Sex Chromosomes Flashcards
What does PAR stand for
pseudoautosomal region
The X and Y chromosomes do what during meiosis
pair and segregate
what is the pseudoautosomal region?
regions b/w X and Y that allow them to pair during meiosis
what is the important PAR region in X and Y chrom
PAR1
what is the only location crossing over occurs in in x and Y chromosomes
Pseudoutosomal region - PAR1
how many copies of PAR1 genes do males have
2 - because it’s on both X and Y chromosome
how many copies of PAR1 genes do females have
2 copies but on one X chromosome it is inactivated
the genes in pseudoautosomal region behave in what way
as if they are autosomes b/c they are on both the X and Y chromsoome
What is SRY
sex determining gene - determines male sex development
Where is SRY located
very close to PAR1 region
what gene is deleted in azoospermia
AZF
If SRY why is present what will happen
male sexual development
What is testes determining factor
SRY
If you are 46, XX with SRY what will happen
phenotypically male
If SRY has recombination what happens
The X chromosome would have SRY and present phenotypically as males or the Y will not have SRY and will present phenotypically as females
Are 46, XX with SRY + be fretil
No, missing other genes for spermatogenesis
46, XY SRY- are what
phenotypcically female
are 46, XY SRY- fertile?
no
need both copies of X chromosome for normal oocyte development
What is the master regulating gene for female developmen
WNT4
What does WNT4 activate to specify ovarian development
DAX1
What does SRY acticate
SOX9
What does SOX9 activate
SF1 and other genes
What does SOX9 inhibit
WNT4 development
What does DAX1 inhibit
SOX9
What does SF1 and other genes do
testes develop
Once ovaries develop, what is produced
estradiol
what does estradiol signal for development
external female genitalia
what do mullerian ducts form
internal female genitalia
Once testes are present what androgen is synthesized
testosterone
what does testosterone initiate development of
external male genitalia & with wolifan ducts the internal male genitalia
Dihydrotestosterone is what
more potent than testosterone
testosterone with 5 alpha reductase makes what
dihydrotestosterone
What does dihydortestosterone do regarding testes
accelerates development of testes
What happens if androgen signaling is not working properly
Androgen insensitivity syndrome
androgens are what
steroid hormones
what hormone does testes produce besides testosterone
MIF - mullerian inhibitory factor
In the absence of AR what pathway will stay active
MIF pathway
What does AR stand for
Androgen receptor
In absence of AR what happens phenotypically
may be external female genitalia but will not be functional
An individual with null mutation in SRY gene would be expected to appear as a:
infertile female
DSD stands for what
Disorders of sex development
what is male pseudohermapharoditism now called
XY DSD
What is female pseudohermaphroditism now called
XX DSD
If there is SOX9 loss of function what happens
testicular development won’t occur, no inhition of female part
What happens if there is SOX9 loss of function or DAX1 gain of function
46 XY sex reversal ,intersex or gonadal dysgenesis is common
What happens if there is DAX1 loss of function or SOX9 gain of function
46, XX sex reversal, intersex or gonadal dysgensis is common
DAX1 loss of function is another form of what
X-linked form of congenital adrenal hyperplasia
very generally what happens so SOX9/DAX1 gain of function
allelic heterogeneity, enhancer mutations, or the usual explanations for variable expressivity: the effect of modifier genes or stochastic events.
what is hermaphroditism
gonads change
what is pseudohermatphrotisism
gonds are what they should be, external genitalia is different
What causes Androgen insensitivey syndrome
mutations in Androgen Receptor Gene
What does AR gene stand for
androgen receptor gene
What does AIS stand for
androgen insensitivity syndrome
AIS is also known as what
XY DSD
XY DSD was formerly called what
male pseudohermaphroditism
What is MOI of AIS
X-linked recessive
how is AIS X-linked recessive
rare transcription factor mutation resulting in recessive inheritance
If pt is 46 XY with AIS what happens
feminization of male genitalia
undermasculinized to ambiguous to complete sex reversal
femal secondary sexual phenotypes
testes develop (why it’s pseudohermaphroditism) ,inferfility
no ovaries or uterus
If pt is 46, XX with AIS what happens
heterozygous carriers
minimally affected
Why are females not reallyk affeted with AIS
females do’nt really use androgens
What is most severe form of AIS
complete androgen insensitivey syndrome (CAIS)
What does CAIS stand for
Complete androgen insensitivyt syndrome
What is intermediate AIS
Partial androgen insensitivy syndrome( PAID)
what is mild form of AIS
mild androgen insensitivity syndrome (MAIS)
Severe
Female genitalia & secondary sex characteristic
Often present as teenagers due to amenorrhea
is what?
CAIS
Intermediate
Variable, predominant male, female or ambiguous genitalia
is what?
PAIS
Mild
Male genitalia with possible undermasculinization, infertility
is what?
MAIS
androgen receptor gene has what repeat
CAG & GGN
In GGN repeat in exon 1 of androgen receptor gene what can the repeated nucleotide be?
anything except A
GGN repeat leads to what aa
glycine
variation in GGN repeat is associated with what
male patterned baldness
CAG repeat in AR gene can lead to what
loss of function of androgen receptor
complete loss of funciton of AR gene is what
AIS
partial loss of function of AR gene is what
male pseudohermaphroditism
What is dosage compensation
in females, one of the x chromosomes is inactivated which balances what is expessed on x chromosome b/w male and females - so males and females express same amount of gene product
What do mammals always use for dosage compensation
X inactivation
What is another term for x chromosome inactivation
lyoniztion
what is lyonization onw called
the lyon law
when is x chromosome inactive in males
in males during spermatogonia
before primordial germ cell can go into meiosis what has to happen with X chromosomes
the inactive x chromosome needs to be reactivated
when will female have both x chromosomes active
during meiosis
will zygote have two active x chromosomes
yes
when does blastocyst inactive x chromosome
week 1
which x chromosome will be inactive in fetus
random
about half of the cells in female adult will have 1/2 what and 1/2 what regarding X chromosome
1/2 maternal X chromosome
1/2 paternal X chromosome
how are females mosaics
they have 1/2 paternal and 1/2 maternal X expresed in their cells
Androgen receptor is a what
transcription factor
If there is 70:30 of paternal/maternal X chromosomes activated is that normal
yes
what do inactive chromosomes do to not be expressed
condensed into heterochromatin
What does inactive x chromosome look like under microscope
Barr body
Even though 1 X chromosome is inactivated, what is not?
PAR1 region - it is still expressed in inactive chromosome
Besides PAR1 region what else stays active in inactive X chromosome
10-15% of chromosome ia active
another 10% if variably active
What is X inacrivation contorlled by
X inactivation center
what does XIC stand for
X inactivation Center
XIC contains what important gene
XIST gene
what gene controls X inactivation
XIST gene
What does XIST stand for
X inactivation specific transcript
what is strange about evolutionary conservation in XIST
it has low evolutionary conservation w/b different species
XIST is a functional:
RNA molecule
Does XIST have an open reading frame
no - it doesnt make protein
Is XIST protein coding
no - it is a functional RNA
XIST is expressed from which chromosomes
both but mainly the inactive one
where is XIST expressed on active X
pinpoint of it
XIST does what to inactive X
coats it and induces chromatin condensation thereofre gene silencing
at what stage does XIST RNA increase dramatically
late blastocyst stage when X chromosomes need to be randomly inactivated
silencing of X chromosome can be blocked by what
antisense RNA
If Xis is overproduced what can happen
it can spread to autosomal sequences and even silence genes in male
blocking factor is expressed from what
autosome NOT sex chromosome
how does blockin factor ensure only one X chromosome will be inactive
there is only enough produced to bind to one X chromosome
Where does blocking factor bind to X chromosome
near Xist gene
the x chromosome that is bound by blocking factor is
active
why is the x chromosome that is bound by blocking factor active
it binds to Xist which stops it from spreading and inactivating the chromosome
how does blockin protein allow activation
stops Xist gene from spreading which would cause inactivation. It binds near xist gene
histone acetylation is associated with what
open chromatin
a = active
histone methylation is associated with what
heterochromatin
What does blocking factor do
binds to presumptive active X
What is nonrandom (skewed) X inactivation
one of the X chromosomes being preferetially activated it’s outside of 70:30 ratio
Even in Nonrandom/skewed X inactivation, what is happening
they are still being randomly activated, it just happens that one of them is more activated than another
skewed is better nerve
X activation is always
random
what can lead to the skewing of X inactivation
If one of the X chromosomes carry a mutation then the cell may die which leads to advantage of one of the X chromosomes being active, and against the other X chromosome being active
If X chromosome and autosome has translocation describe what happens
severe imbalance, part of X is being expressed that shouldn’t be, part of autosome is not being expressed that should be. the cell is not viable so will die.
describe nonrandom X inactivation in female DMD
All genes are expressed in right proportions but there is not functional dystrophin gene expressed
The case where the functional dystrophin gene would be activated ,there is not equal translocation being expressed, part of the X was translocated to a autoaomse so there is extra X being expressed, cell dies
What does SCID stand for
severe combined immunodeficiency
what are the two forms of SCID
ADA Deficiency
X-linked SCID
Desribe ADA deficiency
deficiency of adenosine deaminase
Describe X-linked SCID
Deficiency of IL2RG
Describe how ADA deficiency and X-linked SCID are related
both do not have functional lymphocytes, so they don’t have functional immune system. any little illness is very dangerous for them.
What is MOI for ADA deficiency
AR
What is MOI for X-linked SCID
X-linked recessive
Describe the X-linked skewing you could expect to see in cases like X-linked SCID
mutant X chromosome is inactive in most cell types
What is one way you can look at the inactive vs. active X chromosome when comparing through PCR tests
if it is methylated it is inactive (heterochromatin) so look at the methylation
What SHOULD you see regarding peaks when looking at X chromosome for activation
Should see two smaller peaks b/c half of them should be active in each cell
The X chromosome carrying the mutation will be preferentially
inactivated
What does it mean if you only see one peak when looking at PCR digested with HpaII
one peak means that only one chromsomoe is activated - this means there is mutation in the inactive one. The inactive one is what you see when you digest with HpaII
What does undigested DNA look at on PCR for alleles
what alleles they have, not whether something is active or inactive
What does ATRX stand for
Alpha thalassemia with mental retardation
Where has mutation in ATRX
ATRX gene
What does ATRX gene encode
SWI2/SNF protein
What does SWI2/SNF protein do
chromatin remodelng - helicase that determines chromatin structure and regulates gene expression
Do female carriers of hemophelia have skewed activation?
no
What doe CFNS stand for
craniofrontonasal syndrome
What is MOI of CFNS
X-linked dominant
Where is mutation in CFNS
EFNB1
what does EFNB1 encode
Ephrin B1
severe hyperelorism, coronal synostosis, grooved tip of nose, longitudinal nail split is what disease
CFNS
Which chromosome is the mutation on in ATRX
active X chromsome (this is exception, usually it’s on the inactive)
What protein is affected in CFNS
Ephrin B1
What does defect in Ephrin B1 cause
defect in boundaries
Why are males with CFNS less severe phenotypically than females
They still have boundaries b/c there is no Ephrin B1 expressed at all, so other things make up. So the boundary isn’t perfect but there is still a boundary. In females there is some expression of Ephrin B1, trying to use one signaling pathway, other cells using another signaling pathway, boundary forms incorrectly giving severe phenotype
What is MOI of Rett Syndrome
X-linked dominant
What gender does Rett Syndrome afect
females - affects males so severley they don’t survive
What gene is mtuated in Rett Syndrome
MEPC2
What does MEPC2 encode?
MePC2
What does MePC2 stand for
Methyl CpG-binding protein 2
Why are females and not males affect in X-linked Rett Syndrome
males are so severely affected they die
symptoms: profound mental retardation in females, early onset, characteristic hand-wringing, progressive microcephaly, some have seizures is what disease
rett syndrome
