Скачать презентацию Determination of sex Dr habil Kőhidai László Скачать презентацию Determination of sex Dr habil Kőhidai László

2c90efeb831be578025d8c2e47e02762.ppt

  • Количество слайдов: 36

Determination of sex ? Dr. habil. Kőhidai László Dept. Genetics, Cell- & Immunobiology, Semmelweis Determination of sex ? Dr. habil. Kőhidai László Dept. Genetics, Cell- & Immunobiology, Semmelweis University 2015.

Determination of sex Characterization of sex chrs Main types of sex chrs linked inheritance Determination of sex Characterization of sex chrs Main types of sex chrs linked inheritance § Pathological forms § § §

Main determining factors of sex § Environmental factors - size of body (marine worms) 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

General characteristics of X chromosome § § § 5% of haploide genome House-keeping and 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)

General characteristics of Y chromosome § It was a homologue pair of X chrs 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

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

? § § § Known genes of Y chromosome SRY – sex region of ? § § § 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

Genes of early sex differentiation § SF-1 § WT 1 § SOX 9 § Genes of early sex differentiation § SF-1 § WT 1 § SOX 9 § MIS § DSS § DAX-1 § SRY ‘Steroidogenic’ factor, nuclear receptor which regulates expression of steroid hydroxylases Wilm’s tumor locus determined chrs 11 p 13 ‘SRY-releated HMG-box’, chrs 17 q 24. 3 -25. 1 about 14 genes product of Sertoli-cells; chrs. 19 p 13. 3 regulatory domaine which binds F-1, its promoter binds SRY ‘Dosage Sensitive Sex reversal’, Duplication on chrs Xp 21. 2 -p 22. 2 nuklear hormone receptor, expressed: testis and adrenal gland ‘Sex-determining region product of Y gene, transcription factor

SRY gene § Yp 11. 3 § only one, 850 bp exon § highly SRY gene § Yp 11. 3 § only one, 850 bp exon § highly conserved § 79 amino acid containing HMG box ( ‘Highly Mobile Group of proteins)

DAX 1 Ovary WNT 4 SF 1 Bipotencial WT 1 gonade LHX 9 SRY DAX 1 Ovary WNT 4 SF 1 Bipotencial WT 1 gonade LHX 9 SRY SOX 9 Testis Follicular cells Follicle Theca cells Estrogen Sertoli- SF 1 AMH cells Leydig cells SF 1 Testosteron

Genotype inactive DAX 1 SRY DAX 1 2 copies DAX 1 Gonades Phenotype Testis Genotype inactive DAX 1 SRY DAX 1 2 copies DAX 1 Gonades Phenotype Testis Male Ovary Female Gonade disgenesis Female Ref. : Genetics Review Group (1995)

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

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

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

X Chromosome DAX 1 Y Chromosome SRY SF 1 WNT 1 Ref. : Aberger X Chromosome DAX 1 Y Chromosome SRY SF 1 WNT 1 Ref. : Aberger F. OVARY SOX 9 TESTIS

Sox 9 Promoter Amh Wt-1 Sox 9 SF 1 Gata Ref. : Arango et Sox 9 Promoter Amh Wt-1 Sox 9 SF 1 Gata Ref. : Arango et al. (1999) Amh

Evolution of huma sex chromosomes (1) Sex chrs. Developes SRY (NRY) blocks Recombination 290 Evolution of huma sex chromosomes (1) Sex chrs. Developes SRY (NRY) blocks Recombination 290 -350 Mill. year Autosome birds recomb. Az NRY expansion (RBMY, RPS 4 Y) NRY expansion (SMCY, UBE 1 Y) 230 -300 Mill year 130 -170 Mill year XY egg layer mammals X-chrs. spec. XY Marsupials Non-recomb.

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

X chromosome Human Cat Conserved loci in mammalian X and Y chrs Y chromosome X chromosome Human Cat Conserved loci in mammalian X and Y chrs Y chromosome Human Cat

Testicular feminisation Genotype: XY Testosteron in sera is normal Testis in the abdominal cavity 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

Enhancer Promoter Inactive gene Start Hormone-Rec complex Promoter Active gene Activated enhancer m. RNS Enhancer Promoter Inactive gene Start Hormone-Rec complex Promoter Active gene Activated enhancer m. RNS synthesis REASON: Xq 11 -12 mutation – androgenic receptor

Hermaphroditism True hermaphroditism - Both gonads (ovary and testis) or its tissue is present 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 46 XX – SRY translocation or 46 XXY – loss of Y chrs 46 XY – point mutation of Y chrs 46 XX/46 XY mosaicism (Hermaphroditism is frequent in invertebrates and plants)

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

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

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

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

X kromoszóma inaktiválódása (2) Transcriptional „silencing” Timing of asynchron replication Increased macro. H 2 X kromoszóma inaktiválódása (2) Transcriptional „silencing” Timing of asynchron replication Increased macro. H 2 A Hypoacethylated: H 3; H 4

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

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

Inactivation of X chromosome § Takes place randomly in the early phase of development 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 Xq 13 (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 Nők: functional hemizygotes

PAR regions PAR = pseudo autoszomal region § Never gets inactive § Telomeric position PAR regions PAR = pseudo autoszomal region § Never gets inactive § Telomeric position on the two sex chromosomes § PAR 1 – 2. 6 Mb; PAR 2 – 320 kb § Provide choice for partial meiotic pairing of X-Y chrs § „Obligatory crossing over” in PAR 1 (e. g. Xg blood group, IL-3 receptor)

X chrs PAR 1, PAR 2 Y chrs AR: Androgen receptor CSF 2 RA: X chrs PAR 1, PAR 2 Y chrs AR: Androgen receptor CSF 2 RA: Colony-stimulating factor 2 receptor alpha AZF: azoospermia factor ATRX: Alpha-thalassemia/mental retardation syndrome X-linked IL 3 RA: Interleukin 3 receptor alpha DAZ: Deleted in azoospermia DAX 1: DSS-AHC critical region X chromosome gene 1 SHOX: Short stature homeo box HY: Histocompatibility antigen Y FRA-X: Fragile X syndrome IL 9 R: Interleukin 9 receptor RBMY: RNA-binding motif protein Y chromosome DMD: Duchenne muscular dystrophy SRY: Sex-determining region Y chromosome GK: Glycerol kinase USP 9 Y: Ubiquitin-specific protease 9 Y chromosome Kal 1: Kallmann syndrome 1 ZFY: Zinc finger protein Y-linked POLA: DNA polymerase alpha XIST: X inactivation-specific transcript ZFX: Zinc finger protein X-linked

Frequent problems resulting disfunctions in sexual differentiation § mutations of SRY § disturbed biosynthesis 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)

§ Sex limited inheritance The trait is present in the genotype of both sex, § 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

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

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