Presentation on theme: "Determination of sex ? Dr. habil. Kőhidai László Dept. Genetics, Cell- & Immunobiology, Semmelweis University 2014."— Presentation transcript:
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 inheritance Pathological forms
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 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 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
X chrs has a homologue NO homologue of X chrs HousekeepingTestis Other places Y chrs.
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 ‘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
SRY gene Yp 11.3 only one, 850 bp exon highly conserved 79 amino acid containing HMG box ( ‘Highly Mobile Group of proteins)
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
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)
Y kromoszóma X kromoszóma Ember Ember Macska Macska Conserved loci in mammalian X and Y chrs X and Y chrs
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
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)
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)
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
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
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)
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, 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. XX XY XYXYXX XX
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