Sex Determination & Genitalia Development Flashcards
1
Q
biological sex determination (genotypic vs phenotypic)
A
- Variety of different structures or characteristics present at birth:
Genotypic sex determination:
o Number and type of sex chromosomes
o Absence and presence of sex determining genes (SRY, etc.)
Phenotypic sex determination:
o Type of gonads –> ovaries or testicles
o Internal reproductive anatomy including ducts or uterus
o External genitalia
Biochemical sex determination:
o sex hormone levels
2
Q
sex determination in humans - genetics
A
- Chromosomal and genetic sex is determined at fertilization
- In placental mammals and marsupials Y chromosome is determining male sex and phenotype
- In humans:
o XY: male: Heterogametic
o XX: female:Homogametic - Differentiation and dimorphism arises from circulation of sex steroids including Testosterone, Estrogen, Progesterone, 5ɑDHT
3
Q
genetic determinant of sex in humans in Y chromosome
A
- Presence of Y chromosome –> male
- Absence of Y chromosome –> female
46, XX female
45, X0 female
47, XXX female
46, XY male
47, XYY male
47, XXY male
Traditionally, the symbol ♀ designates female and the symbol ♂ designates male
4
Q
mapping of genes X and Y chromosomes
A
- Half of the genes on Y chromosome also on the X chromosome –> common evolutionary origin
- X chromosome large –> ~ 1500 genes, most unrelated to sex
- Y chromosome got smaller –> 83 genes, most related to sex determination and spermatogenesis
5
Q
Y chromosome
A
- SRY codes for testes determining factor TDF = transcription factor
- TDF directs embryonic gonads to develop into testes –> secretion of male hormones testosterone and Mullerian Inhibiting Substance
- Only passed on through males without any mixing of parental genes –> Y linked inheritance
6
Q
crossing over in male meiosis
A
- Crossing over: Tips of X and Y pair in meiosis in pseudo-autosomal regions: PAR1 and PAR2
- Crossover in PAR1 necessary in male meiosis for proper segregation of chromosomes
- SRY located on boarder of PAR1
- Non-recombining region of Y unique to Y chromosome
- -> gets passed on without crossing over
7
Q
dosage compensation of X chromosomes
A
- Additional X chromosome in females would lead to more gene products expressed compared to males
- Compensation mechanism: Inactivation of all X chromosome more than one (lionization) through silencing:
- Packaging into heterochromatin, high levels of DNA methylation, low levels of histone acetylation
- Not all genes silenced i.e. X-inactive specific transcript (Xist)
- Xist RNA = 17kb transcript is not translated –> thought to be a structural component of the inactivation process by physically associating with the inactive chromosome
8
Q
X inactivation example
A
- Fur pigmentation gene in tortoiseshell or calico cats is X-linked
- Male cats have only one X chromosome –> express only one coat color e.g. black
- Females are genetic mosaics, depending on which copy of the X chromosome is inactivated –> patchy orange/black coat colour
9
Q
development of the gonads - indifferent gonads
A
- Initial stages of gonadal development occur during 5th week
- Primordial germ cells migrate to the gonadal ridges = precursor of gonads
- Primitive sex cords for nutritional support to germ cells & regulation of development
- During early stages of fetal development 2 duct systems arise
- Genetically males & females possess initially both pairs of ducts
- Wolffian ducts = mesonephric ducts: Progenitors of the upper male genital tract
- Müllerian ducts = paramesonephric ducts: Progenitors of the upper female genital tract
- Before the 7th week, gonads of the two sexes are identical in appearance = indifferent gonads
10
Q
Barr Body
A
- In XX females –> one X randomly inactivated ~16 days post fertilization
- Inactive X forms a discrete body within the nucleus = Barr body
- All descendent cells keep same X inactive (mitotic divisions)
- No Barr bodies are observed in Turner (XO) females
- One Barr body is observed in Klinefelter (XXY) males
11
Q
early ovaries and testes
A
after 8th week, gonads change to male genotype if genes on Y chromosome expressed
- ovary develops from the cortex of the indifferent gonad; the medulla regresses
- testis develop form the medulla of the indifferent gonad, the cortex regresses
12
Q
sexual development during gestation
A
- Default pathway of sexual development in mammals is female, unless chemical signals are present that indicate it should develop as a male
- Male development in mammals is directed at every step
- If loss of direction –> subsequent development will follow female pathway
13
Q
sex determination in mammals
A
- testicular differentiation is controlled by time and dosage-sensitive genes
- Sexual differentiation begins when sex determining region Y (SRY) on Y chromosome produces testis determining factor (TDF)
- Presence of TDF directs the bipotential gonad to turn into testes rather that ovaries
- In the absence of a Y chromosome or no SRY the embryo will develop female structures
14
Q
fate of wolfian and mullerian ducts (male)
A
- With TDF: Testis develop from the medulla of the indifferent gonad -> cortex regresses
- Testes start producing testosterone and Muellerian inhibiting factor (MIF)
- Testosterone present –> Wolffian ducts change into male reproductive system
- MIF present – > Muellerian ducts regress
15
Q
fate of wolfing and mullerian ducts (female)
A
- Without TDF: Ovary develops from the cortex of the indifferent gonad –> medulla regresses
- If no testosterone and no Muellerian inhibiting factor –> default is female development
- MIF absent –> Müllerian ducts change into female reproductive system, Wolffian ducts degenerates
16
Q
sexual development in humans - gonads
A
- Differentiation of ovaries or testes from the bipotential gonadal ridge tissue in humans is fully achieved by 13 to 14 weeks, of fetal life
- In the male: Medullary cords develop, no cortical cords
- In the female: Cortical cords develop, medullary cords degenerate
17
Q
sexual development in humans - external genitalia
A
- Up till 8th week, Sex neutral, undifferentiated external genitalia
- Distinguishing sexual characteristics begin to appear during 9th week
- External genitalia not fully differentiated until the twelfth week
18
Q
differentiation of male external genitalia
A
- Genitalia start to masculinize at 8-9 weeks of gestation
- Fetal Leydig cells in testes produce testosterone
- Enzyme 5α-reductase-2 required to convert testosterone to thn androgen dihydrotestosterone (DHT)
- Complete masculinization of external genitalia by DHT by week 14
- In absence of either testosterone or 5α-reductase-2 –> sex neutral external genitalia develop along female lines
19
Q
descent of male testes
A
- Between 3rd month of pregnancy and its end, testes become transferred from the lumbar area into the future scrotum
- Transfer due to a combination of growth processes and hormonal influences -> androgens are an absolute requirement for this migration
- Testes reach internal inguinal ring by week 24
- Testis passing through inguinal canal to reach the scrotum
20
Q
differentiation of female external genitalia
A
- Primary female sexual differentiation occurs slowly in the fetus and does not depend on hormones –> occurs even if ovaries are absent
- X chromosomes bear genes for ovarian development and an autosomal gene also appears to play a role in ovarian organogenesis
- Ovary is not identifiable histologically until about the 10th week
- Primordial follicles develop at ~ 16 weeks: Each primordial follicle consists of an oogonium, derived from primordial germ cell
- Oogonia proliferate > than 7 million primary oocytes produced
o many degenerate before birth
o ~2 million are left at birth - Estrogen produced by the placenta and fetal ovaries appear to be involved in feminization of indifferent external genitalia
- Growth of the primordial phallus gradually ceases and becomes clitoris
- Labia majora are homologous to the scrotum
21
Q
disorders of sexual development (DSD)
A
- Conditions resulting in discordance between genetic, gonadal, or anatomic sex (internal & external structures) –> intersex individuals
- DSD result from mutations of any of the genes involved in typical sex development or differentiation
- Adequate expression of these genes & proper timing of their expression is important: e.g. normal but delayed androgenic effects result in incomplete masculinization of external genitalia while the persistent presence of Müllerian structures results from delayed MIS action
22
Q
ambiguous genitalia
A
- Rare condition where infant’s genital phenotype (external genitals) do not appear to be clearly either male for female
- Many causes have a genetic basis
- Genitals either incompletely developed or characteristics of both sexes present
- Previously surgery straight after birth –> often into female
- Intersex surgery has long-term consequences for affected individuals
- Assigned or genetic sex not always psychological sex –> gender identity
- Now delaying genital surgery on hermaphrodite babies - patient consent
23
Q
true hermaphrodites
A
- Organisms with both male and female reproductive organs
- Common in plant and animal kingdoms, and usually fertile
- Mechanism to avoid self fertilization in plants: Male and female gametes mature at different times –> less likelihood of self-pollination
24
Q
sexual reversal studies (SRY translocation)
A
- SRY located adjacent to PARS region
- In rare cases, SRY locus translocated onto X chromosome during crossing over
- If sperm containing SRY-containing X chromosome fertilises oocyte –> Karyotype will not match phenotypic expression i.e. SRY makes male factor and phenotypic expression but person is genetically female
25
Q
sexual reversal studies (swayer syndrome)
A
- Male karyotype 46, XY
- Y chromosome present –> genetically male
- Y chromosome has accidently lost the SRY gene in crossing over, or SRY mutation making it non-functional
- If no active SRY gene, which encodes TDF –> Development into a phenotypical female, even though person is genetically male
- Testes hidden in abdominal cavity and a female phenotype
26
Q
sexual development studies (XX male syndrome)
A
- Female karyotype: 46, XX
- No Y chromosome –> genetically female
- Offspring who inherit the SRY gene on the X chromosome (or translocation to an autosome)
- Formation of both testicles and ovaries in the same individual
- Incomplete penetrance possible (X inactivation)
- No MIF produced so female internal duct structures present
27
Q
androgen insensitivity syndrome (AIS)
A
- Affects individuals who are genetically male
- Male karyotype 46, XY
- Functional SRY gene –> TDF expressed, but can have outwardly female phenotype due to an underlying androgen insensitivity syndrome (AIS)
- Testes develop, testosterone is secreted but target cells lack receptors for the androgens – no masculinizing effects occur
- SRY has been shown to interact with the androgen receptor
- Female body type and gender identity but sterile
- Individuals can have complete or partial AIS
28
Q
testosterone deficiency
A
- Male karyotype 46, XY
- Functional SRY gene –> TDF expressed, but can have an outwardly female phenotype due to Leydig cells in testes not secreting testosterone
- Internal structures and gonads will develop into male structures, but the external genitalia will be female –> no masculinizing effects occur
- Individuals are sterile and will not go through puberty
29
Q
5-α-reductase deficiency
A
- Male karyotype 46, XY
- Functional SRY gene -> TDF expressed, but can have an outwardly female phenotype due to 5-α-reductase deficiency
- Do not produce enough dihydrotestosterone (DHT)
- Male gonads
- Born with female or ambiguous genitalia
30
Q
mullerian inhibiting substance deficiency
A
- If no gene for Mullerian Inhibiting Substance, Mullerian female ductal structures will form, but the external genitalia will be male due to presence of testosterone
- An affected individual is usually sterile because the testes do not develop normally and the presence of female ducts interferes with sperm transport
31
Q
true cryptochidism
A
- Absence of one or both testes from the scrotum
- Undescended testicle in 3-4% of boys
- Spermatogenesis: Production of viable sperm, is greatly affected by the temperature of the testicle but production of testosterone is not affected by temperature
- Untreated: Risk of infertility, testicular torsion, cancers
o If not descended by 6 months operation
32
Q
complications of sexual reversal issues
A
- olympic committee gender verification for females or males with sexual reversal issues
eg SRY gene, XXY males
33
Q
environmental sex determination
A
- Some reptiles environmental factors determine sex of progeny
- Turtles:
o Eggs incubated above 32°C develop into females
o Eggs below 28°C become male
o Eggs between 28°C-32°C develop into either gender - Some reptiles environmental factors determine sex of progeny
- Alligators:
o Eggs incubated below 30°C all females
o Eggs incubated above 34°C all males
o Temperature sensitive period days 7-21
o Natural sex ratio 5 females : 1 male
34
Q
sex change
A
- Female sexual characteristics are substituted for male ones, or vice versa
- Sex change may occur naturally as part of sequential hermaphroditism e.g. many species of coral reef fish
- Protandrous hermaphrodites: Organisms that are born male and at some point in their lifespan change sex to female e.g. clown fish
- Protogynous hermaphrodites: Organisms that are born female and at some point in their lifespan change sex to male
o Most common form of hermaphroditism in fish in nature
o ~75% of the 500 known sequentially hermaphroditic fish species are protogynous
