X-linked Inheritance.

Sex
Determination.

Specialty: General medicine

Module 2. Theme 3
Year: 1st

Lecturer:
Elena Koshpaeva, PhD
Practical class
Associate professor
Department of Medical Biology and Genetics
Kazan State Medical University
 Sex-Linked Inheritance
• Most animals and many plants show sexual dimorphism; in other words, most
individuals are either male or female.
• Heterogametic sex The sex that is determined by possession of two dissimilar
sex chromosomes. The heterogametic sex produces reproductive cells
(gametes) of two kinds, half containing an X chromosome and half a Y
chromosome.
• Homogametic sex - the sex that is determined by possession of two similar sex
chromosomes. All the reproductive cells (gametes) produced by the
homogametic sex have the same kind of sex chromosome
• In humans, fruit flies: XX => female;
XY => male

• Inheritance of sex is just like any other

trait, except it involve inheritance of an
entire chromosome

• Because there are genes on sex

chromosomes, inheritance of certain trait
can be sex-linked

• Sex – is Mendelian trait

• Ratio: 1XX : 1XY

! The inheritance patterns of genes on the sex chromosomes

are different from those of autosomal genes
 Structure of X- and Y-chromosomes
X chromosome:
• is larger and has a more active euchromatin region than its Y chromosome
• contains around 150 000 000 base pairs (150 Mb) of DNA, approximately 5% of
the genetic content of each cell (in female cell)
• Contains 1400 genes (approx. 900 – structural genes (resp.for protein))
Y chromosome:
Is smaller
contains 79 structural genes
 The number of possible ancestors on the X chromosome
inheritance line at a given ancestral generation follows the
Fibonacci sequence.
 Sex Determination
A biological system that determines the development of a
sexual characteristics in an organism

Sex Linkage
The phenotypic expression of an allele related to the
chromosomal sex of the individual

Sex-linked traits involve genes that are carried only on the X or Y

chromosomes, which are involved in determining the sex of animals.
 Sex Determination

Some mechanisms of sex determination include:

a. Genotypic sex determination, in which sex is
governed by genotype.
b. Genic sex determination, in which sex
chromosomes are not involved.
 Genotypic Sex Determination Systems

Genotypic sex determination may occur two

different ways:
a. In the Y-chromosome mechanism of sex-determination
(e.g., in mammals), the Y chromosome determines sex,
conferring maleness.
b. In the X chromosome-autosome balance system (e.g.,
Drosophila, Caenorhabditis elegans) the ratio between
number of X chromosomes and number of sets of
autosomes determines sex. Y is required for male fertility,
but does not determine sex.
Sex Determination in Mammals

1.Mammals use the Y-chromosome mechanism

of sex-determination, in which the Y
chromosome determines sex by conferring
maleness.
2.Sex of mammals is determined by a gene on
the Y chromosome, testis-determining factor.
In the absence of this gene, gonads develop
into ovaries.
Sex determination in humans
 Evidence for the Y Chromosome Mechanism
of Sex Determination
1. Understanding of the Y chromosome mechanism of sex
determination came from the study of individuals with unusual
chromosome complements. In humans these aneuploidies include:
a. XO individuals, who are sterile females exhibiting Turner syndrome.
Most XO fetuses die before birth. Surviving Turner syndrome
individuals become noticeable at puberty, when secondary sexual
characteristics fail to develop. Other traits include:
i. Below average height.

ii. Weblike necks.

iii. Poorly developed breasts.
iv. Immature internal sexual organs.
v. Reduced ability to interpret spatial relationships.
Evidence for the Y Chromosome Mechanism
of Sex Determination

b. XXY individuals, who are male and have Klinefelter

syndrome. Other traits include:
i. Above average height.
ii. Breast development in about 50% of XXY individuals.
iii. Subnormal intelligence in some cases.
c. XYY individuals are male, and tend to be taller than average.
Fertility is sometimes affected.
d. XXX individuals are usually normal women,
although they may be slightly less fertile and a few
have below average intelligence.
 Evidence for the Y Chromosome Mechanism
of Sex Determination

e. Higher numbers of X
and/or Y
chromosomes are
sometimes found,
including XXXY,
XXXXY, and XXYY.
The effects are similar
to Klinefelter
syndrome.
Dosage compensation of X-linked genes
Many species should have a sex-determination system based on females with
two X chromosomes and males with only one.

In these species, how is the numerical difference of X-linked genes

accommodated?

A priori, three mechanisms may compensate for this difference:

(1) each X-linked gene could work twice as hard in males as it does in
females,

(2) one copy of each X-linked gene could be inactivated in females, or

(3) each X-linked gene could work half as hard in females as it does in males.
Gene dosage varies between the sexes in mammals, because females have two
copies of X while males have one.

Early in development, gene expression from the X chromosome must be equalized to

avoid death. Different dosage compensation systems have evolved in different
organisms.
 Inactivation of x-linked genes in female mammals

In mammals, female somatic cell nuclei

contain a Barr body (highly condensed
chromatin) while male nuclei not.

The Lyon hypothesis explains the

phenomenon:
a.Barr body is a condensed and (mostly)
inactivated X chromosome. Lyonization of
one chromosome leaves one
transcriptionally active X, equalizing gene
dose between the sexes.
b.An X is randomly chosen in each cell for
inactivation early in development (in
humans, day 16 postfertilization).
 Sex-Linked Inheritance
• Sex-chromosome inheritance patterns were first
investigated in the early 1900s in the laboratory of the
great geneticist Thomas Hunt Morgan, using the fruit fly
Drosophila melanogaster

Drosophila melanogaster, the

common fruit fly
100% Red
 Sex-Linked Inheritance
• Sex-chromosome inheritance patterns were first
investigated in the early 1900s in the laboratory of the
great geneticist Thomas Hunt Morgan, using the fruit fly
Drosophila melanogaster

Drosophila melanogaster, the

common fruit fly
50% Red : 50% White
 Sex Linkage
The gene for the trait is located on either the X or Y chromosome.

1. Morgan (1910) found a mutant white-eyed male fly, and used it in

a series of experiments that showed a gene for eye color located
on the X chromosome.
a. First, he crossed the white-eyed male with a wild-type (red-eyed) female.
All F1 flies had red eyes. Therefore, the white-eyed trait is recessive.
b. Next, F1 were interbred. They produced an F2 with:
i. 3,470 red-eyed flies.
ii. 782 white-eyed flies.
c. The recessive number is too small to fit Mendelian ratios (explanation
discovered later is that white-eyed flies have lower viability).
d. All of the F2 white-eyed flies were male.
 Sex Linkage
e. Morgan’s hypothesis was that this eye color gene is located on the X chromosome. If
so,
i. Males are hemizygous, because there is no homologous gene on the Y. The original
mutant male’s genotype was w/Y (hemizygous with the recessive allele).
ii. Females may be homozygous or heterozygous. The wild-type female in the original
cross was w+/w+ (homozygous for red eyes).
iii. The F1 flies were w+/w (females) and w+/Y (males) (females all heterozygous,
males hemizygous dominant).
iv. The F2 data complete a crisscross inheritance pattern, with transmission from the
mutant fly through his daughter (who is heterozygous) to his grandson. The F2 were:

w+ Y
w+ w+/ w+ w+/ Y
Red-eyed females Red-eyed males
w w +/ w w/ Y
Red-eyed females White-eyed males
 Sex Linkage
v. Morgan’s hypothesis was confirmed by an experiment reciprocal to
the original cross. A white-eyed female (w/w) was crossed with a
wild-type male (w+/Y). Results of the reciprocal cross:
(1) All F1 females had red eyes (w+/w).
(2) All F1 males had white eyes (w/Y).
vi. These F1 results are different from those in the original cross, where
all the F1 had red eyes. When the F1 from the reciprocal cross
interbred, the F2 were:
w Y

w+ w+/ w w+/ Y
Red-eyed females Red-eyed males

w w/ w w/ Y
White-eyed females White-eyed males
Reciprocal cross : Homozygous white-
eyed female  red-eyed (wild-type) male
 Sex Linkage

2. Morgan’s discovery of X-linked inheritance showed that

when results of reciprocal crosses are different, and ratios
differ between progeny of different sexes, the gene involved
is likely to be X-linked (sex-linked).
3. This was strong evidence that genes are located on
chromosomes. Morgan received the 1933 Nobel Prize for
Physiology or Medicine for this work.
 Inheritance of an X-linked Recessive Disease Condition
• Haemophilia is a genetic disorder whereby the body’s ability to control
blood clotting (and hence stop bleeding) is impaired
The formation of a blood clot
is controlled by a cascade of
coagulation factors whose
genes are located on the X
chromosome.

When one of these factors

becomes defective, fibrin
formation is prevented -
meaning bleeding continues
for a long time.

Different forms of
haemophilia can occur, based
on which specific coagulation
factor is mutated (e.g.
haemophilia A = factor VIII)
 Inheritance of an X-linked Recessive Disease Condition

Red-green colour blindness is a genetic disorder whereby an individual fails

to discriminate between red and green hues

This condition is caused by a

mutation to the red or green
retinal photoreceptors, which
are located on the X
chromosome

Red-green colour blindness

can be diagnosed using the
Ishihara colour test
 Genes on the human y chromosome
Y-Linked Characteristics

• The Human Genome Project has identified

397 possible genes on the human Y
chromosome
• fewer than 100 of them seem to be
functional

• Only a handful of Y-linked traits had been

detected, even though transmission from
father to son should make such traits easy
to identify in conventional pedigree
analysis.
✓ Exhibit a distinct pattern of inheritance
✓ Present only in males
✓ All male offspring of a male with a Y-linked
trait inherit the trait
✓ Relatively little genetic information on the Y
chromosome
Genes on both the Х and У chromosomes
• Some genes are present on both the X and Y chromosomes,
mostly near the ends of the short arms

• Alleles of these genes do not follow a distinct X- or Y-linked

pattern of inheritance
• Genes are transmitted from mothers and fathers to sons and
daughters alike, mimicking the inheritance of an autosomal
gene

Such genes are therefore

called pseudoautosomal
genes
 Recognizing Sex-linked Inheritance

• Alleles on sex chromosomes are inherited in

predictable patterns
• Y-linked trait can be inherited only from the
paternal grandfather (the father’s father),
never from the maternal grandfather
• X-linked characteristics also exhibit a
distinctive pattern of inheritance
 Sex-Linkage
When writing alleles that are sex-linked, we use a convention like that
more complicated one from back at the beginning: we write the X or Y
normally, and make the allele itself a superscript.

• If the A gene is on the X chromosome, then genotypes can have one

of these alleles: XA, Xa, and Y.
– If there’s no allele, the Y becomes sort of like the “free square” in
the middle of a bingo board. It doesn’t affect the phenotype at all.
– So a man who is XAY will have the dominant version of the trait,
and a man who is XaY will have the recessive version of the trait.
He doesn’t have two little-a’s, true, but there’s also no dominant
allele to “drown out” the recessive allele.
 Sex-Linkage

• if the gene is on the Y chromosome, we could have

the alleles X, YA, or Ya.
• Phenotype:
– XX - Will not have the trait, whatever it is.
– XYA - Dominant phenotype
– XYa - Recessive phenotype
 Sex-Linkage

• Phenotypes for people with a gene on the X-

chromosome
– XBXB - Dominant
– XBXb - Dominant
– XbXb - Recessive
– XBY - Dominant
– XbY - Recessive
 Sex-Linkage
• Punnett Squares for sex-linked traits work like normal,
except that you use the superscripts.
• A Punnett Square for a cross of XBXb with XBY:

XB Xb
50% girl with dominant phenotype

XB XB XB XB Xb 25% boy with dominant phenotype

Y XBY XbY 25% boy with recessive phenotype