Sex Determination & XY Chr. Disorders (Manchester) Flashcards Preview

Ann's M2M - Weeks 3, 4 > Sex Determination & XY Chr. Disorders (Manchester) > Flashcards

Flashcards in Sex Determination & XY Chr. Disorders (Manchester) Deck (45):

What are the advantages of sexual reproduction? (keep it clean now...)

1. Diploidy - protects against effects of mutation. you have a back-up gene
2. Random chromosomal assortment - increases variation
3. Recombination - new gene combos; speciation _protection_
4. Imprinting - regulates gene expression


What are the features / advantages of sexual dimorphism of a species?

1. Division of Labor - particularly w.r.t. reproduction
2. Cooperation
3. Sexually dependent selection - females (XX) have the advantage


Why do females (XX) have the selection advantage over males?

The females "store" the X chromosomes and select the males (only one X). Can select a mate for a specific trait and influence the genotypes that are kept - particularly the traits on the X chromosome.


What are Dr. Manchester's levels of sex?

1. Genetic
2. Gonadal development
3. Anatomic develoment
4. Genital development


In mammals, the embryo is preprogramed to produce a _____(M or F)______ phenotype unless _______________.

Female phenotype is default
unless specific sequences on the Y chromosome are present AND expressed.


Which embryonic structures form the duct systems in males vs. females?

Female (default):
mesonephric ducts regress
paramesonephric ducts ---> female duct system (Fallopian tube etc.)

Y chr. present; SRY/TDF expressed
mesonephric ducts --> male duct system (from testes on up)


Where is the SRY gene located?

SRY (sex-determining region on Y) is located on the Y chromosome.
In particular, on the short arm of Y (Yp) near but not in the pseudo-autosomal region on Yp.


What is the pseudoautosomal region on the X and Y chr's?

Regions where recombination between X & Y can occur during meiosis.


What other genes are on the Y chromosome (as mentioned in lecture)?

1. SRY
2. DAZ gene - expressed only in pre-meiotic germ cells; important for spermatogenesis
3. USP9Y gene - "ubiquitin specific peptidase 9 on Y) - important for sperm production
4. AZFa, b and c - azoospermia factor
5. a lot of satellite DNA on the long arm


What is a Barr body?

The inactivated X chromosome in a female cell
Females are mosaic. Half their cells express one X chr, the other half will express the other X chr.

Barr body is visibly present in interphase.


What gene is in charge of X-inactivation?
Briefly explain how X-inactivation occurs.

XIST gene
is a noncoding RNA that associates with the inactive X
promotes DNA methylation (silencing) and histone protein modifications


How much of an deactivated X chromosome is actually inactive?
What are some consequences of this?

85-90% in inactive.
the other 10-15% 'excapes' inactivation and is in fact expressed.

Females thus express more genes than males.
Helps to explain Turner Syndrome. Even though an X is "inactive" in every female cell, a few genes are still on and are necessary for normal development.


Explain how X-inactivation may not be random.

1. Abnormal X chromosome: the normal one stays active. likely due to death of the cells with the abnormal one active.

2. Balanced X;autosome translocation: ** the normal X is inactivated *** possibly selecting agains inactivation of autosomal genes.

3. Unbalanced X;autosome translocation: inactivation of the abnormal der(X) chromosome.


How might nonrandom X inactivation be deleterious even if the most "normal" X is still active?

If the normal X chromosome carries an X-linked recessive mutation, it is no longer protected by the other X carrying the dominant (non-mutant) allele.

EX: Duchenne Muscular Dystrophy. X-linked recessive; rare cases in females are due to X-inactivation favoring the disease carrying X chr.


Do you remember where the primordial germ cells come from?

The yolk sack! The migrate into the genital ridge


What two genes are responsible for formation of gonads right as the germ cells are migrating into the genital ridge?

SF1 - steriodogenic factor 1
WT - Wilms tumor gene- tumor supressor gene; urogenital development in males

mutations in these genes result in ovaries even in an XY individual


What genes determine if you get ovaries or testes?



What do SOX9 and DAX1 do?

SOX9 gene -> SOX9 protein --> interacts with MIF (mullerian inhibiting factor). crucial for normal male reproductive machinery.

DAX1 gene = dosage sensitive sex reversal, adrenal hypoplasia critical region on X chromosome (woah) - anti-testes gene, antagonist of SRY


SRY gene mainly acts on what gene?



Two DAX genes in males does what?

sex reversal

two DAX in females leads to becoming female. (dosage sensitive!!)


What does MIF do?

MIF produces active regression of Müllerian ducts.
Otherwise the Müllerian ducts become the Fallopian tubes etc.


What is the prostatic utricle?

remnant of Müllerian duct in males. is estrogen responsive so important in prostate cancer.


From what structure does the uterus form?

Müllerian ducts


Development of male external genitalia is __________ dependent.



What example was given in lecture regarding brain sexual dimorphism?

language processing in the brain
female: both sides more
male: one side more


What cells produce MIF in males?

Sertoli cells


What do the leydig cells do in males?

produce testosterone


What does steroid 5-alpha-reductase do?

What does 5-alpha-reductase deficiency do in 46-XY individuals?

Normally stimulates external genitalia developent.

5-alpha-reductase deficiency (autosomal recessive)results in failure of end organs to activate testosterone to dihydortestosterone (DHT)
*incomplete phallic development
*severe hypospadias (pseudovaginal perineal hypospadias)
*ambiguous genetalia


Describe leydig cell hypoplasia

autosomal recessive
lack of testosterone production --> male pseudohermaphriditism

defect is mutation in LHR gene (luteinizing hormone receptor)


In regards to the X & Y's pseudoautosomal regions, where are they and what do they do?

On the distal end of the short arms Xp and Yp is a region (nearly identical to each other) where the X & Y chromosome pair and undergo homologous recombination just like an autosomal homologous pair.

On the other distal end, Xq, Yq is another such region. The q end is smaller.


How many genes does the Y chromosome contain and what are most of these gene for?

Y chr. is very gene poor compared to X and autosomal chrs.

Contains about 50 genes and most are related to male sexual development.


What cells "welcome" the primordial germ cells into the genital ridges and what germ layer are the welcome cells from?

Cord cells from mesoderm



Testis-determining factor. Gene on the Y chr. that directs formation of testis, seminiferous tubules, Leydig cells (Testosterone secreting cells that respond to chorionic gonadotropin from the placenta)


What is dictyone?

The fancy term for the phase of Meiosis I in which the oogonia are suspended for many years until ovulation.


How is SRY implicated in the following two diseases?

46 XX male
46 XY female

(note, other genes in the sex differentiation pathway may be implicated in these same diseases.)

Both are sex-reversal disorders.

One possible cause is by the rare occurance of the SRY gene participating in crossing over during meiosis (or deletion or mutation). Thus, SRY is lost in the 46 XY female individual and gained in the 46 XX male individual.


What would an interstitial deletion on Y possibly cause?

In the proximal regions of the Y chromosome is a number of AZF genes (AZFa, AZFb, AZFc) that when deleted, result in azoospermia. They are thus important for spermatogenesis.


Molecularly, how is X-inactivation accomplished?

Similar to imprinting, CpG repeats in the promoter region of many X genes are methylated (by DNA methyltransferase)

Histone variants also contribute to X inactivation.
Histone variant macroH2A is highly enriched in inactive X chromatin and is a way to cytologically distinguish the active from the inactive X chromosome.


Most of the genes on the inactivated X chromosome that escape in activation are located where?

Most are at the distal Xp region, clustered together.

a small amt are on the distal Xq region.


XIST gene is located?

Which X chromosome expresses the XIST gene?

proximal Xq

expressed only by the INACTIVE X chromosome.


What is the estimated incidence of X-linked mental retardation?

1 in 500 to 1 in 1000


List some general clinical presentations that warrant investigation into sex chromosome-linked diseases.

delay onset puberty
primary or secondary amenorrhea
ambiguous genitalia


List the 4 "well-defined" sex chromosome aneuploidy syndromes.

1. Klinefelter syndrome (47, XXY)
2. XYY syndrome (47, XYY)
3. Trisomy X (47, XXX)
4. Turner syndrome (45, X)


Review the following conditions on p. 110...

1. Camptomelic dysplasia - mutated SOX9; lethal skeletal malformations
2. denys-drash syndrome - autosome abnormality; ambiguous genetalia
3. frasier syndrome - autosome abnormality; XY complete gonadal dysgenesis


Female pseudohermaphroditism - most common cause

CAH - congenital adrenal hyperplasia
deficit in enzymes required for cortisol biosynthesis
results in virilization of female infants

CAH also causes many ambiguous external genetalia cases


Androgen insensitivity syndrome

X-linked (a.k.a. testicular feminization)
46, XY
testes secrete testosterone, but end organs are unresponsive (insensitive) due to lack of androgen receptors

testes present; external genitalia are female