Download SRY gene

Determination of sex
?
Dr. habil. Kőhidai László
Dept. Genetics, Cell- & Immunobiology,
Semmelweis University
2017.
 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)
- 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
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
!
5% of haploid 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
 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
X chrs has
a homologue
Y chrs.
Housekeeping
Testis
Other places
?
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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
 WT1
 SOX9
 MIS
 DSS
 DAX-1
 SRY
!
‘Steroidogenic’ factor, nuclear receptor which
regulates expression of steroid hydroxylases
Wilm’s tumor locus determined chrs 11p13
‘SRY-releated HMG-box’, chrs 17q24.3-25.1
about 14 genes
product of Sertoli-cells; chrs. 19p13.3
regulatory domaine which binds F-1, its promoter
binds SRY
‘Dosage Sensitive Sex reversal’,
Duplication on chrs Xp21.2-p22.2
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 conserved
 79 amino acid containing HMG box
( ‘Highly Mobile Group of proteins)
DAX1
Ovary
WNT4
SF1
WT1
LHX9
Bipotencial
gonade
SRY
SOX9
Testis
!
Follicular
cells
Follicle
Theca
cells
Estrogen
Sertoli- SF1
AMH
cells
Leydig
cells
SF1
Testosteron
Genotype
inactive
DAX1
SRY
DAX1
SRY
DAX1
2 copies
DAX1
Gonades
Phenotype
Testis
Male
Ovary
Female
Gonade
disgenesis
Female
Ref.: Genetics Review Group (1995)
Sexually not differentiated
Male
Female
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)
X
Chromosome
!
DAX1
Y
Chromosome
SRY
SF1
WNT1
Ref.: Aberger F.
OVARY
SOX9
TESTIS
Sox9
Promoter
Amh
Wt-1
Sox9
SF1
Amh
Wt-1
Sox9
SF1
Gata
Ref.: Arango et al. (1999)
Amh
!
Evolution of huma sex chromosomes (1)
Sex chrs. Developes Az NRY expansion NRY expansion
(SMCY, UBE1Y)
SRY (NRY) blocks
(RBMY, RPS4Y)
Recombination
290-350 Mill.year 230-300 Mill year 130-170 Mill year
Autosome
birds
recomb.
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
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
Human
Cat
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
mRNS synthesis
REASON: Xq11-12 mutation – androgenic 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)
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
XY
XX
‘Drumstick’
Barr-bodies
Inactivation of X chromosome (1)
Xist expression
- inhibitor factor
Inhibitor factor
LINE helps in
sreading the effect
Xist RNA coats
the chromosome
!
Inactivation of X chromosome (2)
Transcriptional
„silencing”
Timing of asynchron
replication
Increased macroH2A
Hypoacethylated:
H3; H4
!
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
XY
XX
>
Mary F. Lyon
X
XY
=
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
Nők: 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)
X chrs
PAR1, PAR2
Y chrs
AR: Androgen receptor
CSF2RA: Colony-stimulating
factor 2 receptor alpha
AZF: azoospermia factor
ATRX: Alpha-thalassemia/mental retardation syndrome
X-linked
IL3RA: Interleukin 3 receptor
alpha
DAZ: Deleted in azoospermia
DAX1: DSS-AHC critical region X chromosome gene 1
SHOX: Short stature homeo
box
HY: Histocompatibility antigen Y
FRA-X: Fragile X syndrome
IL9R: Interleukin 9 receptor
RBMY: RNA-binding motif protein Y chromosome
DMD: Duchenne muscular dystrophy
SRY: Sex-determining region Y chromosome
GK: Glycerol kinase
USP9Y: Ubiquitin-specific protease 9 Y chromosome
Kal1: 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 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.
X Y
X X
X Y
X Y
X X
X X
 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