Sertoli-cells; chrs. 19p13.3regulatory domaine which binds F-1, its promoterbinds SRYDSS ‘Dosage Sensitive Sex reversal’,Duplication on chrs Xp21.2-p22.2DAX-1 nuklear hormone receptor,expressed: testis and adrenal glandSRY ‘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)
17 Evolution of huma sex chromosomes (1) Sex chrs. DevelopesSRY (NRY) blocksRecombinationMill.yearAz NRY expansion(RBMY, RPS4Y)Mill yearNRY expansion(SMCY, UBE1Y)Mill yearAutosomebirdsXYegg layermammalsXYMarsupialsrecomb.Non-recomb.X-chrs. spec.
18 Evolution of huma sex chromosomes (1) recomb.not rekomb.X-chrs. spec.Translocationexpansionto PARpMyrNRY(CASKP,DBY)(AMELY,KALP)30-50 MyrX-Y translocationPCDHY3-4 MyrXYNot humananthropoidsNon-anthropoidmammalsHomosapiensProtocadherin X/Y
19 Conserved loci in mammalian Y kromoszómaX kromoszómaEmberMacskaConserved loci in mammalianX and Y chrs
20 Testicular feminisation Genotype: XYTestosteron in sera is normalTestis in the abdominal cavityFeminine statueReasons:error of differentiationafter testosteron action?testosteron can influence development of Wolff-tubule at differentiation?Reason: MUTATION OF TESTOSTERON RECEPTOR
22 Hermaphroditism True hermaphroditism Both gonads (ovary and testis) or its tissue is present in the bodyMale OR female external sexual organs are dominantForms46XX – SRY translocation or 46XXY – loss of Y chrs46XY – point mutation of Y chrs46XX/46XY mosaicism(Hermaphroditism is frequent in invertebrates and plants)
23 Hermaphroditism Pseudo hermaphroditism Gonad of one sex and the opposite external sex organsPh masculinusMixed gonad dysgenesis (45X/46XY – gonadal streak/testis)Testicular feminisation (46XY – pointmutation of Y chrs – testis releases estrogen; ligand is not bind by receptors)Ph femininusAdrenogenital 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 numbernBarr = nX – 1X recessive mutations: some cells in female are „functional hemizygotes” – this may result diseaseAn other form of gene dose compensation:differences in activity of X chrs in the two sex
30 Inactivation of X chromosome Takes place randomly in the early phase ofdevelopment in healthy femaleThe same X chrs gets inactive in the offspringgenerations of cellsA product of Xq13 (Xist) is significant in the processVirtually all genes of X chr turn into inactive phase(except genes responsible for inactivation)Female are mosaic for inactive X chrs as maternaland paternal X chrs get inactive, tooMale: constitutional hemizygotesFemale: functional hemizygotes
32 PAR regions PAR = pseudo autoszomal region Never gets inactive Telomeric position on the two sex chromosomesPAR1 – 2.6 Mb; PAR2 – 320 kbProvide choice for partial meiotic pairing of X-Y chrs„Obligatory crossing over” in PAR1 (e.g. Xg blood group,IL-3 receptor)
33 Frequent problems resulting disfunctions in sexual differentiation mutations of SRYdisturbed biosynthesis of androgensmutations of androgen receptorerrors of AMHXY/XO mosaicismWnt 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 sexE.g. hair, menstruation, pelvic parameters
35 X Y X Y Incomplet sex restriction Crossing over between pseudoautosomal regions of X and Y chrs.XYXY
36 Sex controlled inheritance The trait is expressed in both sex, however its degree is different Normal features:Deepness of soundBaldnessBB+B+B+Diseases:gout 80% MCleft lip/palateAnencephaly - FSpina bifidaMale-baldness (androgenes)Female– normalMale and Female - baldness
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