Theme:

Mendel's laws.

THE LESSON No.1

(урок №1)
Genetic Terminology
 Genetics - the study of gene structure
and action and the patterns of
inheritance of traits from parent to
offspring. Study of heredity.
 Heredity - passing of traits from parent
to offspring
 Trait - any characteristic that can be
passed from parent to offspring
Genetic Information
• Gene – basic unit of genetic information.
Genes determine the inherited
characters.
• Genome – the collection of genetic
information.
• Chromosomes – storage units of genes.
• DNA - is a nucleic acid that contains the
genetic instructions specifying the
biological development of all cellular
forms of life
2
Chromosome Logical Structure.

• Locus – location of a
gene/marker on the
chromosome.

• Allele – alternate form of

a particular gene located
on the identical locus on
homologous chromosome
in the cells of diploid
organisms

• Allele – any of several

forms of a gene, usually
arising through mutation,
that are responsible for
hereditary variation

4
 Allele

β chain

• Each allele originated in a

different individual does not
have the exactly identical
β chain’ sequence. It has slight DNA
variations due to mutation.
• The alteration of a single
nucleotide in the gene for the
beta chain of the hemoglobin
protein turns a normal
hemoglobin gene into a sickle-
cell hemoglobin gene.
• Thus, Allele is one of two or
more versions of a gene.
mother
• In a diploid organism,
that has two copies of
each chromosome,
two alleles make up
the individual's
genotype. An
individual inherits two
alleles for each gene,
one from each parent.

father fertilization
Designer “Genes”
 For any gene, an
individual may possess
only two alleles -
dominant & recessive.
 Dominant - stronger of
two genes expressed in
the hybrid; represented
by a capital letter (R)
 Recessive - gene that
shows up less often in a
cross; represented by a
lowercase letter (r)

7
Dominant vs. Recessive

A dominant allele is expressed

even if it is paired with a
recessive allele.

A recessive allele is only visible

when paired with another
recessive allele.

8
More Terminology
 Genotype - gene combination for
a trait (e.g. RR, Rr, rr) of an
organism
 Phenotype - the physical feature
resulting from a genotype (e.g.
red, white)
 Homozygous genotype - gene
combination involving 2
dominant or 2 recessive genes
(e.g. RR or rr); also called pure -
the two alleles for a trait are
the same (AA or aa)
 Heterozygous genotype - gene
combination of one dominant &
one recessive allele (e.g. Rr);
also called hybrid - the two
alleles for a trait are different
(Aa)

9
Genetic Crosses
• Hybridisation,
hybridization, hybridizing,
interbreeding,
crossbreeding, crossing,
cross – the act of mixing
different species or varieties
of animals or plants and
thus to produce hybrids.
 Types of Genetic Crosses
Example of monohybrid cross
 Monohybrid cross - crossing
parents who differ in only one
trait (AA with aa)
e.g. flower color, seed color,
seed shape
 Dihybrid cross - crossing
parents who differ in two traits
(AAEE with aaee)
e.g. hair color & hair length
 Polyhybrid cross – crossing
parents who differ in more than
two traits

Example of dihybrid cross: black vs. brown and short vs. long

11
Types of Genetic Crosses
• Test-cross - a cross between
an organism whose
genotype for a certain trait
is unknown and an
organism that is
homozygous recessive for
that trait so the unknown
genotype can be
determined from that of the
offspring
Types of Genetic Crosses
• back cross is a crossing of
a hybrid with one of
its parents.
Types of Genetic Crosses
• True Breeding (pure breeding) -
a kind of breeding in which the
parents with a particular
phenotype produce offspring only
with the same phenotype (when
the offspring is exactly like the
parent).
• A true-breeding lineage occurs
when offspring inherit identical
alleles from its parents,
generation after generation
without changes.
Gregor Mendel
(1822-1884)

Responsible for
the Laws
governing
Inheritance of
Traits

15
Gregor Johann Mendel
Austrian monk

Studied the inheritance of

traits in pea plants

Developed the laws of

inheritance

Mendel's work was not

recognized until the turn of the
20th century

16
Gregor Johann Mendel
Between 1856 and
1863, Mendel cultivated
and tested some 28,000
pea plants
He found that the
plants' offspring
retained traits of the
parents
Called the “Father of
Genetics"

17
Mendel's Traits
 Reproduction in Flowering Plants
Pollen contains sperm
Produced by the stamen
Ovary contains eggs
Found inside the flower

Pollen carries sperm to the eggs

for fertilization
Self-fertilization can occur in
the same flower
Cross-fertilization can occur
between flowers
copyright cmassengale 19
Mendel’s Experimental Methods
 Mendel hand-pollinated
flowers using a paintbrush

 He could snip the stamens to

prevent self-pollination

 Covered each flower with a

cloth bag

 He traced traits through the

several generations
copyright cmassengale 20
How Mendel Began
Mendel produced
pure strains by
allowing the plants
to self-pollinate
for several
generations

21
Monohybrid Cross
• Mendel crossed purebred plants with
opposite forms of a trait. He called these
plants the parental generation, or P
generation. For instance, purebred plants
with yellow seeds were crossed with
purebred plants with green seeds.

• Mendel observed that all of the offspring

grew to be plants with yellow seeds.
None resembled the parent with green
seeds. He called this generation of
offspring the first filial , or F1
generation, (The word filial means
“son” in Latin.)
 Trait Gene Genotype
Yellow Y YY, Yy
green y yy

P: ♀ YY × ♂ yy
yellow green

G: Y y

F1 Yy
yellow
 Rule (Law) of Dominance
In a cross of parents that are pure for
contrasting traits, only one form of the
trait will appear in the next generation.
All the offspring will be heterozygous and
express only the dominant trait.
RR x rr yields all Rr (yellow seeds)

copyright cmassengale 25
 Monohybrid Cross
• Mendel then crossed two of the
offspring plants with yellow seeds
produced from his first
YY yy
experiment.

• Mendel called this second

generation of plants the second
Yy
filial, F2, generation. To his
surprise, Mendel observed that
Yy Yy this generation had a mix of plants
with yellow and green seeds. This
occurred even though none of the
YY Yy Yy yy F1 parents were with green seeds.
P (F1): ♀ Yy × ♂ Yy
yellow yellow

G: Y y Y y

F1 YY; Yy; Yy; yy

yellow yellow yellow green

phenotypic ratio: 3 (yellow) :1 (green) 3:1

genotypic ratio: 1 (YY) : 2 (Yy) : 1 (yy) 1:2:1
 Mendel’s Law of Segregation
Mendel's first law of genetics
• Mendel’s first law, the Law of Segregation, has three parts.
From his experiments, Mendel concluded that:

1. Plant traits are handed down through “hereditary factors”

in the sperm and egg.
2. Because offspring obtain hereditary factors from both
parents, each plant must contain two factors for every trait.
3. The factors in a pair segregate (separate) during the
formation of sex cells, and each sperm or egg receives only
one member of the pair.
 Segregation of allele pairs during
meiosis
S = dominant allele s = recessive allele
 Law of Independent Assortment

This law can be illustrated using dihybrid crosses.

A breeding experiment that tracks the inheritance of two
traits.
a. Each pair of alleles segregates independently during
gamete formation
b. Formula: 2n (n = # of heterozygotes)

copyright cmassengale 31
 Dihybrid Cross
Traits: Seed shape & Seed color
Alleles: R round
r wrinkled
Y yellow
y green

RrYy x RrYy

RY Ry rY ry RY Ry rY ry

All possible gamete combinations

copyright cmassengale 32
 Trait Gene Genotype
Yellow Y YY, Yy
green y yy
round R RR, Rr
wrinkled r rr

P: ♀ YYRR × ♂ yyrr
yellow, round green, wrinkled

G: YR yr

F1 YyRr
yellow, round
P (F1): ♀ YyRr × ♂ YyRr
yellow, round yellow, round

YR Yr YR Yr

G: yR yr yR yr

All possible gamete combinations

to obtain offspring genotypes use Punnett Sguare
 Punnett Square
Used to help solve
genetics problems

35
 Dihybrid Cross
F2
RY Ry rY ry Round/Yellow: 9

RY RRYY RRYy RrYY RrYy Round/green: 3

Ry RRYy RRyy RrYy Rryy wrinkled/Yellow: 3

rY RrYY RrYy rrYY rrYy wrinkled/green: 1

9:3:3:1 phenotypic
ry RrYy Rryy rrYy rryy ratio

36
 Law of Independent Assortment
• Mendel's second law.
• For unlinked genes, the alleles from each gene
segregate into the gametes independently of one
another.
• Some genes are linked, which means that they don't
segregate independently of each other and thus
don't give the 9:3:3:1 ratio of F2 offspring. Linked
genes are close together on the same chromosome;
we will deal with this phenomenon later.
 Test Cross
• How could Mendel be sure to have true-inbred pea plants
homozygous for an allele?
• It is not possible to predict the genotype of an organism with
a dominant phenotype. The organism must have one
dominant allele, but it could be homozygous dominant or
heterozygous.

• A solution to this dilemma is a test cross. A test cross is a

breeding experiment, where a (known) homozygous recessive
genotype is crossed with a dominant phenotype with an
unknown genotype. A test cross is a helpful tool to determine
the identity of an unknown genotype of a certain species.
 Test Cross
• Mendel performed many test crosses with his
plants to determine the plant's genotype and
to assure himself that he worked with defined
genotypes during this performed breeding
experiments.
Test Cross
• Generally, in a test cross, an
individual with an unknown
genotype (e.g. or ) is
crossed with an individual with
a known homozygous, recessive
genotype. In the example case
above, it would be a true-
breeding pea plant with white
flowers and the genotype.

• Suppose you were given a pea

plant with the “purple flowers”
phenotype. It’s genotype could
be either one of two
possibilities: either or
 Test Cross
Case 1:
Unknown genotype:

sperm
or
egg cells
known genotype:

•If the genotype of the unknown pea plant was homozygous,

dominant (= ) regarding the trait flower color, then all of the
resulting offspring (= 100%) will have purple flowers color
 Test Cross
Case 2:
Unknown genotype:

sperm
or
egg cells
known genotype:

•If the genotype of the unknown plant was heterozygous (= )

regarding the trait flower color, then the outcome of the cross
will be :  50% of all offspring have purple flowers color; 50%
have white flowers color
 Theme:
Immunogenetics (АВО, Rh, HLA).
Multiple Alleles
Forms of genes interaction

THE LESSON No.3

(урок №3)
 Immunogenetics
• Immunogenetics – the genetics (pattern of inheritance)
of the immune response. For example,
immunogenetics includes the study of Rh, ABO, HLA
and other systems.

• Immunogenetics – the genetics section about the

patterns of inheritance of humans antigen systems.

• antigen - a protein or its complex embedded in the cell

membrane, determining the species and individual
specificity of the organism
Antigens and Antibodies
• An antigen is any
substance that causes your
immune system to produce
antibodies against it.

• An antibody is a protein
produced by B cells that is
used by the immune
system to identify and
neutralize foreign objects
such as bacteria, viruses
and antigens.

• Since antibodies are

proteins, they have a
specific shape & will attach
to the antigen for which
they were made.
 ABO system
Karl Landsteiner
• The ABO blood group
system have been
discovered by the
Austrian scientist Karl
Landsteiner, who
identified the O, A, and B
blood types in 1900.

• The genetic basis of the

ABO blood group system
is an example of multiple
alleles.
1868-1943
 Multiple Alleles
Individual
However, it is possible to Gene
have several different
allele possibilities for
A a
one gene.
Population
Multiple alleles - Three
Gene
or more alleles for a
particular gene (there are
more than two allele C c
possibilities for a gene).
Сch Ch
 Multiple Alleles
• In traits with multiple alleles, each
individual can carry any two of the
several possible alleles.

• The presence of multiple alleles is

best illustrated by the ABO blood
group system and the HLA genes.

• The gene for blood type has 3

possible alleles.
IA, IB, and i (I⁰).
• The ABO gene is located on the long
arm of the ninth chromosome (9q34).

9 chromosome
 The presence of three different alleles means
that there are six possible genotypes
i0 i0

IA IA IA i0

IB IB IB i0

IA IB
 Blood types
In this case both A and B are dominant to O
(recessive).
A and B are codominant (both expressed)

So... there are four human blood types

Phenotype Gene Genotype

Blood type A IA IAIA, Iai

Blood type B IB IBIB, Ibi

Blood type AB IA , IB IA IB

Blood Type O ii ii
• The alleles control the production of enzymes which
catalyze the connect of sugar units to specific protein
on the surface of the red blood cells.
• The sugar complex with protein - is called an
antigens
specific protein

 Allele IA produces antigen A

 Allele IB produces antigen B
 Allele i produces no antigen
 Blood types
1. Type A: has A antigen on red blood cells
(RBC), has anti-B antibodies in the plasma, can
get blood from O and A, can give blood to A
and AB people
 Blood types
2. Blood type B: has B antigen on RBCs, anti-A
antibody, can get blood from O or B, can give
blood to B and AB
 Blood types
• 3. Blood type AB: has both A and B antigens
on RBCs, no antibodies, can get blood from A,
B, AB, and O, can give blood to AB
 Blood types
4. Blood type O: has no antigens on RBCs,
has both anti-A and anti-B antibodies, can get
blood from O only, can give blood to A, B, AB,
and O
The geography of the ABO blood groups
• Blood type O: the
Americas

• Among indigenous
populations of
Central and South
America, the
frequency of O
blood type is
extremely high,
approaching 100%.
It is also high
among Australian
aborigines.
The geography of the ABO blood groups
• Blood Type A: Central and
Eastern Europe

• Type A is common in
Central and Eastern Europe.
In countries such as Austria,
Denmark, Norway, and
Switzerland, about 45-50%
of the population have this
blood type.

• The highest frequencies are

found in small, unrelated
populations. For example,
about 80% of the Blackfoot
Indians of Montana have
blood type A.
 The geography of the ABO blood groups
• Blood type B: Asia
• Blood type B is relatively
common in Chinese and
Indians, being present in
up to 25% of the
population. It is less
common in European
countries and Americans
of European origin,
being found in about
10% of these
populations.
Blood type AB is the least common
It is also the rarest of the blood groups. It is most
common in Japan, regions of China, and in Koreans,
being present in about 10% of these populations.
 Role of ABO system
• Blood Group System is the • Donor - a person who
most important system for provides blood, an
transfusion practice
organ, or semen for
transplantation,
transfusion, etc.
• Recipient - a person
who receives blood,
tissue, or an organ from
a donor.
 Blood types and transfusions
• Blood types vary and your immune system recognises your
own blood type as being self (own)
• Other blood types are recognised as non-self (foreign)
• If a blood which is incompatible with your body is transfused it
will result in the agglutination of the foreign red blood cells
 Donor-recipient compatibility
Recipient
Type A B AB O
A
Donor B
AB
O

Note: old information

= Agglutination • Type O blood may be transfused
into all the other types = the
= Safe transfusion universal donor.
• Type AB blood can receive blood
from all the other blood types =
the universal recipient.
 Rh Factor
• There's another antigen to be
considered - the Rh antigen.

• Rh antigens are named for the

Karl Landsteiner rhesus monkey in which they
were first discovered. Landsteiner
1868-1943 and Wiener reported on an
antibody by guinea pigs and
rabbits when they were
transfused with rhesus monkey
red cells.

• 85% of the population is Rh

positive (Rh +), the other 15% of
the population is running around
with Rh negative blood (Rh -) .
Alexander S. Wiener
1907–1976
 Rh Factor
• The Rh factor genetic information is also
inherited from our parents, but it is inherited
independently of the ABO blood type alleles (a
separate gene).
Rh Factor
• In contrast, the antigens of
the Rh blood group are
proteins.

• These proteins are located

on red blood cell surfaces.

• Antigen may be present or

absent from red blood cells.
If present, the blood type is
said to be Rh positive (Rh+).
If absent, the blood type is
Rh negative (Rh-). A person
who is Rh- will produce
antibodies against Rh+ blood
cells if exposed to them.
 Rh Factor
• The main antigens are D,
C, E, c and e, which are
encoded by three
neighboring gene loci:

1) the RHD gene which

encodes the RhD protein
with the D antigen (and
variants)

1) RHC gene which

encodes the RhC protein
with the C and c
antigens (and variants)

1) RHE gene which encodes

the RhE protein with the
1 chromosome E and e antigens (and
variants)
 Rh Factor
• D, C and E genes are linked and located in first chromosome.

• Three loci carry the Rh genes are so closely linked that they
never separate but are passed from generation to generation
as a unit or gene complex.

• RBCs that are "Rh positive" express the antigen designated

D.
 Role of Rh factor
1) Blood transfusion
• the Rh system is of major importance in blood transfusions. If Rh-
positive blood is transfused into an Rh-negative person, the latter
will gradually develop antibodies called anti-Rh agglutinins, that
attach to the Rh-positive red blood cells, causing them to
agglutinate. Destruction of the cells (hemolysis) eventually results.

• Acute Hemolytic Transfusion Reactions (AHTR) occurs when

incompatible RBC’s are transfused into a recipient who has pre-
formed antibodies (usually ABO or Rh)
 Role of Rh factor
2) Rh factor may play a role in baby's health, so it's important
to know this information early in pregnancy.
If a baby inherits Rh+ blood from the father and the mother is Rh-, problems
can develop if the blood cells of mother and baby mix during birth
Rh Factor and Problems in Newborns (1)
• During pregnancy or
childbirth, small number of
fetal cells may cross
placenta, enter mother’s
bloodstream

• If mother is Rh- and fetus is

Rh+, fetal cells placenta
stimulate production of
antibodies against Rh+
antigen

• If first pregnancy, usually

not harm either the fetus or
mother
Rh Factor and Problems in Newborns (2)

• During second Rh+

pregnancy, mother’s
antibodies cross placenta
and destroy the fetus’ red
blood cells

• Hemolytic disease of fetus

and newborns

• To prevent HDN, Rh- women

given Rh+ antibodies during
pregnancy

• Must be given before mother

produces antibodies against
Rh+ antigen
Hemolytic disease of the newborn
• The disorder in the fetus due to Rh
D incompatibility is known
as erythroblastosis fetalis.
• Symptoms and signs of Hemolytic
disease in the newborn:
– Anemia that creates the
newborn's pallor (pale
appearance).
– Jaundice or yellow discoloration
of the newborn's skin or sclera.
This is caused by bilirubin (one of
the end products of red blood
cell destruction).
– Enlargement of the newborn's
liver and spleen.
– Dyspnea or difficulty breathing.
 HLA system (human leukocyte antigen)
• An example of multiple
allelism except ABO
system is the HLA system

• HLA is the name of the

loci of genes that encode
Jean Dausset for major
Baruj Benacerraf histocompatibility
1916-2009
1920-2011 complex (MHC) in
humans.

• MHC was discovered by

Jean Dausset, Baruj
Benacerraf and George
Davis Snell
George Davis Snell
1903-1996
 • MHC is a set of cell surface
molecules encoded by gene
cluster, HLA complex

• The proteins encoded by

HLAs are those on the outer
part of body cells that are
(in effect) unique to that
person.

• Set of HLA alleles on each

chromosome 6 which are
inherited together is called
Haplotype
HLA Complex on Chromosome 6
HLA Complex
• The main antigens of HLA
system are encoded by
four neighboring closely
linked gene loci: A, B, C
and D.

• Locus D is represented by
three subloci: DP, DQ, DR
•
• The gene of A locus has
21 possible alleles, B – 47,
C – 8, DR – 14, DQ – 36,
DP - 6.
Role of HLA system
Transplantation of Organs
or Tissues
• MHC determines
compatibility of donors for
organ transplant

• Transplanted organ has

different antigens,
molecular identification
tags

• Many alleles, combinations

nearly endless, difficult to
find two people with same
HLA haplotypes
 Successful Transplants
• Successful organ transplants, skin grafts, and
blood transfusions depend on matches
between the HLA

• Many allele combinations, rarely have a

perfect HLA match, often takes long time to
find

• HLA markers of donor and recipient analyzed,

if least a 75% match, usually successful
 Interactions between allelic genes.
Allelic gene • Genes located in the same loci of
homologous chromosomes and are
interaction responsible for the same sign are called
allelic.
• An allele, or allel, is one of a number of
alternative forms of the same gene or
same genetic locus.
• It is the alternative form of a gene for a
character producing different effects.
• Sometimes, different alleles can result
in different observable phenotypic
traits, such as different pigmentation.
• However, many genetic variations result
in little or no observable variation
45
 Interactions between allelic genes

Complete dominance

Incomplete and semi-

dominance

Co-dominance

Over dominance

Interallelic
complementation
IA IB
Allelic exclusion
• Dominance in genetics is a relationship between Complete
alleles of a single gene, in which one allele is
expressed over a second allele at the same gene dominance
locus.
• The first allele is said to be dominant and the
second allele is said to be recessive. When the
relevant gene resides on an autosome (any
chromosome other than a sex chromosome), the
alleles and their associated traits may be referred
to as autosomal dominant and autosomal
recessive.
• Dominance is a key concept in Mendelian The second generation
inheritance, which underlies classical genetics. of plants the second
filial, F2, generation
phenotypic ratio:
Complete dominance occurs when the 3 (yellow) :1 (green)
phenotype of the heterozygote is completely 3:1
indistinguishable from that of the dominant genotypic ratio:
1 (YY) : 2 (Yy) : 1 (yy)
homozygote 1:2:1
 Incomplete and
semi-dominance
• Incomplete dominance (also called partial
dominance) occurs when the phenotype of
the heterozygous genotype is distinct from
and often intermediate to the phenotypes of
the homozygous genotypes.

• For example, the snapdragon flower color is

either homozygous for red or white. When
the red homozygous flower is paired with the
white homozygous flower, the result yields a
pink snapdragon flower. The pink snapdragon
is the result of incomplete dominance. When plants of the F1 generation
are self-pollinated, the
• A similar type of incomplete dominance is found in the four o'clock plant wherein
pink color is produced when true-bred parents of white and red flowers are phenotypic and genotypic ratio of
crossed. In quantitative genetics, where phenotypes are measured and treated
numerically, if a heterozygote's phenotype is exactly between (numerically) that of
the F2 generation will be 1:2:1
the two homozygotes, the phenotype is said to exhibit no dominance at all, i.e. (Red : Pink : White) for both
dominance exists only when the heterozygote's phenotype measure lies closer to
one homozygote than the other.
generations
 Co-dominance
• Co-dominance occurs when
the contributions of both
alleles are visible in the
phenotype.
• To indicate that two alleles are
co-dominant (and that neither
is dominant over the other),
they are both written in
upper-case, with a superscript
to indicate the different
alleles.
• For example, in the ABO blood group system, chemical
modifications to a glycoprotein (the H antigen) on the surfaces of
blood cells are controlled by three alleles, two which are co-
dominant to each other (IA, IB) and dominant over the recessive i0
at the ABO locus. The IA and IB alleles produce different
modifications. The enzyme coded for by IA adds an N-
acetylgalactosamine to the membrane-bound H antigen. The IB
enzyme adds a galactose. The i0 allele produces no modification. Co-dominance occurs when the
Thus IA and IB alleles are each dominant to i0 (IAIA and IAi0
individuals both have type A blood, and IBIB and IBi0 individuals
both have type B blood. But IAIB individuals have both
contributions of both alleles are visible
modifications on their blood cells and thus have type AB blood, so
the IA and IB alleles are said to be co-dominant.)
in the phenotype IV blood type
(genotype IAIB)
 Over dominance
Over dominance hypothesis. Certain
combinations of alleles that can be obtained
by crossing two inbred strains are
advantageous in the heterozygote.
The overdominance hypothesis attributes
to heterozygote advantage the survival of
many alleles that are recessive and harmful
in homozygotes.

Red blood cells Example: the alteration of a

single nucleotide in the gene
for the beta chain of the
hemoglobin protein turns a
normal hemoglobin gene
into a sickle-cell hemoglobin
gene.
Sickle cells Thus, Allele is one of two or
more versions of a gene
 Interallelic complementation
Interallelic complementation is associated with the synthesis in
heterozygotes of two different but functionally similar protein molecules
instead of the one protein molecule of homozygotes. Moreover,
heterozygotes often have hybrid protein molecules made of polypeptide
chains that are synthesized under the control of two different alleles. In
heterozygotes with defective mutant alleles, complementation may be
expressed in a restoration of the ability to synthesize a normally
functioning protein—an ability that would be partly or wholly lost to each
mutant separately.
Interallelic complementation seems to
be the main cause of monogenic
heterosis—the superiority of
heterozygotes over homozygotes in
viability and rate of growth. Detailed
complementation charts have been
constructed for the genes of certain
viruses, bacteria, and fungi.
 Allelic exclusion
• Allelic exclusion is a process by which only one allele of a gene is
expressed while the other allele is silenced. For most genes, the
individual inherits one copy of each gene from each parent.

• At least two distinct selection events can lead to allelic exclusion.

On one hand, one allele of the gene can be transcriptionally
silent, which would result in the expression of only the second
allele. On the other hand, both alleles can be transcribed, in
which case posttrancriptional and posttranslational mechanisms
will lead to the elimination of the protein product of one allele.

Example: Barr body

(nontranscribed X sex
Barr
chromosome in females)
body

44А+ХХ 44А+ХУ
 Non-allelic gene interaction
• With the help of lot of experiments it was found that most of the
characters of living organisms are controlled / influenced /
governed by a collaboration of several different genes.
• This condition where a single character is governed by two or
more genes and every gene affect the expression of other genes
involved (means these genes affect each others expression) is
known as gene interaction.
• In simple way we could say that, in gene interaction, expression
of one gene depends on expression (presence or absence) of
another gene.
• As we know, gene interactions may involve two or more pairs of
genes. But all the gene interactions we have described below
have the two pairs of non-allelic genes, affecting the phenotypic
expression of same character. These interactions produce
modified dihybrid ratios.
 Non-allelic gene interaction
• many traits are controlled by more than one gene (Aa,
Bb, Cc …)
• Phenotypes decided by Interaction between the alleles
of these non-allelic genes
• Mendelian ratios modified.
Non-allelic genes are genes located at different loci on
the same chromosome or on different chromosomes
altogether.
Examples:
1. Complementary
2. Epistasis (dominat and recessive)
3. Polymerism
Mendel's Law of Non-allelic gene
Independent interaction
Assortment
 k

d.e.

r.e.

p
Complementary :
9:3:3:1; 9:6:1; 9:7
Epistasis:
• dominat : 12:3:1; 13:3
• recessive: 9:3:4
Polymerism: 15:1; 1:4:6:4:1
 Complementary: 9:3:3:1 example:
Phenotype color of parrots
Genotype of color
parrots
if both dominant genes (А_ and
B_) are present at one
green
genotype together, they will A_ B_
color
produce the first alternative
variant of a phenotype
If at genotype is present only
one dominant gene BB or Bb, yellow
Aa B_
and another gene present at color
homozygous recessive (aa)
if on the contrary at genotype is
present only one dominant
gene AA or Aa, and another A_ bb blue color
gene present at homozygous
recessive (bb)
If at genotype is present only
aabb white color
recessive genes aabb
Complementary: 9:6:1
 Complementary: 9:7 ratio Ex. hearing inheritance
at the person
These genes are two pairs of non-
allelic dominant genes which
interact, produce oniy tine one
phenotypic character.

In man deaf-mutism is an example

of complementary genes. The
normal hearing & speech In man
develops as a result of interaction
between gene A and B. Whenever
a person is homozygous for either
of the two recessive alleles i. e.
either AAbb or aaBB, he is deaf-
must.
Flower color in Sweet Peas
 Epistasis
• One non-alleles gene mask / suppressing the action of another
gene
• Literally means «sitting upon». One gene sits upon another gene,
prevents it is expression.
• Suppressor gene it is epistatic gene, affected / inactivated gene =
hypostatic gene.

dominate : Different types recessive:

12:3:1; 13:3 9:3:4
if, for example, epistatic gene - if, for example, epistatic gene
dominant gene B (BB or Bb) – recessiev gene b (bb)
 Dominate Epistasis
• Epistasis is when the effect of one gene depends on the presence
of one or more 'modifier genes' (genetic background).
• Involves two pairs of non-allelic genes
• One of the dominant genes inhibits or suppresses the expression
of the other dominant gene.
• Inhibiting gene has no visible effect
• Inhibitory factor interaction is observed in plumage color of
poultry
• Epistasis has a large influence on the shape of evolutionary
landscapes which leads to profound consequences for evolution
and evolvability of traits.
 White leghorn’s white plumage is
monogenic dominant over colored
plumage.
White leghorn when crossed with
white Wyandotte, F1 was white but
segregation in F2 as 13 white: 3 colored.
It is proved that, white leghorn contains
gene C for colored plumage, but in
addition it also contains gene I (inhibiting
gene), which inhibits the colored
expression.
So the genotype of pure breeding
white leghorn must be CCII and that of F2: white 13 : colored 1
Wyandotte’s ccii.
Recessive Epistasis
Recessive Epistasis
Bombay phenotype
 Hh antigen system - also known as Oh or the
Bombay Blood group, is a rare blood type. This
blood phenotype was first discovered in
Bombay, now known as Mumbai, in India, by Dr.
Y. M. Bhende in 1952.
This very rare phenotype is generally present
in about 0.0004% (about 4 per million) of the
human population, though in some places such
as Mumbai (formerly Bombay) locals can have
occurrences in as much as 0.01% (1 in 10,000)
of inhabitants and 1 in a million people in
Europe.
 The first person that was discovered to have the Bombay
phenotype seemed to have an interesting blood type that reacted
to other blood types in a way never seen before. The serum
contained antibodies that reacted with all red blood cells' (RBCs')
normal ABO phenotypes. The red blood cells appeared to lack all
of the ABO blood group antigens plus an additional antigen that
was previously unknown.
Individuals with the rare Bombay phenotype (hh) do not
express H antigen (also called substance H), the antigen which is
present in blood group O. As a result, they cannot make A antigen
(also called substance A) or B antigen (substance B) on their red
blood cells, whatever alleles they may have of the A and B blood-
group genes, because A antigen and B antigen are made from H
antigen. For this reason people who have Bombay phenotype can
donate RBCs to any member of the ABO blood group system
(unless some other blood factor gene, such as Rhesus, is
incompatible), but they cannot receive blood from any member
of the ABO blood group system (which always contains one or
more of A and B and H antigens), but only from other people who
have Bombay phenotype.
It is very important, in order to avoid any complications
during a blood transfusion, to detect Bombay phenotype
individuals because the usual tests for ABO blood group system
would show them as group O. Since Anti-H immunoglobulins can
activate the complement cascade, it will lead to the lysis of RBCs
while they are still in the circulation, provoking an acute
hemolytic transfusion reaction. This, of course, cannot be
prevented unless the lab technologist that is involved has the
means and the thought to test for Bombay group.
 Polymerism or Additive factor:
15:1 1:4:6:4:1
Non-cumulative with Cumulative with
dominance dominance

• Involves two pairs of non-allelic genes

• Affect the same character
• When dominant forms of both the genes are present together they
produce double effect.
• Such genes are called as polymeric or additive genes.
• Polymerism or additive factor observed in case of pericarp color of
wheat (deep red, light red and colorless)
Many traits such as height, shape,
weight, color, and metabolic rate are
governed by the cumulative effects of
many genes – it is polygenic
inheritance.
 Polygenic Traits
• A polygenic trait is determined by the combined
effect of more than one pair of genes, multiple genes.
(poly=many, genic=genes)
Example: eye color and height
Skin color is controlled by more than four genes
Polygenic Inheritance

Polygenic traits are not expressed as absolute or

discrete characters, as was the case with The inheritance of each gene follows
Mendel's pea plant traits. Mendelian rules.

Polygenic traits are recognizable by their Traits are usually quantified by

expression as a gradation of small differences (a measurement rather than counting.
continuous variation). The results form a bell Two or more gene pairs contribute to the
shaped curve, with a mean value and extremes phenotype.
in either direction. Phenotypic expression of polygenic traits
varies over a wide range.
Height in humans is a polygenic trait, as is color
in wheat kernels. Height in humans is NOT Human polygenic traits include
discontinuous . If you line up the entire class a • Height
continuum of variation is evident, with an • Weight
average height and extremes in variation (very • Eye Color
short and very tall ). • Intelligence
• Skin Color
Traits showing continuous variation are usually • Many forms of behavior
controlled by the additive effects of two or
more separate gene pairs.
 Marfan syndrome
Marfan syndrome is known as a connective tissue disorder.
Marfan syndrome is an autosomal dominant disorder.

People with Marfan

• tend to be unusually tall, with long limbs and long, thin fingers.
• defects of the heart valves and aorta.
• it may affect the lungs, eyes, dural sac surrounding the spinal cord,
the skeleton, and the hard palate.
Marfan syndrome
 Environment and Gene Expression
Phenotypes are always affected by their environment.
Expression of phenotype is a result of interaction between genes and
environment.
Environment determines the phenotypic pattern of expression.
Ex. Siamese cats and Himalayan rabbits both animals have dark colored fur on their
extremities. This is caused by an allele that controls pigment production being able only to
function at the lower temperatures of those extremities.

• Penetrance
• Expressivity
Penetrance and Expressivity – Modifications of Phenotypes
Associated with Particular Alleles
Both the degree of penetrance (complete or incomplete) and expressivity
(invariant or variable) are influenced by modifier genes and the
environment.

Dark vs. light coloration in Siamese cats show the effect of environment on
the link between genotype and phenotype.
 Polydactyly • Polydactyly is having extra
fingers and toes.
• There are several forms of this
condition.
• For one form, polydactyly is
65% penetrant: 65% of those
who carry the dominant
polydactyly allele have extra
digits.
• Examining these people, there
is a range of expression: some
have 1 extra digit, some have 2,
etc.
• Also, some of the digits are
Аа, Аа – 50%, but only 65% from functional: have proper bones,
them will have Polydactyly muscles and nerves, while
others are missing vital
50*0,65 = 32,5% components or connections.
 Expressivity
• Expressivity – the degree to which a
genotype is expressed in the phenotype
• Each of these dogs (beagles) has the
dominant allele for piebald (black and
white) spotting
• The degree of spotting varies among
individuals
 Theme:
VARIABILITY
AND
HEREDITARY DISEASES

THE LESSON No.4

(урок №4)
изменчивость и наследственные болезни
The diversity of organisms is one of the most characteristic
features of living things.

Differences between species and within species differences

are observed due to the universal property of living -
variability.

VARIABILITY
the ability of living organisms acquire new
features and properties.
 Genes and the environment

• Phenotypes are always affected by their environment.

• Expression of phenotype is a result of interaction
between genes and environment.
• Environment determines the phenotypic pattern of
expression.
• Expression of genes is affected by environmental factors
such as temperature, altitude, or chemical exposure
• The result may be variation in traits
 There are two main forms of variability:

Non-hereditary Hereditary

or phenotypic, or or genotypic variability

modification variability
сombinative mutational
Continuous variability Discontinuous variability

bell curve
 Gene

Implementation
of hereditary
information

Enzyme

Trait
 Non-hereditary variability or
modification variability, modification
Characteristics of modification are:
• is a change only in phenotype
• Genotype remains unchanged.
• it isn't inherited
• is a change caused by the influence of environmental
factors.
• has the directed character
• represent adaptations to environmental conditions
• are reversible (if they appear in adults)
• has group character. different organisms present the same
variations in identical conditions (in all people UV light
induces skin tanning)
• phenotype variation is determined by genotype – norm of
reaction (under the same condition some people become
darker, others – not)
 Norm of reaction
Each phenotype may vary in determined genotype limits under the
influence of environmental factors – this property is called norm of
reaction.

For different groups of symptoms characterized by a

greater or lesser degree depending on the external
conditions.
Therefore Norm of reaction may be
broad narrow
norm of reaction norm of reaction
the plasticity for that trait the trait itself

Ex.: In humans, such as eye and hair color of the external environment is actually
independent, but the growth is largely affected by the external environment.
Continuous variation is affected by:
• many genes of small effect  traits with a range of small
differences
• the environment  the more factors that influence a trait, the
more continuous the distribution of phenotype
bell curve
• when continuous phenotypes are divided into measurable
categories and plotted as a bar chart, they form a bell-shaped
curve
Characteristic varies amongst the members of a species in a smooth
continuous way from one extreme to the other
Examples:
• mass
• height
• intelligence
• color of organs & organisms
The environment CAN change these variations
 Effects of temperature on gene expression

Effect of Cold on Himalayan Hare (rabbits) Fur Color

Enzyme tyrosinase at low temperatures.

The application of an ice pack to a region of shaved hair results in

black hair growing back instead of the original white color.
 Effects of high altitude on humans
The greatest challenge facing humans at altitude is
the reduction in the partial pressure of oxygen that
results from a fall in barometric pressure.
When faced with this hypoxic challenge, the body
responds in a number of different ways depending
upon the rate and severity with which the stimulus is
imposed.
The acute hypoxia suffered by aviators in an unpressurised aircraft
generates a very different set of physiological responses than the more
chronic form experienced by mountaineers, who typically take several
weeks to reach similar heights.
It is striking to note that someone who ascends rapidly from sea level
to the summit of Mt Everest (8850 m) will lose consciousness within
seconds, while those who have spent several weeks ascending can
often function relatively well.
The human body has both short-term and long-term adaptations to
altitude that allow it to partially compensate for the lack of oxygen.

In the short term, the lack of Full adaptation to high

oxygen is sensed by the carotid altitude is achieved
bodies, which causes when the increase of
• an increase in the breathing erythrocytes and
rate hemoglobin
• The heart beats faster;
The relative importance of "genes" and "environment" is not a unitary
value, and may vary a greater or lesser degree depending on exactly
which environments the genes are expressed in.

E.g. a white man exposed to sunlight (UV irradiation) becomes darker,

but not black.
?

Studies of heritability carried out in a single environment cannot

accurately estimate the Norm of Reaction, and often may not predict
phenotypic response in a different environment.
 Necessary to Tan Instead
of Burn in the Sun

• if the factor of
environment influence
more on time or its force
big, the organism can't skin burning at suntan
кожа, горящая в

adapt загаре
 Phenocopy
Some environmental factors may have a destructive action on
organism.

In this case the phenotype develops beyond the limits of the norm
of reaction and an abnormal modification is produced.

The factors, which produce such abnormal modifications,

are called teratogenes - agents, which can cause a birth defect.

The degree of abnormality depends on the stage of development:

earlier damages are more sever.

Frequently the phenotype resembles a genetic disease (state caused

by mutations), but has arisen by a completely different
(environmentally determined) mechanism.

Such phenotype is called phenocopy.

Effects of altitude on gene expression Эффекты высоты на экспрессии гена
 Penetrance and Expressivity – Modifications of Phenotypes

Both the degree of penetrance (complete or incomplete) and expressivity

(invariant or variable) are influenced by modifier genes and the
environment.

Dark vs. light coloration in Siamese cats show the

effect of environment on the link between genotype
and phenotype.
 PENETRANCE AND EXPRESSIVITY
PENETRANCE
• The frequency with which a dominant or homozygous recessive gene
manifests itself in individuals in a population is called the penetrance of
the gene.
• penetrance depends on both the genotype (e.g. the presence of
epistatic or other genes) and the environment.
• in some cases not all individuals who are known to have a particular
genotype show the phenotype specified by the gene.
• penetrance is complete (100%) when all the homozygous recessive show
one phenotype, when all homozygous dominants show another
phenotype and when all the heterozygotes are alikeю
• if less than 100% of the individuals with a particular genotype exhibit the
phenotype expected, penetrance is incomplete. if, say, 80% of the
individuals carrying a particular gene show the corresponding
phenotype, we say that there is 80% penetrance.
Polydactyly • Polydactyly is having extra
fingers and toes.
• There are several forms of this
condition.
• For one form, polydactyly is
65% penetrant: 65% of those
who carry the dominant
polydactyly allele have extra
digits.
• Examining these people, there
is a range of expression: some
have 1 extra digit, some have 2,
etc.
• Also, some of the digits are
functional: have proper bones,
muscles and nerves, while
others are missing vital
components or connections.
 EXPRESSIVITY
• Expressivity – the degree to which a genotype
is expressed in the phenotype
• expressivity may be described either
qualitatively or quantitatively e.g. if may be
referred to as severe, intermediate or slight.
• like penetrance, expressivity depends on the
genotype and the internal and external
environments, and it may be constant or
variable

Ex. Each of these dogs (beagles) has the dominant

allele for piebald (black and white) spotting
The degree of spotting varies among individuals
 Phenotype Gene Genotype
Polydactyly A AA, Aa
normal a Aa
PENETRANCE 65%

Аа, Аа – 50%, but only 65% from them will have Polydactyly

50*0,65 = 32,5% show the phenotype Polydactyly

 Hereditary or Genotypic
or Discontinuous variability
changes of features signs of the body, due to changes
in the genotype.

combinative variability mutational variability

is due to recombination of arises from changes in
hereditary material (genes and the structure of
chromosomes) during hereditary material.
gametogenesis and sexual
reproduction.
 Discontinuous variation
Produces: Individuals with clear-cut differences with no
intermediates between them

Examples:
• Blood group in humans
• Sex
• Tongue rolling
Either
or
traits

The environment cannot change discontinuous type of variations.

No matter how much you stay in the sun or what you eat – will not
change your blood group!!!
 Characteristics of Hereditary variability
1. Genotype is changed
2. It is inherited - passed from
one generation to the next
3. has the non-directed
character
4. It is random
World's biggest Albino family
- of the Pullan family from India
The ten members of the Pullan family: headed by
Rosetauri Pullan, his wife Mani along with their
three daughters Renu, Deepa and Pooja and three
sons Shankar, Ramkishan and Vijay all have fair
skin, white hair and light colored eyes despite
being Indian.
 COMBINATIVE VARIABILITY
• is due to recombination of hereditary material
Mechanism of combinative variability
• The recombination of chromosomes that occurs during sexual
reproduction, called independent assortment.
• Crossing over and random segregation during meiosis can result
in the production of new alleles or new combinations of alleles.
• Random fertilization also contributes to variation.
Number of gametes variants – 2n , where n is the haploid number of chromosomes
One person has the number of possible gametes – 8 388 608.
Combinative variability meaning: creates a lot of unique genotypes,
causing the formation of new phenotypes.

It is important for natural selection during evolution.

New combinations can be good or bad

An example is the family

combinative variability
 Мутации являются
MUTATIONAL VARIABILITY основным
источником
генетической
изменчивости.
Mutations are the ultimate source of genetic variation.
Mutations is a change of a genetic material.

Mutagenesis is a process by which the genetic information of an

organism is changed in a stable manner, resulting in a
mutation. It may occur spontaneously in nature, or as a
result of exposure to mutagens.
Mutagen is an agent that changes the genetic material of an organism
and thus increases the frequency of mutations above the
natural background level
Mutagen agent Example
• chemical Reactive oxygen species (ROS), Benzene, Polycyclic aromatic
hydrocarbon (PAH), Alkylating agents
• physical Ionizing radiation such as x-rays, gamma rays and alpha
particles, Ultraviolet (tanning beds), Radioactive decay
• biological Virus, Bacteria, Transposon
 Mutation theory Hugo de Vries
(1840 - 1935)
A Dutch botanist and one of the first geneticists. He is a Dutch Botanist
known chiefly for suggesting for introducing the term
"mutation", and for developing a mutation theory of
evolution.
He introduced the term mutations for these
suddenly appearing variations.
In his two-volume publication the Mutation Theory (1900–1903) he
postulated that evolution, especially the origin of species, might occur
more frequently with such large-scale changes than via Darwinian
gradualism, basically suggesting a form of saltationism.
De Vries's theory was one of the chief contenders for the explanation of how
evolution worked, leading, for example, Thomas Hunt Morgan to study
mutations in the fruit fly, until the modern evolutionary synthesis became the
dominant model in the 1930s.
 Basic provisions of the mutational theory
1. mutations are discrete changes of a hereditary material.
2. always changes the genotype
3. may or may not change the phenotype (silent or neutral
mutation)
4. mutations – rare, sudden, spasmodic events.
5. mutations is inherited .
6. mutations arise nondirectional (spontaneously) and, unlike
modifications, doesn't form continuous ranks of variability.
7. mutations can be harmful, useful and neutral.
8. any locus of a chromosome can mutate.
9. the same mutations in the course of evolution can repeatedly
arise.
10. can be detected by molecular biology methods
What are the consequences of mutations?

• Mutations can be advantageous and lead to

an evolutionary advantage of a certain
genotype.

• Mutations can also be deleterious, causing

disease, developmental delays, structural
abnormalities, cancers or other effects.
• Mutations can be caused by external (exogenous) or endogenous
(native) factors, or they may be caused by errors in the cellular
machinery.
• Physical or chemical agents that induce mutations in DNA are
called mutagens and are said to be mutagenic.
Exogenous factors: environmental factors such as sunlight,
radiation, and smoking can cause mutations.
Endogenous factors: errors during DNA replication can lead to
genetic changes as can toxic by-products of cellular metabolism.
 Classification of mutations
• According to the method: spontaneous and induced.

• At the place of appearance in the organism: somatic and

generative.

• On adaptive meaning: positive, negative, neutral.

• On localization in the cell: nuclear, cytoplasmic.

• By changes in the hereditary material:

 GENE MUTATIONS

 STRUCTURAL ABERRATIONS - Chromosomal aberrations

 NUMERICAL ABERRATIONS - Genomic mutations

 By changes in the hereditary material:
Chromosomal Abnormalities
Gene NUMERICAL STRUCTURAL
mutations ABERRATIONS ABERRATIONS
A gene-level mutation Genomic Chromosomal
is a permanent change mutations aberrations
in the sequence of are associated with are associated with
DNA. the change of the change of
number of structure of
chromosomes chromosomes
 Theme:
VARIABILITY
AND
HEREDITARY DISEASES

THE LESSON No.4

(урок №4)
изменчивость и наследственные болезни
 Gene-level mutation
- Gene mutations
• A gene-level mutation is a permanent change in the
sequence of DNA.

• In order for an observable effect, mutations must occur in

gene exons or regulatory elements.

• Gene-level mutations have varying effects on health,

depending on where they occur and whether they alter the
function of essential proteins.

• Changes in the non-coding regions of DNA (introns and

junk DNA) generally do not affect function.
The DNA sequence of a gene can be altered in a
number of ways. The types of mutations include:
gene mutation

Mutations without Frame shift

reading
mutation
frame shift
Mutations without reading frame shift

• A single base change

in DNA sequence
during DNA
replication.
• A point mutation may
be silent, missense,
or nonsense.
 MISSENSE NONSENSE
SILENT
MUTATION MUTATION
A change in the
genetic sequence that • A change that results
does not change the change in one in the coding for a
protein sequence. DNA base pair that stop codon rather
This can occur results in the than an amino acid.
because of substitution of one • This is signal to stop
redundancy in the amino acid for building a protein.
genetic code where another in the • A shortened protein is
an amino acid may be protein made by a generally non-function
encoded for by
multiple codons. gene. or its function is
impeded.
SILENT

• A change in the
genetic sequence that
does not change the
protein sequence.
This can occur
because of
redundancy in the
genetic code where
an amino acid may be
encoded for by
multiple codons.
MISSENSE MUTATION
• change in one DNA base pair
that results in the substitution of
one amino acid for another in
the protein made by a gene.
• Not all missense mutations are
deleterious, some changes can
have no effect.
In this example, the
nucleotide adenine is
replaced by cytosine in the
genetic code, introducing
an incorrect amino acid into
the protein sequence.
• A nonsense mutation is also a change in NONSENSE
one DNA base pair.
• A change in the genetic code that results MUTATION
in the coding for a stop codon rather
than an amino acid.
• altered DNA sequence prematurely
signals the cell to stop building a protein.
• This type of mutation results in a
shortened protein.
• The shortened protein is generally non-
function or its function is impeded.

In this example, the

nucleotide cytosine is
replaced by thymine in the
DNA code, signaling the cell
to shorten the protein.
 – This type of mutation
Frameshift mutation occurs when the addition
or loss of DNA bases
changes a gene’s reading
frame.
– A reading frame consists of
groups of 3 bases that each
code for one amino acid.
– A frameshift mutation shifts
the grouping of these bases
and changes the code for
amino acids.
A frameshift mutation changes the
– The resulting protein is
amino acid sequence from the site of usually nonfunctional.
the mutation. Insertions, deletions, and
duplications can all be
frameshift mutations.
 INSERTIONS DELETIONS DUPLICATIONS
• It removal a piece of A duplication
An insertion DNA.
changes the number • Small deletions may consists of a piece
of DNA bases in a of DNA that is
remove one or a few abnormally copied
gene by adding a base pairs within a
piece of DNA. one or more times.
gene, larger deletions
can remove an entire
gene or several
neighboring genes.
 Insertion
An insertion
changes the
number of DNA
bases in a gene
by adding a
piece of DNA.
As a result, the
protein may not
function
properly.

In this example, one nucleotide (adenine) is added in the

DNA code, changing the amino acid sequence that follows.
 Deletion
– A deletion changes the
number of DNA bases
by removing a piece of
DNA.
– Small deletions may
remove one or a few
base pairs within a
gene, while larger
deletions can remove
an entire gene or
several neighboring
genes.
– The deleted DNA may
alter the function of the
resulting protein(s).
In this example, one nucleotide (adenine) is
deleted from the DNA code, changing the amino
acid sequence that follows.
 Duplication
– A duplication
consists of a piece of
DNA that is
abnormally copied
one or more times.
– This type of mutation
may alter the function
of the resulting
protein.

A section of DNA is accidentally duplicated

when a chromosome is copied.
Splice Site mutation
• A change in the genetic
sequence that occurs at
the boundary of the exons
and introns.
• The consensus sequences
at these boundaries signal
where to cut out introns and
rejoin exons in the mRNA
(DSS).
• A change in these
sequences can eliminate
splicing at that site which
would change the reading
frame and protein sequence.
 Repeat expansion
– Nucleotide repeats are
short DNA sequences
that are repeated a
number of times in a
row.
– For example, a
trinucleotide repeat is
made up of 3-base-pair
sequences, and a
tetranucleotide repeat is
made up of 4-base-pair
sequences. A repeat
expansion is a mutation
that increases the
number of times that the
short DNA sequence is
repeated.
In this example, a repeated trinucleotide
– This type of mutation
sequence (CAG) adds a series of the amino can cause the resulting
acid glutamine to the resulting protein. protein to function
improperly.
 Sickle-cell disease (SCD), or sickle-cell anaemia
(SCA) or drepanocytosis,

• Sickle cell disease (SCD) is a common name for several inherited

disorders that affect red blood cells.
• Sickle cell anemia (SCA) is the most common form of SCD.
• Hemoglobin consists of four protein subunits, two subunits called
alpha-globin and two subunits called beta-globin.
• The HBB gene provides instructions for making beta-globin.

Missense
mutation
• is a hereditary blood disorder, characterized by red
blood cells that assume an abnormal, rigid, sickle Red blood cells
shape.
• Individuals who inherit two copies of this mutation
(one from each parent) will develop SCD.
• Individuals who inherit only one copy of the
mutation may not have symptoms of SCD, but are
Sickle cells
known as "carriers" because they can pass on the
mutation when they have children.
Sickle-cell disease occurs more commonly among people whose
ancestors lived in tropical and sub-tropical sub-saharan regions
where malaria is or was common.
Where malaria is common, carrying a single sickle-cell allele
(sickle cell trait) confers a selective advantage.
Specifically, humans with one of the two alleles of sickle-cell
disease show less severe symptoms when infected with malaria.
 Signs and symptoms
• Stroke, which can result from a progressive narrowing of blood vessels,
preventing oxygen from reaching the brain. Cerebral infarction occurs in children
and cerebral haemorrhage in adults.
• Cholelithiasis (gallstones) and cholecystitis, which may result from excessive
bilirubin production and precipitation due to prolonged haemolysis.
• Avascular necrosis (aseptic bone necrosis) of the hip and other major joints,
which may occur as a result of ischaemia.
• Decreased immune reactions due to hyposplenism (malfunctioning of the spleen).
• Acute papillary necrosis in the kidneys. Chronic renal failure due to Sickle cell
nephropathy
• Leg ulcers
• typical symptoms are shortness of breath, decreased exercise tolerance and
episodes of syncope
• During pregnancy, intrauterine growth retardation, spontaneous abortion, and
pre-eclampsia.
• Chronic pain
• Pulmonary hypertension
• Life expectancy is shortened. In 1994, in the US, the average life expectancy of
persons with this condition was estimated to be 42 years in males and 48 years in
females, but today, thanks to better management of the disease, patients can live
into their 70 years or beyond.
 Phenylketonuria (PKU)
• Phenylketonuria (PKU) is an autosomal
recessive

• metabolic genetic disorder characterized by a

mutation in the gene for the hepatic enzyme
phenylalanine hydroxylase (PAH)

• The PAH gene is located on chromosome 12

in the bands 12q22-q24.1. More than 400
disease-causing mutations have been found in
the PAH gene.

• PKU is rare – it is estimated to affect 1 in every

10,000 babies born
Phenylalanine hydroxylase (PAH)
• This enzyme is necessary to
metabolize the amino acid
phenylalanine (Phe) to the
amino acid tyrosine (Tyr) .

• The body takes in phenylalanine

in the form of protein in food.

• When PAH activity is reduced,

phenylalanine accumulates in
their blood, and other tissues

• Children with PKU excrete

phenylalanine in their urine.
phenylalanine is
converted into phenyl
pyruvate (also known
as phenylketone), which
can be detected in the From tyrosine,
urine. there are further
connections to
the biosynthesis
of
phenyl phenyl phenyl catecholamines,
pyruvate acetate lactate
melanin,
liver hormones, etc.
brain

kidneys
phenylalanine tyrosine
 Phenylketonuria (PKU)
• phenylalanine is converted into
phenylpyruvate (also known as
phenylketone), which can be detected in
the urine.
 Phenylketonuria (PKU)
From tyrosine, there are further connections to
the biosynthesis of catecholamines, melanin,
hormones, etc.
A defect in the
transformation of
phenylalanine will lead to
an excess of Phe and a
deficit of Tyr in the body.
Babies born with PKU usually have
no symptoms at first.
But if the disease is left untreated,
babies experience severe brain
damage  Developmental delays
intellectual disability

A "musty or mousy" odor of skin, hair,

sweat and urine (due to phenylacetate
accumulation)

• Patients with phenylketonuria have

reduced melanin synthesis
• They have hypopigmentation
(excessively fair hair and skin)
Signs of classic PKU include:
• Irritability
• Hyperactivity
• EEG abnormalities
• seizures
• Microcephaly
• progressive impairment of cerebral
function.
• hypopigmentation (excessively fair hair
and skin)
• Dry, scaly skin
• A "musty or mousy" odor of skin, hair,
sweat and urine (due to phenylacetate
accumulation)
• Developmental delays intellectual
disability
 Metabolic pathways
• Phenylalanine is a large, neutral amino acid
(LNAA). LNAAs compete for transport across the
blood–brain barrier (BBB) via the large neutral
amino acid transporter (LNAAT).
• If phenylalanine is in excess in the blood, it will
saturate the transporter. Excessive levels of
phenylalanine tend to decrease the levels of other
LNAAs in the brain. However, as these amino acids
are necessary for protein and neurotransmitter
synthesis, Phe buildup hinders the development of
the brain, causing intellectual disability
Untreated PKU can lead to
intellectual disability
Newborn screening
• PKU is commonly included in
the newborn screening panel
of most countries
• Measurements of
concentration of Phe and the
ratio of Phe to tyrosine
determine both of which will
be elevated in PKU.
• test typically performed 2 – 7
days after birth, using
samples drawn by neonatal
heel prick
Treatment for PKU
PKU is treated with a special low-protein diet, which reduces
the levels of phenylalanine in the body and prevents brain
damage.

Diet avoids foods such as meat, chicken, fish, eggs,

cheese, legumes and dairy products, and controls the
intake of many other foods (such as potatoes and cereals).
Treatment for PKU

In addition, patients must take an

amino acid supplement to ensure
that they are getting all of the
nutrients required for normal
growth and good health.

Patients who are diagnosed early and

maintain a strict diet can have a normal life
span with normal mental development.
Inheritance phenylketonuria

• PKU is known to be an
autosomal recessive
genetic disorder.
Therefore, if both parents
are carriers for PKU,
there is a 25% chance
their child with develop
the disorder, a 50%
chance their child will be
a carrier, and a 25%
chance their child will
neither develop nor be a
carrier for the disease.
 Albinism
• Albinism (from Latin albus,
"white“)is a autosomal recessive
disorder characterized by the
complete or partial absence of
pigment in the skin, hair and eyes
due to absence or defect of
tyrosinase, a copper-containing
enzyme involved in the
production of melanin.
• Albinism affect all vertebrates,
including humans.

• Albinism is associated with a number of

vision defects, such as photophobia,
nystagmus and astigmatism.
• Lack of skin pigmentation makes for
more susceptibility to sunburn and skin
cancers.
phenyl phenyl phenyl
pyruvate acetate lactate

liver
brain tyrosinase

kidneys
Galactosemia

• Galactosemia is a rare autosomal

recessive metabolic disorder that
affects an individual's ability to
metabolize the sugar galactose
properly.

• Its incidence is about 1 per 60,000 births for

people of European ancestry
• Friedrich Goppert (1870–1927), a German
Physician, first described the disease in
1917
Lactose in food (such as dairy products) is broken
down by the enzyme lactase into glucose and
galactose.

lactase

Galactosemia is sometimes confused with lactose

intolerance, but galactosemia is a more serious condition.
Galactose is converted into
glucose by the action of three
enzymes, known as the Leloir
pathway.
There are diseases associated with deficiencies of each of
these three enzymes

locus Enzyme name

Type 1 9p13 galactose-1- classic galactosemia

phosphate uridyl
transferase

Type 2 17q24 galactokinase galactokinase

deficiency

Type 3 1p36- UDP galactose galactose epimerase

epimerase deficiency, UDP-
p35 Galactose-4-
epimerase deficiency
 Signs and symptoms of galactosemia
• Infants with galactosemia can develop symptoms in the first
few days of life if they eat formula or breast milk that contains
lactose.
• The signs and symptoms of galactosemia result from an inability to
use galactose to produce energy. Affected infants typically
develop:
1. feeding difficulties
2. Vomiting
3. lack of energy (lethargy)
4. Poor weight gain
5. Convulsions
6. Irritability
7. Enlarged liver (hepatomegaly)
8. yellowing of the skin and whites
of the eyes (jaundice)
9. Fluid in the abdomen (ascites)
10. Bleeding
 Complications of galactosemia
• overwhelming bacterial infections (sepsis) and shock.
• Affected children can have serious, irreversible effects or
even die within days from birth.
• Without treatment, mortality in infants with
galactosemia is about 75%.
liver
• galactose 1-phosphate
accumulates in various tissues
• galactose transformed into
galactitol kidneys

• galactitol accumulates in body

tissues and is excreted in the
urine
• Accumulation of galactitol has
been attributed to many of the
negative effects of galactosemia
(Cataracts) brain
 Complications
Other serious complications of galactosemia can include:

• liver damage, cirrhosis

• renal failure
• Cataracts
• brain damage
• Ataxia
• speech difficulties
• intellectual disability
• ovarian failure
• Diminished bone density
Diagnosis
• most infants are diagnosed
on newborn screening.
• Infants affected by galactosemia typically present with
symptoms of lethargy, vomiting, diarrhea, failure to thrive,
and jaundice. None of these symptoms are specific to
galactosemia, often leading to diagnostic delays.
Laboratory tests
A galactosemia test is a blood test (from the
heel of the infant) or urine test:
1. Amino acids in the urine and/or blood
plasma (aminoaciduria)
2. Ketones in the urine
3. Low blood sugar -glucose (hypoglycemia)
4. high levels of galactose in the blood or urine
5. Enzyme activity in the red blood cells
Prenatal diagnosis
• Prenatal diagnosis by
directly measuring the
enzyme galactose-1-
phosphate uridyl
transferase
• If the family of the baby has
a history of galactosemia,
doctors can test prior to
birth by taking a sample of
fluid from around the fetus
(amniocentesis) or from the
placenta (chorionic villus
sampling or CVS).
Treatment • The only treatment for classic
galactosemia is eliminating lactose and
galactose from the diet.
• Infants with classic galactosemia cannot
be breast-fed due to lactose in human
breast milk and are usually fed a soy-
based formula.
Diet • Calcium supplements are recommended.

• NOT ALLOWED: All forms of milk, cheese, yogurt, cottage

cheese, cream cheese, ice cream, sherbert, pudding,
creamed soups and sauces, milk chocolate.

• CAUTIOUSLY READ LABELS to look for milk products in

bread, crackers, cookies, chips, cereal, pancakes, hot dogs,
bologna, breaded meat and fish, gravy, processed foods,
artificial sweeteners, non-dairy creamers, drugs.

• ALLOWED: Most other meats, eggs, legumes, fruits,

vegetables, grains, breads, soy milk, fats, and sweets that do
not contain galactose or lactose.
Inheritance Galactosemia
• Galactosemia is
autosomal recessive
disorder
• If both parents carry an
abnormal gene that can
cause galactosemia, each
of their children has a 25%
chance of being affected.
 Theme:
VARIABILITY
AND
HEREDITARY DISEASES

THE LESSON No.4

(урок №4)
изменчивость и наследственные болезни
 By changes in the hereditary material:
Chromosomal Abnormalities
Gene NUMERICAL STRUCTURAL
mutations ABERRATIONS ABERRATIONS
A gene-level Genomic Chromosomal
mutation is a mutations aberrations
permanent change are associated are associated
in the sequence of with with
DNA. the change of the change of
number of structure of
chromosomes chromosomes
 Numerical Chromosomal Aberrations
Genome mutation - loss or gain of whole chromosomes
Changes in chromosome number
• Aneuploidy Nondisjunction (non-separation of
• Polyploidy chromosomes and chromatids ) – they can
occur during meiosis
 EUPLOIDY ANEUPLOIDY
is the difference in the Variation that includes one or
chromosome number that two chromosomes in the
takes place because of diploid set of an organism
increase or decrease of results in aneuploidy.
full set of chromosomes.
 Cause of the Abnormal Chromosome Number
• In nondisjunction, pairs of homologous chromosomes do not
separate normally during meiosis

Nondisjunction  meiotic or mitotic error during

which certain homologous chromosomes or sister
chromatids fail to separate

• As a result, one gamete receives two of the same type of

chromosome, and another gamete receives no copy

• Nondisjunction can also occur in mitosis

• Polyploidy is a condition in which an
organism has more than two
complete sets of chromosomes
– Triploidy (3n) is three sets of
chromosomes
– Tetraploidy (4n) is four sets of
chromosomes
• Polyploidy is common in plants, but
not animals
• Polyploids are more normal in
appearance than aneuploids
 • Aneuploidy results from the
fertilization of gametes in which
nondisjunction occurred

• Offspring with this condition

have an abnormal number of a
particular chromosome

• A monosomic zygote has only

one copy of a particular
chromosome: 2n-1

• A trisomic zygote has three

copies of a particular
chromosome: 2n+1
One of the mitotic
spindle is not formed • A polysomic zygote has three
or more copies of a particular
chromosome: 2n+2, 2n+3…
 Meiosis I

Nondisjunction

Meiosis II

Nondisjunction

Gametes

n+1 n+1 n–1 n–1 n+1 n–1 n n

Number of chromosomes

(a) Nondisjunction of homologous (b) Nondisjunction of sister

chromosomes in meiosis I chromatids in meiosis II
 Distinguish between trisomy and triploidy.
• Trisomy  an aneuploid cell that
• Triploidy  polyploid
has a chromosome in triplicate:
chromosome number with 3n
2n+1
 Chromosomal Alterations
• Large-scale chromosomal alterations often lead to
spontaneous abortions (miscarriages) or cause a
variety of developmental disorders!

• trisomy (2n+1) - 47 - compatible with life

• polysomy (2n+2, 3, 4…)
• monosomy (2n-1) - autosomal – incompatible with life
- sex chromosomal - compatible with life
• nullisomy - incompatible with life
 Human Disorders Due
to Chromosomal Alterations
• Alterations of chromosome number and structure
are associated with some serious disorders

• Some types of aneuploidy appear to upset the

genetic balance less than others, resulting in
individuals surviving to birth and beyond

• These surviving individuals have a set of symptoms,

or syndrome, characteristic of the type of
aneuploidy
 Chromosomal diseases (cause - genome mutation)
Disease Karyotype
AUTOSOMES
TRISOMY-21 (DOWN SYNDROME) 47,21+
TRISOMY- 8, 9, 13 (PATAU), 47, 13+
TRISOMY- 18 (EDWARDS) 47, 18+
SEX CHROMOSOMES
KLINEFELTER: 47, XXY
Trisomy/Polysomy-XXY, XXXY, etc. 49, XXXY, etc.
TURNER: 45, XO
Monosomy - XO
TRIPLE X SYNDROME: 47, XXX
Trisomy X - XXX
 Aneuploidy of Autosomal Chromosomes
• Nondisjunction of autosomal chromosomes produces a variety
of aneuploid conditions

P: ♀ 44 × ♂ 44
21 21 21 21

G: 22 22 22
21 21 21
Lethal, nonviable

F: 44
21 21 21
Down Syndrome (Trisomy 21)
• Down syndrome is an aneuploid
condition that results from three
copies of chromosome 21

• Occur in about 1 per 1000 babies

born each year.

• The frequency of Down syndrome

(trisomy) increases with the age
of the mother.

• Down syndrome karyotype is 47,

21+

• Down syndrome in mosaic or

mosaic trisomy, karyotype is
46,21 / 47,21+
• Mosaicism - presence of two or more populations of cells with
different genotypes in one individual who has developed from a
single fertilized egg.
• So, person with chromosomal disorder only in some of the cells
is called mosaic. Individuals with this pattern may have fewer
symptoms because they still have some normal cells.
Down Syndrome (Trisomy 21)
Clinical symptoms
• Some degree of mental retardation,
from mild to severe. In most cases, the
mental retardation is mild to moderate
(IQ 25-50)
• flat face + epicanthus
• congenital heart defects
• neck skin folds
• skeletal muscle hypotonia
• hypermobility of joints
• increased risk of acute leukemias
• mortality 40% until 100% (cardiac
complications)
 Hand signs in
Down Syndrome

• Abnormally short
fingers
(brachydactyly)
• Very short pinky
finger
• Simian crease on
two hands
• Fingerprints: 10
ulnar loops
• Palm: AtD-angle is
57o or larger:
Down Syndrome (Trisomy 21)
• Adults with Down
syndrome
demonstrate
strengths in:
- Visual memory
- Vocabulary
- The use of reading
and writing
- The use of hand
signs and gestures to
communicate
- The motivation to
communicate
 Diagnosis of chromosome diseases

• Because some characteristics of Down syndrome may be

present in babies without Down syndrome, a
chromosomal analysis (karyotyping) is necessary in
order to confirm the clinical diagnosis.

• A blood sample is taken from the baby to perform this

test.
 Patau Syndrome • Patau syndrome is an aneuploid
condition that results from three
(Trisomy 13) copies of chromosome 13
• Patau syndrome karyotype is 47, 13+
• Patau syndrome in mosaic or mosaic
trisomy, karyotype is 46,13 / 47,13+
• The incidence of Patau syndrome is 1 / 4000 – 1 /
10000 newborns.

Clinical symptoms
Multiple abnormalities,
most of which are
incompatible with life.
• Head: microcephaly, scalp defects, malformed and lowset ears.
• Facial: sloping forehead, nose broad and flat, hypertelorism, hypotelorism, ocular
anomalies such as microophthalmia or anophthalmia, absence of iris, cataract,
iris coloboma, cleft lip and cleft palate.
• Neurologic: Holoprosencephaly, in which the
brain is not divided completely into halves, is
often present and is generally signaled by the
presence of midline facial defects.
• Limbs: polydactyly or sindactyly.
• Cardiac malformations: represents 80% of all
malformations: patent ductus arteriosus,
ventricular septal defect, interatrial septal
defect, dextrocardia.
• Genitourinary malformations: polycystic
kidney, renal duplicaton, double ureter,
testicular agenesis and cryptorchidism in boys,
clitoral hypertrophy and two-horned uterus in
girls.
• Capillary hemangiomas on the face, forehead
and neck.
Edwards Syndrome • Edwards syndrome is an aneuploid
(Trisomy 18) condition that results from three copies
of chromosome 18
• Edwards syndrome karyotype is 47, 18+
• Edwards syndrome in mosaic or mosaic
trisomy, karyotype is 46,18 / 47,18+
• Trisomy 18 occurs in 1 in 3,000 live births.
Unfortunately, most babies with Trisomy 18 die before
birth

Clinical symptoms
Multiple abnormalities,
most of which are
incompatible with life.
Edwards Syndrome (Trisomy 18)
Clinical symptoms • Nervous system and brain - mental
retardation and delayed
development, high muscle tone,
seizures, and physical malformations
such as brain defects
• Head and face - small head
(microcephaly), small eyes, wide-set
eyes, small lower jaw
• Heart - congenital heart defects
such as ventricular septal defect
• Bones - severe growth retardation,
clenched hands with 2nd and 5th
fingers on top of the others, and
other defects of the hands and feet
• Malformations of the digestive tract,
the urinary tract, and genitals
 Aneuploidy of Sex Chromosomes
• Nondisjunction of sex chromosomes produces a variety of aneuploid
conditions
P: ♀ 44A+XX × ♂ 44A+XY

G: 22A+X 22A+Y
22A+XX 22A+O

F: 44A+XXX, 44A+XXY, 44A+XO, 44A+YO

Lethal, nonviable
If a pair of sex chromosomes fails to separate during the formation of an egg (or
sperm), this is referred to as nondisjunction. When an abnormal egg unites with a
normal sperm to form an embryo, that embryo may end up missing one of the sex
chromosomes (X rather than XX). As the embryo grows and the cells divide, every
cell of the baby's body will be missing one of the X chromosomes.
Klinefelter syndrome (47, XXY)
• 1:1000 males
• additional X is either of
paternal or maternal origin
• advanced maternal age,
history of irradiation of either
of parents

• Klinefelter syndrome
karyotype is 47, XXY

• Klinefelter syndrome in
mosaic or mosaic trisomy,
karyotype is 46,XY / 47,XXY
Klinefelter syndrome (47, XXY)
Clinical symptoms
• wide range of clinical
manifestations
• distinctive body habitus -
increase length between
soles and pubic bone
• reduced body and facial
hair
• Gynecomastia (Breast
growth)
• testicular atrophy -
impaired spermatogenesis
- sterility (rarely fertility! -
mosaics)
Turner syndrome (45, X0)
• 1:3000 females

• Turner syndrome is
caused by a missing
or incomplete X
chromosome.

• Turner syndrome
karyotype is 45, XO
• Turner syndrome in
mosaic or mosaic
monosomy,
karyotype is 46,XX
/ 45, XO
 Turner syndrome (45, X0)
Clinical symptoms
• primary hypogonadism in
phenotypic female
(underdeveloped ovaries,
Individuals are sterile, and
lack expected secondary
sexual characteristics)

• growth retardation (short

stature, wide and webbed
neck, low posterior hairline,
broad chest)

• Mental retardation typically

not evident.
Лимфедема стоп
 Triple X Syndrome (Trisomy X)
• 1 out of 1000 females
• 3 copies of the X chromosome in each cell
typically due to nondisjuction during
meiosis.
• Triple X syndrome karyotype is 47, XXX
• Triple X syndrome in mosaic or mosaic
trisomy, karyotype is 46,XX / 47, XXX
• Usually no major physical differences.
• tall stature; small head (microcephaly); vertical skinfolds
that may cover the inner corners of the eyes (epicanthal
folds); speech and language; mild learning disabilities,
such as dyslexia (developmental reading disorder); or
weak muscle tone.
• Sometimes these women cannot reproduce, have
irregular menstrual cycles, but most Triple X females
seem to have normal fertility.
• Aneuploidy of Sex
Chromosomes is
determined using
Analysis of sex
chromatin in
buccal scrapings
 Structural Aberrations
Chromosome mutation - a type of mutation
involving alteration(s) in chromosome structure,
including breakage and loss of chromosomal
segments.

Changes in chromosome structure

• Chromosomal Deletion
• Chromosomal Duplication
• Chromosomal Inversion
• Chromosomal Translocation
Alterations of Chromosome Structure
Breakage of a chromosome can lead to four types of changes in
chromosome structure:
• Rings: A portion of a chromosome has broken off and formed a
circle or ring. This can happen with or without loss of genetic
material.
Fig.1 Mechanisms
Two DNA breaks in each arm at the top and bottom causing:
• Distortion of Chromosomal morphology
• Proximal end fusion and ring formation
• Loss of distal material as ends break away
Also:
• Potential loss of Genetic material and
• Dysregulation of gene expression
• Alteration in cellular life cycle
• Formation of Ring 20 associated with epilepsy
Ring formation in other chromosomes may cause mental retardation
Fig.2 Mechanisms
• Fusion of dysfunctional Telomere of the same
chromosome
• Shortening of telomeric DNA and Recombination with
the other arm of the same chromosome
• Detachment of protective proteins from chromosomal
ends
• May or may not be associated with Loss of Genetic
material
• Possible alteration of gene expression
• Isochromosome: Formed by the mirror image copy of a
chromosome segment including the centromere.
 Fragile X syndrome
Structural aberrations also include some
disorders which are characterized by
chromosomal instability and breakage.

One example, is the creation of a fragile

site on the X Chromosome - Fragile X
syndrome.

Boys are worse affected by this because

they only have one X-Chromosome but
even in girls, Fragile X syndrome can cause
learning difficulties.
 Chromosomal diseases (chromosome mutation)
Disease Karyotype
cri du chat (“cry of the cat”), 46, 5pˉ
Down Syndrome (Translocation) 46XY,t(14q21q),
46XX,t(14q21q).
18p , 13p deletion syndrome 46, 18pˉ
46, 13pˉ
18q, 13q deletion syndrome 46, 18qˉ
46, 13qˉ
18p, 13p duplication syndrome 46, 18p+
46, 13p+
18q, 13q duplication syndrome 46, 18q+
etc. 46, 13q+
Types of deletion include the following:
• Terminal Deletion - a deletion that occurs towards the end of a
chromosome.
• Intercalary Deletion / Interstitial Deletion - a deletion that occurs
from the interior of a chromosome.
• Microdeletion - a relatively small amount of deletion (up to 5Mb
that could include a dozen genes).

Microdeletion is usually found in children with physical abnormalities.

A large amount of deletion would result in immediate abortion
(miscarriage).

Chromosomal
Deletion
Cri du chat syndrome, chromosome 5p deletion
syndrome, or Lejeune’s syndrome
• One syndrome, cri du chat (“cry of the
cat”), results from a specific deletion in
chromosome 5: 46, 5pˉ
• A child born with this syndrome is
mentally retarded and has a catlike cry;
individuals usually die in infancy or early
childhood
 Clinical symptoms
• feeding problems because of difficulty
8 months 2 years swallowing and sucking;
• low birth weight and poor growth;
• severe cognitive, speech, and motor
delays;
• behavioral problems such as
hyperactivity, aggression, tantrums,
and repetitive movements;
• unusual facial features which may
change over time;
• Excessive drooling;
• small head and jaw;
• wide eyes;
4 years 9 years • skin tags in front of eyes.
 Translocations are chromosomal abnormalities
Reciprocal
translocation Centric Fusions or
Robertsonian translocation

which occurs between two acrocentric

chromosomes of groups G and D

A. Two non-homologous
A. normales
chromosome pairs
Chromosomen
B. Reciprocal
paar
translocation
B. centric fusion of
two
non-homologous
chromosome
Down Syndrome (Translocation)

• The extra chromosome 21

material may also occur
due to a Robertsonian
translocation in 2–4% cases.

• In a male affected with

Down syndrome it results in
a karyotype of
46XY,tr(14q21q), in female
– 46XX,tr(14q21q).
Down Syndrome (Translocation)
• The long arm of chromosome
21 is attached to another
chromosome – 13, 15, often
chromosome 14. This may be a
new mutation or previously
present in one of the parents.

• The parent with such a

translocation is usually normal
physically and
mentally; however, during
production of egg or sperm
cells there is a higher chance of
creating reproductive cells with
extra chromosome 21 material.
Down Syndrome (Balanced translocation)

• Balanced translocation
carrier between chromosome
21 and 14 in male.

• The phenotype is normal.

• Karyotype - 45, XY, tr (21/14)

 Down Syndrome (Translocation)

• This results in a 15% chance of having a child with Down

syndrome when the mother is affected and a less than
5% risk if the father is affected. Some children without
Down syndrome may inherit the translocation and have
a higher risk of having children of their own with Down
syndrome. In this case it is sometimes known as familial
Down syndrome.
 Translocation trisomy in heritable Down Syndrome

In the germline of an asymptomatic individual, reciprocal translocation between

the long arms of Chromosomes 14 & 21 results in gametes that carry a large
portion of Chromosome 21 on a Chromosome 14 centromere. In combination with
a standard gamete from the other parent, this results in a 2n=46 karyotype with
a segmental aneuploidy for Chromosome 21, producing a Down Syndrome infant.
The karyotype is formally desribed as 2n = 46, t(14q21q).
Chromosomal
Inversion
Chromosomal
Duplication
 Anti-mutagenic mechanisms
in multicellular animals

• programmed cell death

(apoptosis)

• The genetic code

is degenerate, or
redundant.
All but two (met, trp) of the
amino acids are specified by more
than one codon (from 2 to 6 ).
• Diploid karyotype in
somatic cells

• non-coding sequences
(introns).
• Tandem Repeats

• Repair

• DNA methylation
 Theme: Medical Genetics

THE LESSON
Modul 2 : No.5
Genetics (урок №5)
Модуль 2:
Генетика
Genetic counseling
• Genetic counseling -
specialized medical care

• Purpose: prevention of
hereditary diseases
• Genetic counseling is the process, by
which patients or relatives, at risk of
an inherited disorder, are advised of
the consequences and nature of the
disorder, the probability of
developing or transmitting it, and
the options open to them in
management and family planning.
This complex process can be
separated into diagnostic (the actual
estimation of risk) and supportive
aspects
 Stages of counseling
1. Establishment or
refinement of diagnosis
2. Prediction Calculator
offspring
3. Consultation (explanation
of the mechanism of
inheritance of the
disease, the risk of having
an affected child, help
Genetic counseling session
deciding)
 Genetic professionals:
• Assess the risk of a genetic disorder by researching a family's
history, evaluating medical records, and conducting a physical
examination of the patient and other family members when
indicated.
• Weigh the medical, social and ethical decisions surrounding
genetic testing.
• Provide support and information to help a person make a
decision about testing.
• Interpret the results of genetic tests and medical data.
• Provide counseling or refer individuals and families to support
services.
• Serve as patient advocates.
• Explain possible treatments or preventive measures.
• Discuss reproductive options.
 Reasons
Families or individuals may choose to attend counseling or
undergo prenatal testing for a number of reasons:

• Family history of a genetic condition or chromosome

abnormality
• Molecular test for single gene disorder
• Increased maternal age (35 years and older)
• Increased paternal age (40 years and older)
• Abnormal maternal serum screening results or ultrasound
findings
• Increased nuchal translucency measurements on ultrasound
• Strong family history of cancer
• Predictive testing for adult-onset conditions
 Types of genetic testing
• Diagnostic testing: genetic testing performed in a
symptomatic individual to confirm or exclude a genetic
condition.
• Predictive testing: genetic testing in a healthy high-risk
relative for a specific later-onset monogenic disorder.
• Susceptibility testing (risk profiling): a genetic test of a
marker or several genetic markers with the aim to detect an
increased or decreased risk for a multifactorial condition in a
healthy individual.
• Pharmacogenetic testing: testing for a genetic susceptibility
for adverse drug reactions or for the efficacy of a drug
treatment in an individual with a given genotype.
• Carrier testing: a genetic test that detects a gene mutation
that will generally have limited or no consequence to the
health of that individual.
 Types of genetic testing
• Prenatal testing: a genetic test performed during a
pregnancy, where there is increased risk for a certain
condition in the fetus.
• Preimplantation genetic diagnosis: testing the presence of a
mutation, linked haplotype or chromosomal change in one or
two cells of an embryo in a family with a previously known
risk for a Mendelian or chromosomal disorder, in order to
select the unaffected embryos to be implanted.
• Genetic screening: testing where the target is not high-risk
individuals or families, but where the test is systematically
offered to the general population or a specific group (eg,
newborns, young adults, an ethnic group).
 Diagnosis methods of Genetic Diseases

Provisional methods Precise methods Scientific methods

Dermatoglyphics 1) Biochemical test 1) Somatic cell
Phenotypic analysis (screening) hybridization
Pedigree Analysis 2) Cytogenetic analysis or 2) Twin study
Cytogenetic Test 3) Population
Methods (Chromosomal genetics statistical
analysis): methods
̶ Buccal scraping or 3) Molecular analysis
smear (Sex chromatin (DNA sequencing)
test)
̶ Karyotyping
̶ FISH
3) Molecular analysis (DNA
sequencing)
4) Prenatal Diagnosis
 Provisional methods

Preliminary methods used to:

1) identification the possible disease of the
patient in order to send him to precise
diagnosis
2) determination disease development of the
patient in the future
 Provisional methods

Dermatoglyphics
̶ the study of the skin ridge patterns on fingers, toes, palms
of hands, and soles of feet.
̶ The patterns are used as a basis of identification and also
have diagnostic value because of associations between
certain patterns and chromosomal anomalies.

There are 3 kinds of skin ridge patterns study:

• Fingers analysis
• Palms analysis
• Soles of feet analysis
 Fingerprints
• fingerprints will remain unchanged during an
individual’s lifetime
 Fingerprinting
• A fingerprint is an INDIVIDUAL
CHARACTERISTIC
– no two have yet been found to possess identical
ridge characteristics.
 Anatomy of the Fingerprint
• Skin is composed of layers of
cells:

• Epidermis (outer portion) and

dermis as inner skin.

• In a cross section- a boundary

of cells separating the
epidermis from the dermis is
made up of dermal papillae-
these determine the form and
pattern of ridges on the
surface.

• Dermal papillae develop in the

fetus and remain unchanged
during life.
Sir Francis Galton
• Sir Francis Galton, a British
anthropologist and a
cousin of Charles Darwin,
began his observations of
fingerprints as a means of
identification in the 1880's.

• In 1892, he published his

book, "Fingerprints",
establishing the
individuality and
permanence of
fingerprints. The book
included the first
classification system for
fingerprints.
Types of Prints
 Types of Prints
• Fingerprints have general ridge patterns for
classification:
Отпечатки пальцев
имеют основные
гребневые узоры, что
• Divided into three classes: позволило их
классифицировать
– LOOP
– WHORL
– ARCH

• 60-65% of population has loops

• 30-35% whorls

• and 5% arches.
 Петля должна иметь один или несколько
гребней, поступающих из одной стороны

Loop отпечатка, и выходящих с той же

стороны.

• Loop must have one or

more ridges entering
from one side of the
print and exiting from
the same side.
– If loop opens toward
little finger= ulnar loop
– Opens from the thumb=
radial loop
 Type-lines
• Pattern area of the loop
is surrounded by two
diverging ridges known
as type-lines (A, B).
 Deltas
• The ridge point
Delta nearest the type-
line divergence is
the DELTA.
– Triangular in
shape.
– ALL LOOPS HAVE
ONE DELTA
 Core
Core = center of
the pattern.
 Whorls
• Whorls- 4 distinct groups:
– Plain
– Central pocket Простая
– Double loop
центральный карман
двойная петля
случайная.
– Accidental.

• All whorl patterns have type

lines and a minimum of two
deltas.
 Arches
• Arches- least common
has 2 patterns- plain Дуги - наименее
распространены,
arches and tented имеют 2 узора-
простые дуги и
палаточные.

• Do not have:
– type lines
– deltas
– or cores
Palms analysis
• Simian crease
(transverse crease on
the palm). These are
seen in 6% and 11%
respectively of normal
individuals, but are also
associated with certain
disorders.
Palms analysis
• Axial triradius - on the
ulnar side of the palm near
the wrist.

• The angle whish is

determined from the
triadic point at the base of
the palm to the points at
the bases of the forefinger
and pinky is called AtD-
angle. The normal count is
between 35° and 45°.
Anything below or higher
suggests mental
retardation.
Palms analysis
• In the hands of people with
an 'autosomal trisomy' the
axial triradius is usually
observed at a higher region of
the ulnar side of the palm

• Palm: AtD-angle is 57o – 81o -

Down syndrome
• AtD-angle is 74 - 108o - Patau
syndrome
• AtD-angle is 66o - Turner
syndrome
• AtD-angle is 42o - Klinefelter
syndrome
 Provisional methods
Pedigree Analysis
• Pedigree: a family history that shows how a trait is inherited
over several generations

• Pedigrees are usually used when parents want to know if they

are carriers of a particular disorder

• Classical cross fertilization breeding experiments as

performed by Mendel are not allowed in humans! Human
geneticists are not allowed to selectively breed for the traits
they wish to study!

• One of most powerful tools in human genetic studies is

pedigree analysis.
 Possibilities of the Pedigree Analysis

1. Determine character of trait: hereditary or not

2. Determine the mode of inheritance
3. Determine gene penetrance
4. Determine linkage groups
5. chromosome mapping;
6. study the intensity of the mutation process;
7. study the interaction of genes
8. genetic counseling (Determine the probability of an affected
offspring for a given cross).
 Stages of work
1. Gathering information about the family
(examination, testing)
2. construction of pedigree
3. Pedigree analysis
4. Conclusions
 Making a Pedigree
Symbols used in pedigree charts
A marriage with five children, two
• Normal male daughters and three sons. The eldest
son is affected by the condition.
• Affected male
• Normal female
• Affected female
• Marriage
Eldest child  Youngest child
Standard
Pedigree
Symbols
Standards for the construction of pedigrees.

• Proband - the person for

whom compiled pedigree
(indicated by arrow)

• Siblings - brothers and sisters

of the proband

• Generations are numbered

with Roman numerals

• Pedigree members numbered

in Arabic numerals

• Members of one generation

are on the same level
 Organising the pedigree chart
• Generations are identified by Roman numerals Individuals in each
generation are identified by Arabic numerals numbered from the left
• Members of one generation are on the same level
• Therefore the affected individuals are II3, IV2 and IV3

I
1 2

II
1 2 3 4 5 6 7

III
1 2 3 4 5 6

IV
1 2 3 4 5
 General patterns of inheritance

Autosomal: Sex-linked: Mitochondrial

1. dominant X-linked recessive
2. recessive X-linked dominant
Y-linked (holandric)
 Autosomal dominant
There are four hallmarks of autosomal dominant inheritance:
1. Each affected individual has an affected parent; there is no skipping of
generations.
2. Males and females are equally likely to be affected. About 1/2 of the
offspring of an affected individual are affected (the recurrence risk is
1/2).
3. Normal siblings of affected individuals have all normal offspring.
4. The defective product of the gene is usually a structural protein, not an
enzyme. Structural proteins are usually defective when one of the allelic
products is nonfunctional; enzymes usually require both allelic products
to be nonfunctional to produce a mutant phenotype
Autosomal dominant
Examples:

1. polydactyly
2. myopia (short sight)
3. Huntington disease.
4. acondroplasia (short-
limbed dwarfism)
5. polycystic kidney
disease
6. hypercholesterolemia

35
 Autosomal recessive
There are five hallmarks of autosomal recessive inheritance:
1. Males and females are equally likely to
be affected.

2. On average, the recurrence risk to the

unborn sibling of an affected individual
is 1/4.

3. The trait is characteristically found in

siblings, not parents of affected or the
offspring of affected.

4. Parents of affected children may be

related. The rarer the trait in the general
population, the more likely a
consanguineous mating is involved.

5. The trait may appear as an isolated

(sporadic) event in small sibships.
Autosomal recessive
The disease appears in
male and female
children of
unaffected parents.

Examples:

• Cystic fibrosis
• Tay-Sachs
• Hemochromatosis
• Phenylketonuria (PKU)
• Galactosemia
• Albinism

38
 Notes
• Cystic fibrosis – disease affecting the mucus lining of the
lungs, leading to breathing problems and other difficulties
• Huntington disease - or Huntington's chorea is an inherited
disorder characterized by abnormal body movements called
chorea, and loss of memory. The disease is caused by somatic
expansion of trinucleotide repeat sequences. The incidence is
5 to 8 per 100,000. It takes its name from the New York
physician George Huntington who first described it precisely
in 1872.

39
 X-linked inheritance
• Male passes his X
chromosome daughter
and Y-chromosome
passes son.
• Therefore male never
passes its X-linked
disease sons!!!

Males with a single Y- or X-linked

allele are described
as hemizygotes, because only one
allele is present.
 X-linked dominant
• disease have both males and females in each generation (as well as with
an autosomal dominant inheritance. But
• affected father never passes the trait to his sons but passes it to all of his
daughters
• affected female passes the disease to half of her daughters and half of
her sons.
X-linked dominant
Example:

• fragile X syndrome,
• Vitamin D resistant rickets
• Rett syndrome (RS)
• some forms of retinitis
pigmentosa
• Chondrodysplasia Punctata
 Notes
• Fragile X syndrome - is a genetic condition that
causes a range of developmental problems including
learning disabilities and mental retardation. Usually
males are more severely affected by this disorder
than females. In addition to learning difficulties,
affected males tend to be restless, fidgety, and
inattentive. Affected males also have characteristic
physical features that become more apparent with
age.

43
X-linked recessive
•the disease is never passed from
father to son.

•Males are much more likely to

be affected than females. If
affected males cannot reproduce,
only males will be affected.

•All affected males in a family are

related through their mothers.

•Trait or disease is typically

passed from an affected
grandfather, through his carrier
daughters, to half of his
grandsons
X-linked recessive
Example:

• hemophilia
• Color blindness
• Duchenne muscular
dystrophy
• X-linked severe
combined immune
disorder (SCID)
• some forms of
congenital deafness
pedigree of hemophilia in royal family
 Y-linked inheritance
Since only males normally have a Y chromosome, Y-linked genes
can only be transmitted from father to son.
Y-linked inheritance is also called holandric inheritance.

e.g. excessively hairy ears or

"hypertrichosis of the pinna“
Mitochondrial inheritance
• This type of inheritance applies to genes in
mitochondrial DNA
• Mitochondrial disorders can appear in every
generation of a family and can affect both
males and females, but fathers do not pass
mitochondrial traits to their children.
• E.g. Leber's hereditary optic neuropathy
(LHON)

48
Theme: Medical Genetics
 Precise methods
• 2 main method is used for the gene diseases
diagnosis: Biochemical test and Molecular
analysis

• The major method to diagnose chromosomal

diseases is Cytogenetic analysis
 Precise methods

Gene diseases Chromosomal diseases

1) Biochemical test Cytogenetic analysis or

(screening)
2) Molecular analysis
(DNA sequencing)
Cytogenetic Test Methods
(Chromosomal analysis):
̶ Buccal scraping or smear
(Sex chromatin test)
̶ Karyotyping
̶ FISH
 Methods of gene diseases diagnosis
Biochemical methods
• Biochemistry is carried out at the cellular or subcellular level,
generally on cell extracts.

• Biochemical methods are applied to the main chemical

compounds of genetics—notably DNA, RNA and protein.

• Biochemical techniques are used to determine the activities

of genes within cells and to analyze substrates and products
of gene-controlled reactions.

• Genomics has provided a battery of diagnostic tests that can

be carried out on an individual’s DNA. Some of these tests can
be applied to fetuses in utero.
Qualitative biochemical methods
• Chemical tests are used to
distinguish certain inherited
conditions of humans
• e.g., urinanalysis and blood
analysis reveal the
presence of certain
inherited abnormalities –
phenylketonuria (PKU),
cystinuria, alkaptonuria,
galactosemia.
• In blood and urine detected
abnormal metabolic
products (e.g.,
phenylpyruvate PKU)
 Quantitative biochemical methods
• cells are ground up and the
substituent chemicals are
fractionated for further analysis.
Special techniques (e.g.,
chromatography and
electrophoresis) are used to
separate the components of
proteins so that inherited
differences in their structures
can be revealed.
• For example, more than 100
different kinds of human
Alkaline hemoglobin hemoglobin molecules have
electrophoresis been identified.
 Chromatography
• Chromatography is the collective term for a
set of laboratory techniques for the separation
of mixtures.
• The mixture is dissolved in a fluid called the
mobile phase, which carries it through a
structure holding another material called the
stationary phase. The solvent may be water,
but it is often a buffer solution, a mixture of
organic solvents, or even a gas.
• The various constituents of the mixture travel
at different speeds, causing them to separate.
The separation is based on differential
partitioning between the mobile and stationary
phases.
• Separation can be used to identify the
Thin layer components of the mixture, or it can be used
chromatography of to isolate pure chemicals.
plant pigments
Column chromatography
 Electrophoresis
• Electrophoresis - method for
separating mixtures based on
urine protein electrophoresis different speeds components in
the electric field
• Substitution mutations that
result in the replacement of one
amino acid by another with a
different electrical charge can
lead to slight changes in the
overall charges of the protein.
These allelic variants (in DNA)
give rise to protein variants
called allozymes that differ
glomerular proteinuria (heavy slightly in electrical charge.
albumin, * = transferrin) Protein electrophoresis is used
to detect allozyme variation.
Electrophoresis
• Tissue extracts are introduced
into a solid support medium (a
gel) in the sample wells at the
Origin on the right-hand side of
the gel.
• An electrical field is applied:
many proteins have a net
negative charge and will
migrate from the Origin at the
cathode ("black," "negative")
end towards the anode ("red",
"positive") end of the field. The
positions of the protein
products are detected either
directly by staining, or by
coupled enzymatic reactions.
 Principle of the agarose gel electrophoresis method

The DNA is loaded into preformed pockets (= wells) of a prepared gel-like matrix called
agarose gel . After application of a constant, electric DC current to the electrophoresis
chamber the negatively charged DNA molecules start to move through the gel matrix
to the positive electric pole (= anode) of the electrophoresis chamber
 Methods of gene diseases diagnosis
Molecular analysis. DNA • The polymerase chain reaction
(PCR) generates multiple copies
sequencing
of a DNA segment.
Polymerase Chain Reaction
• After denaturing the double-
stranded DNA, complementary
synthetic oligonucleotide primers
are annealed on each side of the
fragment of interest.
• A heat-stable polymerase then
extends the oligonucleotides and
synthesizes the complementary
strand. This cycle is repeated 25
to 30 times. The number of DNA-
amplified DNA segments is thus
doubled after every PCR cycle.
 Sequence analysis Step 1. Amplification.

• A. The segment of DNA to be sequenced is PCR-amplified

using normal nucleotides (i.e., dATP, dTTP, dGTP and dCTP)
and fluorescently labeled, dideoxy nucleotides (i.e., ddATP,
ddTTP, ddGTP, ddCTP). (Dideoxy nucleotides arrest chain
elongation).
 Sequence analysis Step 1. Amplification.

• B. The DNA segment is copied when normal nucleotides are

incorporated. Copying ceases when a dideoxy nucleotide is
incorporated. By this process, many different-sized fluorescently
labeled DNA fragments are produced.
 Sequence analysis.
Step 2. Sequence determination.
• The fragments are
sorted by length. A
sequencing machine
reads the fluorescent
wavelengths to
determine which
nucleotide is at the end
of each fragment.
Sequence analysis. Step 3. Sequence reporting.

• Sequence data are typically displayed on an

electropherogram as colored peaks. Each peak represents
a nucleotide, corresponding to the letter above it.
 Methods of chromosomal diseases diagnosis
Normal
♂ Sex chromatin test

• Sex determination
from buccal mucosa
scrapes (This test
may help establish
46, XY the sexual identity of
newborns).
♀

46, XX
 Sex chromatin test
Abnormal

• establish the
chromosomal
diseases caused of
♀ ♂ change of sex
chromosome number
Basic Methodology
• sample collection
• quickly smear of the
sample on slide
• staining with Acetic-
orcein
• covering coverslip
• viewing under a
microscope
Barr body
Karyotyping • detects numerical
and/or structural
chromosome
abnormalities in
metaphase cells.
• Routine banded karyotype
detects
Abnormal number of
chromosomes

 Large duplications
and deletions

 Balanced
rearrangements
(translocations,
inversions)
Procedure of karyotyping
 Basic Methodology
1. Collection of 10ml of blood with heparin
2. Setting of culture
- 8 ml of medium
- 0.1 ml of PHA-M
- 0.5 ml of blood/plasma
- 2 ml of autologus plasma/FCS
1. Incubate at 37C for 72 hours
2. Harvesting of culture
- Spindle inhibitors – Colchicine/colcemed (0.1g/ml)
- Hypotonic treatment – 0.075M KCl
- Fixation (3:1 methanol : acetic acid)
1. Preparation of slides
2. Slides stained with 4% Giemsa for 20-25min
3. Screening of slides to study the morphology of chromosome
4. Construction of karyotype
Banding
• Details of banding
Banding of X pattern of the
chromosome chromosome (also
called "idiogram").

• Note the
nomenclature of
arms, regions,
bands, and sub-
bands.

• On the right side,

the approximate
locations of some
genes that cause
disease are
indicated.
 Fluorescent in situ hybridization - FISH
fluorescent in situ hybridization: (FISH) A technique used to identify the
presence of specific chromosomes or chromosomal regions through
hybridization (attachment) of fluorescently-labeled DNA probes to
denatured chromosomal DNA.

FISH detects small (submicroscopic) chromosome

• Deletions
• Duplications
•Translocations
• Is applicable to interphase cells
 Basic Methodology
Step 1. Preparation of probe.

• A probe is a fluorescently-labeled segment of

DNA complementary to a chromosomal region
of interest.
 Step 2. Hybridization.

• Denatured chromosomes fixed on a microscope slide

are exposed to the fluorescently-labeled probe.
Hybridization (attachment) occurs between the probe
and complementary (i.e., matching) chromosomal
DNA.
 Step 3. Visualization.

Green signal =
Normal control

Pink signal =
Chromosome region of interest

Patient with deletion:

Normal control:
Two green signals
Two green signals
One pink signal
Two pink signals

• Following hybridization, the slide is examined under a

microscope using fluorescent lighting. Fluorescent signals
indicate the presence of complementary chromosomal DNA;
absence of fluorescent signals indicate absence of
complementary chromosomal DNA.
 Prenatal Diagnosis

Non-invasive prenatal testing Invasive prenatal testing

(NIPT)

1) Screening of Amniocentesis
 AFP
 hCG Chorionic Villus Sampling (CVS)
 Unconjugated estriol (uE3) Percutaneous umbilical blood
 Inhibin-A sampling (PUBS) -
2) Ultrasound cordocentesis
 Non-invasive prenatal testing (NIPT)

First-trimester screening:

Includes ultrasound and serum screening

Performed at 10 wks 3 days - 13 wks 6 days

Ultrasound Serum screening:

̶ PAPP-A (Pregnancy-
associated plasma protein A)
̶ Free b-hCG

Выполняется на 10 недели3 дня - 13 нед 6 дней

Сывороточный скрининг
•Белок А плазмы, связанный с беременностью
•Свободный хорионический гонадотропин
человека
Ultrasound
• Noninvasive, uses
reflected sound waves
converted to an image

• Transducer placed on
abdomen

• See physical features of

fetus, not chromosomes

• Singleton gestation

• May ID some
chromosomal
abnormalities by
physical features

• Nuchal translucency (NT)

• The NT (fluid beneath the skin behind baby’s neck) is a small
collection of fluid that lies just under the skin at the back of the baby’s
neck. This is usually well visualized with ultrasound and is measured to the
nearest 100th of a centimeter.
 Second Trimester Maternal Serum Screening
for Aneuploidy
• The second trimester screen as we know it today consists of 3 or 4
markers that can be measured between 15 and 20 weeks gestation and
is referred to as the triple or quad screen.

• A triple screen includes measurement of AFP, hCG, uE3, a quad screen

includes inhibin-A.

• Detection rate in women

– <35: 60-75% for DS
– >35: 75% or more
– >80% for trisomy 18
• Positive screening rate 5%
̶ AFP
– hCG “Triple” “Quad”
– Unconjugated estriol (uE3)
– Inhibin-A
Alpha-fetoprotein (AFP)
• Glycoprotein of
unknown function
• Used to screen for open
NTDs (Neural Tube
Defects)
– 15-22 weeks gestation
– Detection rate 80-85%
• Used to screen for
trisomy 21
– 15-20 weeks gestation
– Detection rate 20-25%
Human Chorionic Gonadotrophin
• the MOM values
increase in
pregnancies
affected by
Down Syndrome
such that about
half of the values
Serum levels in DS often >2.5 MoM
are above 2.0
MOM for each of
those markers.
 Unconjugated Estriol (uE3)
• Synthesized from DHEAS, converted to 16aOH-
DHEAS in fetal liver and then to uE3 by placenta
• Low levels associated with:
– Trisomy 21
– Trisomy 18
– Triploidy
– Smith Lemli Opitz
– Steroid sulfatase deficiency
– Fetal demise
– Congenital adrenal hypoplasia
 Inhibin-A
• Polypeptide hormone
• Secreted by granulosa & Sertoli cells
• In pregnancy secreted by fetoplacental
unit, peaks at 8-10 weeks then declines
until 20 and rises gradually until term
Biochemical marker profile in second
trimester:
 Invasive prenatal testing
• Amniocentesis
– performed at 15-17 weeks gestation
• Chorionic Villus Sampling (CVS)
– performed at 10-12 weeks gestation
• Percutaneous umbilical blood sampling (PUBS) - cordocentesis
– performed in second and third trimesters
– usually prompted by ultrasound abnormalities of fetus
 Amniocentesis
• is a medical procedure in which a small amount of amniotic
fluid, which contains fetal tissues, is sampled from
the amnion or amniotic sac surrounding a developing fetus

• Diagnose > 100 disorders, cells analyzed for chromosomal

and biochemical disorders

• Risk of infection and spontaneous abortion

• Normally only used when:

– Advanced maternal age
– History of chromosomal disorder
– Parent with chromosomal abnormality
– Mother carrier of X-linked disorder
Removal of about 20
ml of amniotic fluid
containing suspended
cells that were
sloughed off from the
fetus

Biochemical analysis of
the amniotic fluid after Centrifugation
the fetal cells are
separated out
Fetal cells are
Analysis of fetal cells to removed from
determine sex the solution

Cells are grown

in an incubator

Karyotype analysis
 Chorionic Villus Sampling (CVS)
Review of CVS Procedures • The genetic material
in chorionic villus cells
is the same as that in
the baby's cells.

• Performed earlier
than amniocentesis
– 6–10 weeks vs. 16
weeks

• Karyotypes available
within a few hours or
days

• Increased risk of
spontaneous abortion
(1.5–2%)
 Percutaneous umbilical blood
sampling (PUBS) - cordocentesis
• is a highly specialized
prenatal test in which
a sample of the
baby's blood is
removed from the
umbilical cord for
testing.
• Cordocentesis can
only be done later in
the pregnancy, from
about 18 - 24 weeks,
when the umbilical
cord has adequately
developed.
Cordocentesis might be offered when:
• The desired information can't be obtained any
other way
• Results from other prenatal tests are unclear
• Test results might have a significant impact on
the immediate management of the pregnancy
 Fetal Cells Analyzed
• Several methods including:
– Karyotyping
– Biochemical analysis
– Recombinant DNA techniques

• DNA analysis is most specific and sensitive

 Preimplantation Genetic Diagnosis
(PGD)
-method is needed for a successful Extracorporeal fertilization (In
Vitro fertilization) – IVF

IVF - Treatment of infertility

-The essence of IVF method provides for ovum fertilization is

being conducted outside woman’s organism, and then is
provided the implantation of the embryo into uterine cavity

Предимплантационная генетическая диагностика - метод, необходимый для

успешного экстракорпорального оплодотворения (Оплодотворения In vitro)
ЭКО – лечение бесплодия
Суть метода ЭКО предусматривает проведение оплодотворения яйцеклетки
вне организма женщины, а затем обеспечивается имплантация эмбриона в
полость матки
Preimplantation Genetic Diagnosis (PGD)
• Eggs collected, fertilized,
allowed to develop

• ~Third day of fertilization,

embryo has 6–8 cells

• For PGD, one cell, a

blastomere, is removed

• DNA extracted and tested

• Embryo without genetic

Embryo - Blastomere disorder are implanted
into mother
Theme: Medical Genetics
 Scientific methods
Twin study

phenotype = genotype + environment

• Twin studies reveal the

absolute and relative
importance of
environmental and genetic
influences on individuals in
a sample.
• Twin studies are part of the
methods used in behavior
genetics
• The classic twin study
Researchers use this method to design relies on studying
Estimate the heritability of traits twins raised in the same
Quantify the effect of a person's family environments.
shared
 There are two types of twins:
"identical" or monozygotic "Fraternal" or dizygotic (DZ)
(MZ) • developing from two fertilized
eggs
• developing from a single fertilized
egg • share only about 50% of their
genes (same as non-twin
• share all of their genes
siblings).
 Stages of work
1. Selection of twins studied traits
2. Determination of zygosity (monozygotic
always have the same sex, blood type,
similar in appearance)
3. Analysis of the studied trait
If the trait is present in both twins, they are
called concordant
If studied trait manifested in only one of the
twins, they are called discordant
4. Calculation of the coefficient of heredity
 H = % similarity (MZ) - % similarity (DZ)
100 -% similarity (DZ)
Where: H- index of heredity,
(MZ) - identical twins
(DZ) - fraternal twins
H = 1 -feature is fully determined hereditary component
H = 0 -the sign is determined of the environment (This does
not happen! Genotype influences even for infectious diseases)
H = 0.5 -the sign is determined approximately equal
influence of heredity and environment
• The classical twin design compares the similarity of monozygotic
(identical) and dizygotic (fraternal) twins. If identical twins are
considerably more similar than fraternal twins (which is found for most
traits), this implicates that genes play an important role in these traits. By
comparing many hundreds of families of twins, researchers can then
understand more about the roles of genetic effects, shared environment,
and unique environment in shaping behavior.
• Классическая сдвоенной сравнивает сходство монозиготных
(идентичных) и дизиготных (братские) близнецы. Если идентичные
близнецы значительно больше похожи, чем двойняшек (который
находится для большинства черт), это подразумевает, что гены играют
важную роль в этих черт. Сравнивая многие сотни семей близнецов,
исследователи могут затем понять больше о роли генетических
эффектов, общей среде и уникальной среде в формировании
поведения.
• The presence of a given
genetic trait in only one
member of a pair of
identical twins (called
discordance) provides a
powerful window into
environmental effects.
• Twin concordances for seven psychological traits (sample size shown
inside bars), with DZ being fraternal and MZ being identical twins
• Modern twin studies have shown that almost all traits are in part
influenced by genetic differences, with some characteristics showing a
strong influence (e.g. height), others an intermediate level (e.g.
intelligence quotient) and some more complex heritabilities, with
evidence for different genes affecting different aspects of the trait — as in
the case of autism.
• Современные исследования близнецов показали, что почти все черты
отчасти под влиянием генетических различий, с некоторыми
характеристиками, показывая сильное влияние (например, высоты),
другие промежуточный уровень (например, коэффициент
умственного развития) и некоторых более сложных наследуемость, с
признаками для различных генов, влияющих на различные аспекты
признака - как и в случае аутизма.
 twin registries
• now twin registries constitute an
important resource for the
identification of specific genes
and their interactions both with
other genes and with the internal
and external environment.
• Теперь близнецы реестры
представляют собой важный
ресурс для идентификации
специфических генов и их
взаимодействия как с другими
генами и с внутренней и
внешней среды.
 Population Genetics
• The most important genetic characteristics of
the population - the frequency of alleles and
genotypes
 The Hardy-Weinberg Principle
Godfrey H. Hardy: Working independently just a
few years after the rediscovery
English
mathematician of Mendelian genetics they
(1903) concluded that:
The original proportions
of the genotypes in a
population remain
constant from generation
Wilhelm
Weinberg: to generation
German physician
(1908)
 The Hardy-Weinberg Principle
• p = frequency for dominant allele in the population
• q = frequency for recessive allele in the population
• Calculate allele frequencies with a binomial equation:
p+q=1
• because there are only two alleles:
p + q must always equal 1 (100% of the alleles)

• [Note: more alleles can be handled, e.g., with three alleles: p + q + r = 1]

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 The Hardy-Weinberg Principle
Р: ♀ АА х ♂ аа • Assume that the
population consists of
А homozygotes:
G: а
dominant and
recessive.
F1 Аа • Then all of the first
generation will be
heterozygous
 The Hardy-Weinberg Principle
• Individual of the first
Р: ♀ Аа х ♂ Аа generation will form two
types of gametes.
G: А а А а • Denote the frequency of
p q
gametes carrying the
p q
dominant allele А as p and
F1 АА , Аа, Аа, аа the frequency of gametes
carrying the recessive а
pxp pxq pxq qxq allele as q
• Then in the second
generation, we obtain the
p2 + 2pq + q2 = 1 following results:
 The Hardy-Weinberg Principle
Calculate genotype frequencies with a binomial
expansion
(p+q)2 = p2 + 2pq + q2 = 1
• p2 = individuals homozygous for dominant allele
• 2pq = individuals heterozygous for the alleles
• q2 = individuals homozygous for recessive allele

• because there are three phenotypic classes:

p2 + 2pq + q2 must always equal 1

square root квадратный корень 16

 The Hardy-Weinberg Equilibrium
• Relates allele and genotype frequencies under
certain limiting conditions
p2 + 2pq + q2 = 1 (the Hardy-Weinberg Equation)
If we apply the equation to the flower color gene, then:
p2 = the genotype frequency of RR
2pq = the genotype frequency of Rr
q2 = the genotype frequency of rr
If p = 0.7 and q = 0.3, then:
Frequency of RR individuals = p2 = (0.7) 2 = 0.49
Frequency of Rr individuals = 2pq = (2)(0.7)(0.3) = 0.42
Frequency of rr individuals = q2 = (0.3) 2 = 0.09
The Hardy-Weinberg Principle

p = 0.6 and q = 0.4 and therefore p + q = 1.0

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 The Hardy-Weinberg Equilibrium If:

1. The population size is very large

2. Random mating is occurring
3. No mutation occurs
4. No selection occurs
5. No alleles transfer in or out of the
population (no migration)
Then allele frequencies in the population will
remain constant through generations
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