6 -1

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
PENENTUAN JENIS KELAMIN
Proses untuk menentukan bahwa
organisme/individu tersebut jantan
atau betina


Seks
Physical

Psychological

Sociological


Komponen perkembangan seksual dan
identitas seksual meliputi aspek :
PRIMARY AND SECONDARY SEXUAL CHARACTERISTICS IN
MALES AND FEMALES
TDF GENE
HORMONES
HORMONE RECEPTORS AND GENE REGULATION
AIS MUTATION
SEX CHROMOSOME ANEUPLOIDE
KLINEFELTER SYNDROME
TURNER SYNDROME



SEX AND CHROMOSOMES

X AND Y

SEX AND HORMONES



6 -4
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Pada tahun 1950an telah ditemukan
kromosom Y yang berperanan penting
dalam determinasi seks
Manusia mempunyai 23 pasang kromosom
22 pasang disebut kromosom autosom
Sepasang kromosom seks
Females are XX
Males are XY



6 -6
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Sex chromosomes determine gender.
Human males are the
heterogametic sex with two
different sex chromosomes,
(XY).

Human females are the
homogametic sex (XX).

In other species sex (Birds
& Reptiles)
determination differs:
male birds ZZ
female birds ZW
6 -7
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Kromosom sex
XX = female - homogametic sex


XY = male - heterogametic sex

X X
X
Presence of Y chromosome is always Male
Male determining factor on short arm of Y
chromosome
6 -8
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Sex chromosomes
X and Y -> male

X and X -> female
6 -9
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Genes on the Y chromosome
Terdapat 3 macam gen pada
kromosom Y.

1. Genes shared with X
chromosome define the
pseudoautosomal regions
(PAR)

2. Genes similar to X
chromosome genes are X-
Y homologs

3. Genes unique to the Y
including SRY gene
6-10
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Peranan gen SRY pada aktivitas
perkembangan
6 -11
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Sexual development
Pada awal
perkembangan ada 2
kemungkinan menjadi
laki-laki atau wanita
Belum ada gonad yang
terbentuk sampai
menjelang umur 6
minggu
Embrio berkemang
menjadi laki-laki atau
wanita setelah ada
informasi dari
kromosom Y.
Sexual development
6 -13
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Genital development pathway
Genes involved in Human Sex
determination
6-16
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Mutations in genes involved in sexual
development affect gender
Mutation/absence of:
SRY gene Normal female development

Anti-Mullerian hormone gene Mullerian ducts persist in male

Testosterone gene Early development as female
Masculinization at puberty

DHT converting enzyme External structures lack signal
and develop as female,
internal structures are male.
4 komponen untuk determinasi seks
Gonadal sex
alat kelamin
Somatic sex
sel soma mengalami mitosis.
Mereka dapat dibedakan menjadi primer dan
sekunder
Perkembangan sekunder dibedakan menjadi
pertumbuhan bulu dan tubuh
Sex identification
Sexual orientation

LAKI-LAKI
Gonadal sex
Mempunyai testes untuk menghasilkan gamete
atau sperma
Somatic sex characteristics
Primer : mempunyai
penis dan scrotum
Sekunder :
Pertumbuhan bulu
Bulu dahi (kumis, jenggot), rambut di dada dll
Tubuh
pelvic berkembang, perkembangan oto terlihat
pada paha dan tubuh bagian atas

Secara umu perkembangan otot lebih cepat dibandingkan
dengan wanita

WANITA
Gonadal sex
Mempunyai Ovarium untuk menghasilkan telur
(ovum)
Primer : Pertumbuhan
Clitoris, labia, vagina, cervix, uterus, fallopian
tubes, dan mempunyai kemampuan untuk
melahirkan anak
Sekunder :
Bulu : lack of body hair
Tubuh :
rounded hips, breasts, ability to nurse offspring, menstrual
cycle, increased body fat composition, decreased upper body
strength, decreased ability to generate muscle mass at a fast
rate



Sexual identification
refers to our sex roles

Sexual orientation
defines our choices in sexual
partners



6-21
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Effect of castration and testosterone on adult male and
female behavior
6-22
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Hermaphroditism

True hermaphrodites
adults have both ovaries and testis at the same time
see in many lower vertebrates
earthworms

Pseudohermaphrodites
presence of both sexes in one individual, but at
different stages of life .
6-23
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Hermaphrodites
Suatu kasus, androgen insensitivity (AIS) partial: Hanya
sedikit merespon terhadap testeosteron yang dihasilkan
testes. Perkembangan genital Genital dua macam,
Perkembangan genital laki-laki komplengkap, genital
wanital tidak lengkap. Keadaan demikian biasanya disebut
hermaphrodite.

Kasus lain : Terjadi congenital adrenal dysplasia, Kelenjar
adrenal menghasilkan testosteron dengan jumlah yang
tidak normal pada embrio wanita. Dapat juga disebabkan
oleh perkembangan genital ambiguous, disebut
hermaphrodite.

Kasus lain (jarang) : chimera terjadi perkembangan embrio
campuran. Seseorang mempunyai kromosom XX dan XY.
Dia mempunyai testis dan ovarium disebut true
hermaphrodite.

6-24
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Male pseudohermaphroditism
- genotype is XY
- have testis (TDF functioning) (TDF testis determining
factor)
- produce MIH - female internal ducts degenerate
- produce testosterone
- male internal structures develop normally
- don't make DHT
- 5a-reductase activity
- fetus falls to generate male external structures
- default is a basic indifferent female forms
- child appears to be a girl
- raised as girls
- at puberty, genetically driven male phenotype emerges
from an apparent female phenotype
During male meiosis a synaptonemal
complex forms and one chiasma will
always form in this region
This results in regular exchange of material
between the tips of XP and YP
Any genes in this region are inherited as
thought they are autosomal and that is
why it is called the pseudoautosomal
region PAR
Contains 10 -20 known genes including the
RSP gene for making ribosomes

6 -26
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
This mutant hybrid chromosome is called an
X (TDF) chromosome (TDF testis
determining factor)

When it fertilizes an X bearing egg it results
in a 46 XX (TDF) male

When the corresponding mutant y
chromosome fertilizes an egg it results in
a 46 XY female
SEX REVERSAL
Karyotype is XX but this individual will
develop as an XY male because of the
presence of the testes determining factor
gene
Remember the presence of testes
determines gonadal sex in males
Even though these individual will look male
they will suffer from testicular atrophy or
small testes and sterility
What causes the sterility?
SEX REVERSAL
When a sperm carrying a Y (delTDF)
chromosome fertilizes an X bearing egg
the result is an
XY(delTDF) zygote
This individual develops as female even
though the karyotype is XY
Ovaries are reduced and eggs that are
produced will not survive
Have a female build but little pubic or
underarm hair
SEX REVERSAL
Can also have XY females without a
crossover event

Differ from normal males by only a
point mutation within the TDF gene

During fetal development the gonads
remain undifferentiated until about
the 6th week

The gender of the fetus is clearly
evident by the end of the fourth
month of gestation

The gonads, testes and ovaries, are
not the only source of testosterone
or estrogen in the developing fetus

6 -32
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Treatment should involve

genetic evaluation to determine the
sex chromosome composition

surgical evaluation to determine
gonadal sex or the presence of
ovaries and testes


The only step in sexual differentiation
that is controlled by genes is the
development of testicles by the testes
determining factor gene or TDF (and
genes like SOX9, DAX1 and WNT4,
carried in other chromosomes)

Once that is done the rest is determined
by the hormones produced by the
testicles or ovaries or adrenal cortex

HORMON
Chemical messengers dihasilkan oleh sel
tertentu, dilepaskan melalui aliran darah
menuju ke sel target

Hormon mengatur ekspresi gen pada sel target

Diantaranya adalah:

testosterone
dihasilkan oleh testis dan korteks adrenal pada laki-
laki
estrogen
Dihasilkan oleh ovarium dan korteks adrenal pada wanita


HORMONES
Travel in the blood stream to receptors on
the target cell

Receptors bind the hormone and carry it
across the plasma membrane of the cell to
the nucleus

Once inside the nucleus the hormone binds
to DNA to promote gene expression

It is the protein products of these genes that
lead to sexual differentiation



HORMONE RECEPTORS AND GENE
REGULATION
Gen TDF terdapat pada kromosom Y dan
mengkode perkembangan testis yang
menghasilkan testosteron

Reseptor testosteron diatur oleh gen yang
terdapat pada kromosom X

Gen AR atau reseptor androgen mengkode
untuk reseptor testosteron

Mutasi pada gen TDF menyebabkan
terjadinya testicular feminization

Individu dengan kromosom XY dan
kromosom Y normal mempunyai gen TDF
normal
HORMONE RECEPTORS AND GENE
REGULATION
Mereka tidak dapat merespon efek
maskulinisasi testosteron disebabkan
tidak ada reseptor transport testosteron
melewati membran sel

Perkembangan pada individu dengan
fenotip wanita yang steril

Mutasi demikian diketahui sebagai AIS
mutation ( androgen insensitivity
syndrome)
ANDROGEN INSENSITIVITY SYNDROME (AIS)
Produce testosterone
This is where they differ from the XY (TDF del)
individuals
They have no receptors to transport
testosterone across the cell membrane
Referred to as AIS females
Occur 1/20,000 births
Taller than average
External genitals are female
Vagina looks normal from the outside
Newborn is declared a girl and raised as such

ANDROGEN INSENSITIVITY SYNDROME
In utero AIS females develop testes because
TDF gene present so their gonadal sex is male
Produce MIF and Mullerian ducts regress
But the cells of the embryo cannot sense
testosterone
Instead they respond to the low levels of
estrogen being produced by the adrenal cortex
and develop as female
At birth appear female
No vagina, cervix, uterus or fallopian tubes

3 WAYS TO MANIFEST TESTICULAR FEMINIZATION
1. XY (TDF del)
no testosterone

2. XY point mutation of TDF gene
no testosterone

3. XY with normal Y but with AIS mutation
so no receptors for testosterone

All these individuals will be tall



SEX DETERMINATION IN HUMANS REQUIRES 4
ELEMENTS TO BECOME MALE
1. Y chromosome intact TDF gene (no point
mutations)

2. Sensing mechanism in the indifferent
gonad to the testes determining factor

3. Testosterone or estrogen produced by the
gonads

4. Testosterone or estrogen receptors in the
somatic tissues intact. No AIS (androgen
insensitivity syndrome)
SEX CHROMOSOME ANEUPLOIDY
Aneuploidy refers to an abnormal number of
chromosomes
Such anomolies occur often enough that
they have been recognized and studied by
medical science
We will discuss 3 different cases of
anuploidy
Klinefelter males XXY
XYY
Turner syndrome XO


6 -44
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
What determines gender?
Number of X chromosomes, or
presence of Y chromosome?
Individuals with unusual chromosome
combinations provide a clue:

X0
XXY
XY females
XX males
Female with Turner syndrome
Male with Klinefelter syndrome
=> Y chromosome determines gender.
SRY gene missing
Small bit of Y with SRY gene present
=> SRY gene on Y chromosome determines gender.
KLINEFELTER
Klinefelter males have an extra X
chromosome so they karyotype as XXY
males

Occurs 1/1000 live births

1940 Harry Klinefelter at Massachusetts
General Hospital described a syndrome
occurring in males not usually detected
until after puberty



KLINEFELTER
The testes are atrophied and do not produce
much testosterone
The level may be so low as to be about the
same amount as the estrogen produced
by the adrenal cortex
Because the level is so low during puberty
these individuals do not undergo normal
development of male secondary sex
characteristics, including muscular upper
body, narrow hips and chest and facial
hair



XYY MALES
1961 researchers at Roswell Park Memorial
Institute in Buffalo New York made the
first discovery of a male with karyotype
47 XYY

He was tall and of average intelligence and
did not have any serious physical
problems

Did not attract widespread interest until 4
years later



XYY MALES
1965 Jacobs in Scotland looked at the
chromosomes of 197 mentally subnormal
males with violent tendencies

They found 7 of those males had a 47 XYY
karyotype

7/197 = 1/28 a much higher ration than
among other groups of males tested
XYY occurs 1/1000 live births
Among tall males about 1/325
Among tall penal inmates 1/30



XYY MALES
XYY males are over represented in mental
and penal institutions
Large scale study done by the Danish
government suggested that tall males with
lower intellectual function are more likely
to be convicted of crimes regardless of
their karyotype
XYY karyotype is over represented in tall
males 1/325
More than 95% of all XYY males are not in
prision



6 -50
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
What is the consequence for females of having two X
chromosomes, while males have only one?

Females are XX, males are XY


6 -51
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
X Inactivation

- one X chromosome in each female cell is inactivated
- inactivation is a random process
Some cells - turn off dads X
Some cells - turn off moms X

Inactivated X chromosome can be seen in females cells
as the Barr body - Murray Barr (1949)
6 -52
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
X Inactivation
Interphase: Chromomes cant be stained, but a
dark-staining body is visible in the nuclei of
cells of female mammals
Barr Body: Inactive X
6 -53
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
6 -54
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Drumstick
Drumstick shaped
nuclear appendage.
1,5 m in diameter
and attached to the
nucleus by a
filament. Inactive X
chromosome of the
female.
6 -55
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Sessile Nodule

Inactive X
chromosome
found as nodule
on neutrophils of
females.
6 -56
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Which X gets inactivated?
Mary Lyon & Lianne Russell
(1961) proposed that one or
other of X becomes
inactivated at a particular
time in early development.
Within each cell,which X
becomes inactivated is
random.
As development proceeds, all
cells arising by cell division
after than time have the
same X inactivated as the
parent cell.

6 -57
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
In 64-cell embryos
Adult female
mammals are
mosaics for
genes on the X
chromosome.
6 -58
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Genetic Mosaics
calico cats are almost always
female
one X chromosome carries the
allele for black coat color
the other X chromosome carries
the allele for orange coat
color
in 64-cell embryos, one of each
pair of X chromosomes and
its genes are randomly
silenced
daughter cells inherit active or
inactive X chromosomes,
creating a cat with patches of
coat color

X
O
X
o

6 -59
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Tortoiseshell (calico) coat color
6 -60
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Tortoiseshell (calico) coat color
6 -61
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Tortoiseshell (calico) coat color
6 -62
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
6 -63
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
anhidrotic ectodermal dysplasia
6 -64
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
X
b
active

X
B
active
spotting gene - autosomal
6 -65
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Fig. 6.13
6 -66
Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
X-inactivation reveals alleles in cats heterozygous for the fur color gene
Genotype is X
yellow
/X
black

Yellow patches: black allele is inactive Black
patches: yellow allele is inactive
X
yellow
/X
black
X
yellow
/X
black