Transcript Lecture 1. The subject and the main tasks of Medical Genetics

Furdela Victoria
MD. Assistant
Pediatrics Department #2
GENETICS is the science that deals with
heredity and variation in organisms,
including the genetic features and
constitution of a single organism, species,
or group, and with the mechanisms by
which they are effected
Genetic variations cause
inherited diseases
Environmental
Diseases
Genetic Diseases
- Infection
- Cystic fibrosis
- Traumas
- Down syndrome
- burns
- Sickle cell disease
- Phenilcetonuriae
- Environment
Diseases with
heredity
predisposition
- Cardiovascular
Disease
- DM type 2
- cancer
- Genes

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
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 Locus
– location of a gene/marker
on the chromosome.
 Allele
– one variant form of a
gene/marker at a particular locus.
Locus1
Possible Alleles: A1,A2
Locus2
Possible Alleles: B1,B2,B3
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Most human cells
contain 46 chromosomes:


2 sex chromosomes (X,Y):
XY – in males.
XX – in females.
22 pairs of chromosomes
named autosomes.
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 Phenotype
- the physical description of the
character in an individual organism

i.e a green eyes
 Genotype
- the genetic constitution of the
organism

Mutation - a change in the genetic material,
usually rare and pathological

Polymorphism - a change in the genetic
material, usually common and not pathological
The colure of eyes, the colour of
skin is heredity
The colour and structure of our
hair is also heredity
 Homozygote
- an organism with two identical
alleles
 Heterozygote
- an organism with two different
alleles
 Hemizygote

- having only one copy of a gene
Males are hemizygous for most genes on the sex
chromosomes
sister
chromatids
telomeres
centromere
unreplicated
chromosome
replicated
chromosome
Each chromatid consists of a very long strand of DNA. The DNA is
roughly colinear with the chromosome but is highly structured around
histones and other proteins which serve to condense its length and
control the activity of genes.
Centromere
A region within chromosomes
that is required for proper
segregation during meiosis
and mitosis.
Telomeres
Specialized structures
at chromosome ends
that are important for
chromosome stability.
•monogene disorders (diseases or traits where the
phenotypes are largely determined by the action, or lack
of action, of mutations at individual loci);
•multifactorial traits (diseases or variations where the
phenotypes are strongly influenced by the action of
mutant alleles at several loci acting in concert);
•chromosomal abnormalities (diseases where the
phenotypes are largely determined by physical changes
in chromosomal structure - deletion, inversion,
translocation, insertion, rings, etc., in chromosome
number - trisomy or monosomy, or in chromosome origin
- uniparental disomy);
•mitochondrial inheritance (diseases where the
phenotypes are affected by mutations of mitochondrial
DNA); and
•Congenital malformations
inner organs or parts of body)
(congenital defects of
1.
2.
3.
4.
Deletion – during cell division, especially
meiosis, a piece of the chromosome breaks off,
may be an end piece or a middle piece (when
two breaks in a chromosome occur).
Inversion – a segment of the chromosome is
turned 180°, same gene but opposite position
Translocation – movement of a chromosome
segment from one chromosome to a nonhomologous chromosome
Duplication – a doubling of a chromosome
segment because of attaching a broken piec
form a homologous chromosome, or by unequal
crossing over.
5.
6.
7.
Monosomy – only one of a particular type
of chromosome (2n -1)
Trisomy – having three of a particular type
of chromosome (2n + 1)
Polyploidy – having more than two sets of
chromosomes; triploids (3n = 3 of each
type of chromosome), tetraploids (4n = 4
of each type of chromosome).
 Addition
or deletion of entire
chromosomes or parts of chromosomes
 Typically
more than 1 gene involved
 1%
of paediatric admissions and 2.5% of
childhood deaths
 Classic
example is trisomy 21 - Down
syndrome
Down Syndrome
KARYOTYPE
 Single
mutant gene has a large effect on the
patient
 Transmitted in a Mendelian fashion
 Autosomal dominant, autosomal recessive, Xlinked, Y-linked
 Osteogenesis imperfecta - autosomal dominant
 Sickle cell anaemia - autosomal recessive
 Haemophilia - X-linked
 The
most common yet still the least
understood of human genetic diseases
 Result
from an interaction of multiple
genes, each with a minor effect
 The
susceptibility alleles are common
 Type
I and type II diabetes, autism,
osteoarthritis
What about mapping polygenic
disorders?
Environment
Gene1
Gene 2
Gene 3
Gene 4
PHENOTYPE
Polygenic
diseases are common
Disorder
Schizophrenia
Asthma
Hypertension (essential)
Osteoarthritis
Type II diabetes (NIDDM)
Frequency (%)
1
4
5
5
6
Unrelated affected individuals share
ancestral risk alleles
Augustinian Monk at
Brno Monastery in
Austria (now Czech
Republic)
Not a great teacher but
well trained in math,
statistics, probability,
physics, and interested in
plants and heredity.
While assigned to teach,
he was also assigned to
tend the gardens and
grow vegetables for the
monks to eat.
Mountains with short,
cool growing season
meant pea (Pisum
sativum) was an ideal
crop plant.
1. The Law of Segregation:
Genes exist in pairs and alleles segregate
from each other during gamete formation,
into equal numbers of gametes. Progeny
obtain one determinant from each parent.
2. The Law of Independent Assortment
Members of one pair of genes (alleles)
segregate independently of members of
other pairs.
Standard pedigree symbols
Male,
affected
Male, heterozygous for
autosomal recessive trait
Female,
unaffected
Female, heterozygous for
Autosomal or X-linked
recessive trait
Male,
deceased
Mating
Consanguineous
mating
Pregnancy
Dizygotic
(non-identical)
twins
Monozygotic
(identical)
twins
Spontaneous abortion
or still birth
When studying rare disorders, 5 general
patterns of inheritance are observed:
Autosomal recessive
 Autosomal dominant
 X-linked recessive
 X-linked dominant
 Mitochondrial

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



the locus is on an autosomal
chromosome and only one
mutant allele is required for
expression of the phenotype
Affected males and females
appear in each generation of
the pedigree.
Affected mothers and
fathers transmit the
phenotype to both sons and
daughters.
e.g., Marfan disease.
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


the locus is on an
autosomal
chromosome and both
alleles must be mutant
alleles to express the
phenotype
The disease appears
in male and female
children of
unaffected parents.
e.g., cystic fibrosis
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

Affected males pass the
disorder to all daughters
but to none of their sons.
Affected heterozygous
females married to
unaffected males pass the
condition to half their sons
and daughters
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




Many more
males than
females show
the disorder.
All the
daughters of an
affected male
are “carriers”.
None of the sons
of an affected
male show the
disorder or are
carriers.
e.g., hemophilia
If the locus is
on the X
chromosome and
both alleles must
be mutant alleles
to express the
phenotype in
females
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


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)
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A polygenic phenotype
An affected individual
with unaffected parents
Affected individual joining
the family, emphasizing the
common nature of the disease
No clear inheritance pattern
 Genetic
anamnesis (presents of heredity
family diseases, infant death, abortions, fetus
death, long barrenness)
 Dysmorphic signs
 Low birth weight
 High morbidity and mortality
 Mental retardation
 Ocular and ear defects
 Skeleton abnormalities
 Abnormalities of internal organs
Example of dysmorphic signs
Example of dysmorphic signs
Mongoloid eyes
Antimongoloid eyes
Child
with congenital pathology
 Congenital pathology in one of
parents
 Congenital pathology in
relatives
Abnormalities of pregnancy
Drawing
the pedigree or family
tree
Cytogenetic method
Prenatal diagnostics
Method of dermatoglyphics
Population-statistic method
Examination of twins
It
is important to draw the pedigree
or family. This method helps to show
the number of involved family
members, their sexes and ages of
onset etc.
to determine the type of inheritance
and further chances of recurrence of
the inherited disorder.
Cytogenetic method
• This method give us possibility to
examine X and У sex chromatin
and chromosomes to establish
karyotype.

The essence of the method
consists in the analysis of skin
patterns (drawings) on the
palms and soles. Most
informative method for
chromosomal syndromes, when
the distal axial triradius
detected, an excess of arches
on the fingers, the absence of
distal interphalangeal creases,
radial loops on the I, IV and V
fingers, transversal crease (in
Down's syndrome in the 40 -60%
of cases).
 It
is very important method of prenatal
diagnose which give the possibility to
estimate sex of fetus, some hereditary
diseases and after genetic counseling to
decide the question about abortion
This
method study the genetic
structure of population, its genetic
fund, factors and regularity of
keeping and changing in next
generation
Twins method
• This method helps us to study the
role of environment and heredity in
formation of normal and pathologic
signs
Avoid
of marriage with relatives
Have no child
Adoption of child
Artificial impregnation
Ascertainment the risk of
heredity pathology in a family
Gene
engineering
Forbidding of marriage with
relatives
Mixing of population
Establishing of recessive genes
and their treatment
Both
parents should be included
in genetic counseling
Enough time should be given for
counseling
The counselor should be flexible
and should not impose decision
on the family