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Determination of sex ? Dr. habil. Kőhidai László

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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 It was a homologue pair of X chrs in a previous phase of phyligeny Phenotype of somatic cells is determined by the 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 - at the development of testis - presence of gonocytes is not a prerequisite

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

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 17q 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 Bipotencial gonade Ovary Testis Follicular cells Theca Sertoli- Leydig Follicle AMH Testosteron SRY SOX9 DAX1 WNT4 SF1 WT1 LHX9 Estrogen

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

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

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

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

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

16 Sox9 Promoter Amh Wt-1 SF1 Sox9 Amh Wt-1 SF1 Sox9 Gata Amh
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 Autosome birds XY egg layer mammals XY Marsupials recomb. Non-recomb. X-chrs. spec.

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

19 Conserved loci in mammalian
Y kromoszóma X 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 REASON: Xq11-12 mutation – androgenic receptor
Inactive gene Enhancer Promoter Start Hormone-Rec complex Active Activated enhancer mRNS synthesis 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 Inactivation of X chromosome (1)
Xist expression - inhibitor factor Inhibitor factor LINE helps in sreading the effect Xist RNA coats the chromosome

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

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 XY XX > Mary F. Lyon XY X =

30 Inactivation of X chromosome
Takes place randomly in the early phase of development in healthy female The same X chrs gets inactive in the offspring 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) Female are mosaic for inactive X chrs as maternal 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)

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

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+ Diseases: gout 80% M Cleft lip/palate Anencephaly - F Spina bifida Male-baldness (androgenes) Female– normal Male and Female - baldness

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