Sex Determination

and
Inheritance Related to Sex

Some Terminologies
Hermaphroditism: both sexes in the same
organism
Monoecious: both male and female reproductive
structures in the same organism
Dioecious: either male or female reproductive
structures in one organism

Chromosomal Sex-Determination Systems:

Sex chromosomes and non-sex chromosomes
(autosomes)
XX-XO system:
XX female
XO male
Example: grasshoppers

XX-XY system:
XX female
XY male
Example: some plants, insects, reptiles, and all mammals

Chromosomal Sex-Determination Systems

ZZ-ZW system:
ZZ male
ZW female

Which one is the homogametic?

Examples: Birds, snakes, butterflies, some amphibians,

and fishes

Concept Check 1
How does the heterogametic sex differ from the
homogametic sex?
a. The heterogametic sex is male; the homogametic sex is
female.
b. Gametes of the heterogametic sex have different sex
chromosomes; gametes of homogametic sex have the
same sex chromosome.
c. Gametes of the heterogametic sex all contain a Y
chromosome.
d. Gametes of the homogametic sex all contain an X
chromosome.

 Haplodiploidy system:
Haploid set male
Diploid set female
Examples: Bees, wasps,
and ants

Genic Sex-Determining System

In some plants and protozoans, sex is genetically
determined, but there are no obvious differences in the
chromosomes of males and females: there are no sex
chromosomes.
Genic sex determination: genotypes at one or more loci
determine the sex of an individual plant or protozoan.
No sex chromosomes, only the sex-determining genes

Environmental Sex Determination

Environmental factors :
Limpets position in the stack
Temperature in turtles

Sex Determination in Drosophila melanogaster

D. melanogaster has 8 chromosomes:

3 pairs of autosomes + 1 par of sex chromosomes

Genic balance system: in D. melanogaster, the dosage of

X chromosomes determines sex.
For example, both XY and XO flies are phenotypically male.
In contrast, both XX and XXY flies are phenotypically female.

X : A ratio (X, number of X chromosomes;

A, number of haploid sets of autosomes)

Concept Check 2
What will be the sexual phenotype of a fruit fly with
XXYYY sex chromosomes and two sets of
autosomes?
a.
b.
c.
d.

male
female
Intersex
metamale

Sex Determination in Humans

Chromosomal sex is determined at

fertilization
Sexual differences begin in the 7th week
Sex is influenced by genetic and
environmental factors
Females (generally XX) do not have a Y
chromosome
Males (generally XY) have a Y chromosome

Sex Determination in Humans

Three levels to sexual development:
chromosomal sex: presence or absence of the Y
chromosome
gonadal sex (primary sex determination): whether the
gonads develop as testes or ovaries depends on the
presence or absence of the SRY gene, usually found on the Y
chromsome
phenotypic sex (secondary sex determination): all of the
internal and external structures develop along male or female
lines depending on which hormones are secreted by the
gonads.
Phenotypic sex also has a couple of distinct systems: the
internal ducts, and the external genitalia
Two important times: pre-natal development and puberty

Chromosomal Sex Determination

We have 46 chromosomes: 23
pairs, one set from each parent.
One pair of chromosomes is the
sex chromosomes, X and Y.
the other chromosomes just have
numbers: 1-22.

A person with 2 X chromosomes

(46,XX) is female, and a person
with an X and a Y (46,XY) is male.

Human karyotype: chromsomes

stained to show bands, from a male

The Role of Sex Chromosomes

The X chromosome contains genetic information

essential for both sexes; at least one copy of an X is
required.
The male-determining gene is located on the Y
chromosome. A single Y, even in the presence of several
X, still produces a male phenotype.
The absence of Y results in a female phenotype.

Meiosis

Reproduction involves putting one copy of each chromosome into each sperm cell
or egg cell: the process of meiosis. So, meiosis starts with 46 chromosomes,
chooses one from each pair, and puts 23 chromosomes in each sperm or egg.
For males, 1/2 the sperm get an X chromosome, and the other 1/2 get a Y chromosome.

Sometimes meiosis goes wrong (non-disjunction), and a sperm or egg might get 2
sex chromosomes, or 0 sex chromosomes, leading people with 47 or 45
chromosomes. More on this later...

Fertilization
Fertilization means the
sperm joins the egg,
creating the zygote,
which is the first cell of
the new individual
person.
23 chromosomes
from sperm plus 23
from the egg
restores the total of
46 chromosomes.
And, the new
individual is now
either 46,XX (female)
or 46,XY (male)

The SRY Gene

How the Y chromosome determines sex.
The SRY gene, located on the Y chromosome, is the
primary determinant of sexual development.
That is, if a developing embryo has a functional SRY
gene in its cells, it will develop as a male. And, if there is
no functional SRY, the embryo develops as female.
Although the SRY gene is usually on the Y chromosome, it
occasionally gets transferred to the X.
this leads to 46,XX males
Also, sometimes the SRY gene is inactivated by mutation.
Leading to 46,XY females (Swyer syndrome)
it is also possible to have a partially inactive SRY gene,
leading to ambiguous genitalia

Pseudoautosomal Regions (PARs)

regions on Y chromosome that share
homology with regions on the X
chromosome
synapse and recombine with it during
meiosis
Presence of such a pairing region is
critical to segregation of the X and Y
chromosomes during male
gametogenesis

Y chromosome
Y chromosome
contains:
the malespecific region
of the Y (MSY)
a sexdetermining
region of the Y
(SRY)

Sex Determination in Humans XX-XY

SRY gene on the Y chromosome determines maleness
Turner syndrome: XO; 1/3000 female births
Klinefelter syndrome: XXY, or XXXY, or XXXXY, or
XXYY; 1/1000 male births
Poly-X females: 1/1000 female births, XXX

Male

Sperm with Y chromosome

Egg with X sex chromosome

Fertilized by

Embryo with XY sex chromosomes

Sex-determining region of
the Y chromosome (SRY)
brings about development
of undifferentiated gonads
and testes

Fertilized by

Genetic
sex

Gonadal
sex

Testes secrete masculinizing

hormones, including
testosterone, a potent androgen

In presence of testicular
hormones, undifferentiated
reproductive tract and
external genitalia develop
along male lines

Female

Sperm with X chromosome

Embryo with XX sex chromosomes

No Y chromosome, so no
SRY. With no masculinizing
influence, undifferentiated
gonads develop into ovaries

No androgens secreted

Phenotypic
sex

With no masculinizing
hormones, undifferentiated
reproductive tract and
external genitalia develop
along female lines

Mutations that Alter Phenotypic Sex

Hemaphrodites
Have both male and female gonads

Androgen insensitivity
XY males become phenotypic females

Pseudohermaphroditism
XY males at birth are phenotypically female;
at puberty develop a male phenotype

Variant Conditions

The large majority of people develop as either completely

male or completely female. However, 1% or more of the
population has some variant condition.

Chromosomal variations
Gene mutations
External conditions

A few important terms:

Gynecomastia: development of breasts in a male
Hypospadias: the urethra exits the male body at the base of the
penis instead of at the tip, due to failure of the urethra to
become enclosed by the urogenital folds.
Hermaphrodite: a person exhibiting both male and female
characteristics
a true hermaphrodite has both testicular and ovarian
tissue, sometimes as separate organs but more frequently
as an ovotestis: a single organ with different parts. Very
rare.
Male pseudo-hermaphrodite has testes and no ovaries; a
female pseudo-hermaphrodite has ovaries and no testes.
Worth noting: the Intersex Society of North America finds the
term hermaphrodite offensive, and prefers intersex.

Chromosomal Variants

Meiosis, the form of cell division that generates the

sperm and eggs, carefully puts exactly 1 copy of
each chromosome pair into each cell.
Sometimes meiosis goes wrong and puts 0 or 2
copies of some chromosome into a sperm or egg
cell.
the best example of this: Down syndrome, which
starts with a sperm or egg with 2 copies of
chromosome 21.
Maternal age effect: more frequent in older mothers

The sex chromosomes are quite tolerant of variants.

Most common types involve 45 or 47 chromosomes

There are many other, rarer types, with 48 or even
49 chromosomes, such as 49,XXXXY. Such
conditions almost always lead to serious mental
deficiencies.
The general rule: if the Y is present, the person
is internally and externally male.

Klinefelter Syndrome: 47,XXY

Occurs about 1 per 500 male births. It is the

most common type of sex chromosome variant.
The presence of the Y chromosome causes a
47,XXY person to be male, both externally and
internally, because the testes are formed.
Root symptom: small testes, leading to low
testosterone levels. Most, but not all, are sterile.

At puberty, reduced facial and body hair, broader

hips, breast development.

47,XXY children tend to be taller, less physically

strong and coordinated, and more quiet and
shyer than their peers. Some language and
learning problems are common: often slow to
learn to speak and read.

Testosterone replacement therapy helps with

some of the physical symptoms. Speech therapy
and educational services also help.

46,XX males, with the SRY

gene on the X, have the
Klinefelter appearance.

Turner Syndrome: 45,X

Only one X chromosome, sometimes called XO.

Since there is no Y chromosome, the primary
gonad is the ovary, and 45,X people are female.
About 1 in 2500 live female births.
10% of all spontaneous abortions (miscarriages) are
due to Turner syndrome; about 98% of all Turners
embryos die before birth

Ovaries completely non-functional, so 45,X women

are sterile, with no production of sex hormones and
development of secondary sexual characteristics at
puberty.
Some characteristic physical abnormalities: short
stature, low hairline, webbed skin at neck. Kidney
and circulatory system problems

Often have problems with spatial reasoning and

mathematics. Also social difficulties: inability to
understand others emotions.

Can be treated with growth hormone and estrogen.

You need 2 X chromosomes for

proper ovarian development.
46,XY females (non-functional
SRYgene) resemble Turners

47,XYY

About 1 in 1000 live male births. Most XYYs are never

detected: a very mild condition.
since 1960, newly discovered chromosome variants arent
given the discoverers name
It was once thought to create hyper-aggressive males with a
tendency towards criminal behavior.
Richard Speck, the killer of eight student nurses in 1966,
pretended (falsely) to be an XYY to obtain leniency.
A 1968 letter to the Lancet claimed that XYY men were in
prison at a rate "25-60 times as high as the prevalence in
the general population, based on finding 2 XYYs.
the plot of Aliens 3 involves a prison planet for XYYs.
XYYs are generally normal in appearance, but with average
height about 7 cm above expected and normal build. Perhaps
acne is more common than average, but this is disputed.
They are often more physically active, somewhat delayed in
emotional maturity, and have a slight increase in learning and
speech problems.
Fertile, normal sex drive, very rarely pass 2 Ys to sons.

1970s British TV series:

He had an extra Y, which
made him a macho criminal!

47,XXX
About 1 in 1000 live female births. So mild
as to be only rarely detected. Also called
triplo-X.
Originally called superfemale (early
1960s). <rolls eyes>
Widely varying symptoms, including none
at all.
Slightly more passive and quiet as babies,
less assertive, delayed motor and linguistic
skills. Delayed emotional maturity and
social skills. Some have slightly decreased
intelligence and learning difficulties.

Lower back problems are common.

Fertility normal, dont generally pass 2 Xs
to children.

Both terms refer to people who have 2 different chromosome

sets in different cells. For example, a 46,XX/47,XXY person
has some cells with 46 chromosomes and other cells with 47.
A mosaic starts out with a single fertilized egg. During an
early cell division in the embryo, one cell gained or lost a
chromosome. (This is non-disjunction, the same event that
happens in meiosis to generate Klinefelters, etc.)
A chimera starts out with two separate fertilized eggs,
fraternal twins. The two embryos fuse together to form a
single individual.
It is not uncommon to have fraternal twins sharing some
blood cells, a blood chimera
fused embryo chimeras are very rare: there are about 3040 known XX/XY chimeras (and undoubtedly an equal
number same sex chimeras). tetragametic chimera
Chimerism is probably the way most true hermaphrodites,
who have both ovarian and testicular tissue, are formed.
However, actual XX/XY chimeras have been everything
from normal male, through various degrees of ambiguous
genitalia, to normal female.
Sexual development can be quite variable in such people,
because the characteristics depend on which cells have which
chromosome complement.

Mosaics and
Chimeras

Gene Mutations

The variants up to now all involve whole chromosomes, which have lots of
genes on them. The effects of changing the dosage of many genes tend
to be widespread but mild. (or completely lethal, as with most non-sex
chromosomes).
Now we are going to look at several gene mutations. In these cases, only
one gene is affected, but it is completely knocked out. This can lead to
large effects, but limited to a few subsystems in the body.
Rates are different: for chromosome changes, about 1 in 1000 births is a
typical frequency. For gene mutations, each parent needs to contribute a
mutated copy of the gene, so rates are usually 1 in 10,000 births or less.
Inheritance is also a factor here: most chromosomal variants are
spontaneous events and dont run in families. Gene mutations are usually
inherited variants: there is often a family/community history of the variant
type.
New mutations do occur spontaneously, but its rare. Most gene variants are
inherited from the parents.

5-alpha Reductase Deficiency (5ARD)

5-alpha reductase is the enzyme that converts testosterone
into DHT. If both copies of the gene that makes this enzyme
are defective, the person has 5-ARD.
Recall that DHT is responsible for the development of
male external genitalia
At birth, people with 5-ARD have undescended testes and
male ducts (with no female ducts), but genitalia that appear
somewhere between female and ambiguous, including a a
very small penis with hypospadias (which appears to be an
enlarged clitoris), and a short vagina. Often raised as girls
At puberty, the increase in testosterone is large enough that
some DHT gets made, and they develop a male appearance:
the testes descend, the penis enlarges, facial hair appears,
the voice deepens, muscles develop.
Large group in the Dominican Republic: maybe 1 in 90 men.
Called Guevedoces, a corruption of huevos a los doce
(eggs--testicles- at age 12). Raised as girls, they easily
switch to the male role.
Other groups found in Malta, Jordan, Pakistan, New
Guinea
Also, a character on the TV show
Nip and Tuck has this condition

Guevodoces Case

Androgen Insensitivity

Incidence about 1 in 20,000 births

Used to be called testicular feminization. 46,XY with normal

(undescended) testes. The testes secrete testosterone, but the cells
lack a receptor for it. No receptor = no response to the hormone.
Complete androgen insensitivity, CAIS.

As a result, the male ducts (vas deferens, epididymus, seminal

vesicles) are not present. However, the testes secrete MIS, which
causes the female ducts (uterus, fallopian tubes, upper vagina) to
degenerate.

External genitalia develop as male if DHT is present, but

testosterone and DHT use the same receptor. So, female
external genitalia, including the lower 2/3 of the vagina.

At puberty, the testes again secrete testosterone. The enzyme

aromatase converts it into estradiol. Thus, female secondary sexual
characteristics develop. Often voluptuously feminine. No
menstruation of course: no ovaries and no uterus. Pubic and armpit
hair is usually scant or absent.

Occasionally, the undescended testes can become cancerous, so they

are often surgically removed after puberty is complete (so as to get
normal female development).

Partial Androgen Insensitivity

Sometimes, the testosterone receptors work

inefficiently, due to less drastic mutations than in
CAIS. In these cases, the body cells respond in a
variable manner to testosterone, leading a a wide
variety of ambiguous genitalia. PAIS = partial
androgen insensitivity. Also called Reifenstein
syndrome.

there is also mild androgen insensitivity (MAIS),

which leads to completely male appearance
internally and externally, but with some impairment
of masculinization at puberty.

Variable symptoms: can be predominantly male

(with hypospadia, abnormal scrotum, small penis),
predominantly female (with enlarged clitoris, fused
labia, separate vaginal and urethral openings), or
ambiguous genitalia (microphallus--less than 1 cm
long), labia-like scrotum, hypospadia,
gynecomastia.
Similar variability in male internal ducts; females
ducts are usually absent due to MIS secretion.
Sometimes people with PAIS change gender
identity after puberty, in either direction.

Congenital Adrenal Hyperplasia

The adrenal glands sit on top of the kidneys and secrete a

variety of steroid hormones, including cortisone (stress
response), aldosterone (salt balance) and androgens (male sex
hormones).
Steroid hormones are made from cholesterol through a series
of biochemical steps. Any one of these steps can be inactivated
by mutation. However, about 95% of CAH cases involve
defects in the enzyme 21-hydroxylase.
21-hydroxylase is needed to make cortisol and aldosterone (but
not androgens). Cortisol is secreted in response to the pituitary
hormone ACTH, in a feedback loop. So, if there isnt enough
cortisol being made, more ACTH is made, and this causes the
adrenal gland to grow larger (hyperplasia).
And, all of those steroid molecules that were destined to
become cortisol and aldosterone get diverted into male sex
hormones (androstendione and testosterone), which dont need
the 21-hydroxylase.
Very little effect on male fetus, which is already making
testosterone, except that after birth the lack of salt regulation
can lead to death from excess salt secretion (salt-wasting).

Female fetuses with 21-hydroxlase deficiency have

some problems due to the flood of androgens released
by the adrenal gland. The ovaries are normal, and the
female (Mullerian) ducts are also normal (since no MIS is
made).

Main effects are on the external genitalia: enlarged

clitoris, sometimes with an enclosed urethra (i.e. like the
penis), labia can fuse and become scrotum-like, vaginal
opening can be partly or completely closed.

Appearance at birth varies a lot. Some appear to be

normal male with undescended (because non-existent)
testes. However, the chromosomes are XX, the gonads
are ovaries, and the uterus and fallopian tubes are
usually intact.

Normally, very little androgen is made in childhood. CAH

causes excess androgens throughout life, leading to
rapid growth, but an early closure of the bone growth
plates: a very short adult. Also: early puberty, with
menstrual problems (and poor sperm production in
males).

The other hormones, aldosterone and cortisol, need to

be replaced. The cortisol replacement calms the ACTH
activity, leading to less androgen production.

CAH

CAH is the most frequent cause

of non-standard genitals in
genetically female (XX) children.

Some Environmental Causes

Progestin-induced virilization. Progestin was used to prevent

miscarriages in the 1950s and 60s. Related to this is the use of androgens
to treat endometriosis during that time period, and occasional accidental use
of androgens. 160 known cases.
XX fetuses develop as normal females with functioning ovaries, but they may
develop some male secondary characteristics and often have enlarged clitorises.
Effects are very similar to CAH.

Freemartin: usually seen in cattle: female and male twins, with testosterone
from male leaking over to the female due to a shared placenta. Normal
female appearance, but undeveloped ovaries and masculinized behavior.
Rare or unknown in humans.
Aldous Huxleys book Brave New World has human freemartins created
by hormone treatment of fetuses.

Dosage Compensation
Equalizes the amount of X
chromosome products in
both sexes
In XX females an inactivated
X chromosome forms a Barr
body in each cell
XY males do not contain
Barr bodies

Dosage Compensation

Mechanisms that generate the same amount of X-linked

gene product regardless of chromosome dosage
Mammals: One of two X chromosomes in the
female cell is inactivated
Drosophila: X chromosome in males generates twice
the amount of gene product when compared to females
C.elegans:ActivityofgenesonBOTHXchromosomesis
halvedtoequalactivityofgenesonsingleXchromosomein
males.

Lyon Hypothesis
One X chromosome is genetically active in the body cells;
the second is inactive and tightly coiled
Either the maternal or paternal chromosome can be
inactivated
Inactivation is permanent (reset in germ cells)
Inactivation of second X equalizes the activity of X linked
genes in males and females

Cytological correlates of X-inactivation in mammals

Barr body:
Present in somatic XX nuclei
Not present in XY nuclei
In X-chromosome aneuploids, all but one X
become Barr bodies
Females

Barr bodies

Active X

XX

XO

XXX

XXXX

Cytological correlates of X-inactivation in mammals

Barr body:
Present in somatic XX nuclei
Not present in XY nuclei
In X-chromosome aneuploids, all but one X
become Barr bodies
Females
XX
XO
XXX
XXXX

Barr Bodies Active X

Males Barr Bodies Active X
1
1
XY
0
1
0
1
XXY
1
1
2
1
XXXY
2
1
3
1

Females Are Mosaics for X-Linked Genes

Some cells express
the maternal X and
others express the
paternal X
Cats heterozygous
for orange and black
gene must carry two
X chromosomes
Fig. 7.16

Calico cats are always female

Woman Heterozygous for

Anhidrotic Ectodermal
Dysplasia

EM of Barr Body

Fig. 7.17

X Inactivation Center (Xic)

Contains several genes
The XIST gene causes
the chromosome to
become coated with XIST
RNA and inactivated.
Occurs at approximately
32-cell- embryo stage
Fig. 7.18

4.2 Sex-Linked Characteristics Are Determined

by Genes on the Sex Chromosomes
X-Linked White Eyes in Drosophila
Nondisjunction and the Chromosome Theory of Inheritance
X-Linked Color Blindness in Humans
Symbols for X-Linked Genes
Dosage Compensation
Z-Linked Characteristics
Y-Linked Characteristics

X-Linked Characteristics
X-linked white eyes in Drosophila

What is a sex-influenced trait?

A sex-influenced trait is controlled by a pair of
alleles found on the autosomes. (Not on sex
chromosomes)

Its expression is influenced by gender

(presence of hormones such as: estrogen,
progesterone, testosterone, etc.).
Sex-influenced traits vary in the degree of the
phenotypic expression.

Example: Pattern Baldness

It can occur in both males and females,
but is influenced by the hormone
testosterone.

The combination of alleles lead to different

phenotypic expressions depending on gender.

What is the probability that you will be bald if your father is

homozygous and balding, and your mother is homozygous
and not balding?

Father = BB x Mother = BB
All offspring are BB
If you are male, then you will
be bald.
If you are female, then you will not be bald.

Actually, Its not that simple

Many human traits are controlled
by
several different alleles and
environmental
factors. These
traits are polygenic,
such as
height. (Actually the man at
the
right is a pituitary giant at 79
due to an uncontrolled amount
of growth hormone)

This means that we cannot fully explain pattern baldness

using sex-influenced inheritance. It is not easy to explain
that diversity found in different ages of onset, as well as
the severity of baldness.

Another Example: Singing voice

The genotype that causes males to have a
tenor voice (highest male singing voice), causes
females to have a contralto voice (the deepest
female singing voice).

The genotype that causes males

to have deep bass voices, is the
same genotype that causes females
to have high soprano voices.

Peacock plumage
The plumage of a male peacock is highly
decorated and colored, while the plumage of a
female peahen is dull by comparison.

A variety of peacock feathers

Sex-Influenced Traits
Expressed in males and
females
Usually controlled by
autosomal genes
Generally phenotypic
variations are due to
hormonal differences
between the sexes
An example is male
pattern baldness
Fig. 7.20

Chapter 7 Human
Heredity by Michael

Sex-influenced traits
Some autosomal genes govern traits that show up in
both sexes but their expression differs because of
hormonal differences
example: pattern baldness in males. b allele is recessive
in one sex and dominant in the other

Male

Female

b+/b+

non-bald

non-bald

b+/b

bald

non-bald

b/b

bald

bald

Chapter 7 Human
Heredity by Michael

Sex-Limited Traits
Genes that produce a phenotype in only one sex
Examples
Precocious puberty
Secondary sex characteristics

Chapter 7 Human
Heredity by Michael