Transcript Mutation

Mutation :
A change in the DNA at a particular Locus in
an organism . The Term is used Loosely to
include Point Mutations involving single gene
change , as well as chromosomal change .
Mutation Based on Location of Mutation :
1- Germ line mutations : are mutations
occurring in gametes .
2- Somatic mutations : are mutations occurring
in any cell in the body except germ cells .
3- Autosomal mutations : are mutations within
genes located on autosomes (chromosomes
1- 22 ) .
4- X- Linked mutations : are mutations within
genes located on the X- chromosome .
Point Mutation : Involve the Addition or Deletion or
Inversion or Substitution of a few bases with in genes
Point Mutation :
Mutation Based on Type of
Molecular change :
A-Silent Mutation : Triplet Codes for same amino acid :
GCA
GCC both code for alanine (amino acid). (Figure 2).
B- Neutral Mutation : Triplet codes for different but
functionally equivalent amino acid :AAA
AGA changing
basic Lysine to basic Arginine ( at many positions , will not
alter Protein Function ) .
C- Missense Mutation : a mutation that changes a codon
specifying an amino acid to a codon specifying a different and
non functional amino acid .
D- Nonsense Mutation : a mutation that changes a codon
specifying an amino acid to atermination codon .
CAA
UAA changing from a codon for Glycine to a
termination codon .
Mutation Based on Type of Molecular change :
Frame Shift Mutation :
Any Addition or Deletion of base pairs that is not a
multiple of 3 result in a frame shift in DNA segments that
code for Proteins . ( Figure 2 ) .
gene Mutation can arise Spontaneously or they can be Induced :
Spontaneous Mutations :
arise from a variety of sources including :
1-Errors in DNA replication . 2-Spontaneous Lesions . 3-Transposible
genetic elements .
Induced Mutations :
are produced when an organism is exposed to
Mutagenic agent or Mutagen ( Radiation , Chemical agent ) .
Thalassemia :
Is a group of inherited blood diseases that affect a
person's ability to produce hemoglobin in red blood cells . A
person with thalassemia does not have enough hemoglobin
or red blood cells, which can cause mild to severe anemia .
Hemoglobin : is a protein found in red blood cells . It carries
oxygen to all parts of the body .
Normal hemoglobin( also called hemoglobin A) has 4 protein
chains, two alpha globin chains and two beta globin chains,
and iron containing chemical group called heme .
Genetics :
The genes that code for the globin chains of hemoglobin are found
on chromosome 11 and 16 .
Each person has ( 4 alpha globin genes located on chromosome 16 ) that
code for alpha globin chains of hemoglobin( two from each parent ) and
each person has ( 2 beta globin genes located on chromosome 11)
controlling the production of beta globin chains of hemoglobin( one from
each parent ) .
This keeps the production of protein chains equal . Thalassemia occurs
when a globin genes fails( mutation occurs) and the production of globin
protein chains is thrown out of balance .
The genes that code for the globin chains of hemoglobin are found
on chromosome 11 and 16
.
Types of Thalassemia :
Thalassemia are classified into alpha or beta according to the affected
globin genes alpha or beta .
Alpha Thalassemia or α- Thalassemia :
Alpha thalassemia occurs when one or more of the 4 alpha globin genes
varies or missing. ( absence or deficiency of alpha chain synthesis) .
Classification of alpha Thalassemia :
1- Silent carriers : People with only one gene affected and have no sign
of illness .
2- Alpha Thalassemia Trait or ( Minor ) : People with two genes affected
and have mild anemia and are considered carriers .
3- Hemoglobin H disease : People with three genes affected and have
moderate to severe anemia .
4- Alpha Thalassemia major or ( Hydrops fetalis ) : Babies with all four
genes affected, could not survive and usually died before birth
Alpha Thalassemia major or
( Hydrops fetalis ) :
Beta Thalassemia or β- Thalassemia :
Beta Thalassemia occurs when one or both of the two beta globin
genes needed for making the beta globin chain of hemoglobin are variant
Classification of Beta Thalassemia :
1- Beta Thalassemia minor or ( Trait ) : People with only one gene
affected, a person is a carrier and has mild anemia .Smaller red blood
cells that are lighter in colour due to lack of hemoglobin .
2- Beta Thalassemia Intermediate : People with two genes variant and a
person may have moderate anemia, and bony deformities due to bone
marrow trying to make more blood cells to replace defective ones .
3- Beta Thalassemia Major ( Cooley's anemia ) : Complete absence of two
beta globin genes, enlarged spleen, lightly coloured RBCs, severe anemia
Beta Thalassemia major treatment by blood transfusion every month and
iron chelating and bone marrow and stem cells transplant .
Blood film in normal person and in β- Thalassemia major patient
showing Hypochromia and Microcytosis :
Normal
Thalassaemia
Blood film in β-Thalassemia major
Pathophysiology of
–Thalassemia/Hb
E Disease
Major
Inheritance of Thalassemia :
Both types of Thalassemia are inherited in the same manner
Autosomal Recessive Inheritance :
1- If both parents have normal hemoglobin :
all their children will be normal 100% . ( Figure 10 )
Inheritance of Thalassemia :
2- If only one parent has Thalassemia trait ( also called carriers ) :
50% chance of having a child with thalassemia trait . and
50% chance of having a normal child ( Figure 11)
none of the couples children will get thalassemia major .
Inheritance of Thalassemia :
3- If both parents have Thalassemia trait ( carriers ) :
25% chance of having a child with Thalassemia major
50% chance of having a child with Thalassemia trait ( carriers )
25% chance of having a normal child
( Figure 12)
Inheritance of Thalassemia :
4- If a Thalassemic major marries a Thalassemic carrier :
in each pregnancy there is a :
50% chance that the child will be Thalassemic major and a
50% chance that it will be a carrier . (Figure 13)
Inheritance of Thalassemia :
5- If a Thalassemic major married a normal :
all the children will be carriers 100% . (Figure 14)
Normal
Father
Thalassemic
Mother
All children will be carriers
Inheritance of Thalassemia :
6- If one Thalassemic major marries another thalassemic major :
all their children will be Thalassemics major 100% . ( Figure 15 )
Karyotype Test
Karyotype : is a test to examine chromosomes in a sample of body cells,
which can help identify genetic disease .
This test can:
•
Count the number of chromosomes
•
Look for structural changes in chromosomes
In a karyotype, chromosomes are arranged and numbered by size,
banding pattern and centromere position from largest to smallest. This
arrangement helps scientists quickly identify chromosomal alterations
that may result in a genetic disorder. Human cell nucleus contain 46
chromosomes ( 44 autosomes and 2 sex chromosomes ) . ( Figure 16 )
Nucleus
Normal human male karyotype
Human Chromosome Groups
the chromosomes are numbered 1 to 22 from longest to shortest.
The last pair are the sex chromosomes and are placed on the
karyotype after the 22nd pair.
The chromosomes can be separated into groups, based on their
length and the position of the centromere.
( Figure 17 )
Application of Karyotype :
Diagnosis of genetic disease because its used to detect :
A – Abnormalities in chromosome number
B – Abnormalities in chromosome structure.
C - Molecular diagnosis of cancer .
A- Abnormalities in chromosome number :
Abnormalities in chromosome number resulted from nondisjunction
nondisjunction : a chromosome pair fails to separate at anaphase of
either the first or second meiotic division . This produces a sperm or
oocyte that has two copies of a particular chromosome, or none,
rather than the normal one copy .
When such a gamete fuses with its partner at fertilization the zygote
has either 45 or 47 chromosomes instead of the normal 46 .
( Figure 18 )
Nondisjunction of
chromosomes in
meiosis and
fertilization
1- Down Syndrome ( Mongolism ) :
A child with Down Syndrome has 47 chromosomes instead of 46
chromosomes because Trisomy for chromosome 21
( three copies of chromosome 21 autosome ). ( Figure 19 and 20 ).
(Figure 20)
(Figure 21)
Nondisjunction
and sex
chromosomes
Nondisjunction
and autosome
chromosomes
2- Turner Syndrome :
abnormal Female with 45 chromosomes , the sex chromosome is X
chromosome only . ( Figure 21 and 22).
3- Klinefelter Syndrome :
Abnormal male with 47 chromosome, the sex chromosomes are
XXY . ( Figure 21 and 23 )
4-Triple X Syndrome :
Female with 47 chromosomes, the sex chromosomes are : XXX
( figure 21 and 24 ) .
B - Abnormality in Chromosome Structure :
Structural abnormalities results from chromosomal breakage and abnormal
reunion .
1- Deletion 2- Duplication 3- Inversion 4- Translocation
5- Ring chromosome
1- Deletion :
Cri Du Chat Syndrome : The syndrome associated with deletion
of part of short arm of chromosome 5 . ( Figure 25 ) .
4 - Translocation :
The transfer of a segment of one chromosome to another chromosome .
Examples of cancers associated with Translocation :
Chronic Myelogenous Leukemia
In Chronic Myelogenous Leukemia a reciprocal translocation between
chromosome 9 and chromosome 22 forming Philadelphia chromosome
It results in one chromosome 9 longer than normal and one chromosome 22
shorter than normal , the latter is called the Philadelphia chromosome
This translocation is designated t ( 9 ; 22 )
Philadelphia
Chromosome
(Figure 26 )
The diagnostic Karyotype abnormality for
Chronic Myelogenous Leukemia shows
reciprocal translocation t ( 9 : 22 )
( Figure 27 )
Philadelphia
chromosome
5 - Ring chromosome :
A chromosome loses telomeres and the ends fuse forming a circle .
( Figure 28 )
Mechanism of ring chromosome :
Human Karyotype from bladder carcinoma showing
ring chromosome in addition to other chromosomal abnormalities .
( Figure 29 )
Somatic Mutation or Cancer :
Cancer is a genetic disease that arises from mutations in genes
controlling many aspects of cellular function .
All cancer cells share 2 fundamental properties :
1- abnormal cell growth and division ( cell proliferation )
2- and apropensity to spread and invade other parts of the body
( metastasis ) . ( figure 30)
Difference between cancer and
other genetic diseases :
1-
cancer is caused by mutations that occur
predominantly in somatic cells. Only about (5 - 10% )
percent of cancers have ahereditary component.
2- cancers rarely arises from a single mutation, but from
the accumulation of many mutations , as many as six
to twelve .
The mutations that lead to cancer affect multiple
cellular functions, including repair of DNA damages,
cell division, apoptosis, cellular differentiation,
majority behavior, and cell to cell contact.
Karyotype of cancer cell showing :
Translocations , Deletion ,
Aneuploid characteristic
features of cancer cell.
( figure 31 )
Genetic Control of Metabolism :
Metabolism occurs by sequences of chemical reactions , each
step of which is catalyzed by a specific enzyme . each enzyme
is , in turn , specified by one or more genes . The genetic
control of metabolic pathway may thus be diagrammed as in
( Figure 32 ) :
When Mutations occur in genes, leads to the
enzyme is not produced or canot function .
Genetic disorders that result from loss of
enzyme activity resulting from mutation in
genes encoding these enzymes are called
Inherited Metabolic Disorders. Example of
Inherited Metabolic Disorders
The metabolism of Phenylalanine and
Tyrosine in Humans . ( Figure 33 ) .
Albinism
(Tyrosinase –negative type)
Phenylketonuria
Phenylalanine
Tyrosine
3,4Dihyroxy phenylalanine
Tyrosinase
Phenylalanine
hydroxylase
Albinism
(Tyrosinase –positive type)
Tyrosine
Tyrosinosis
Transaminase
Phenylpyruvic acid
(Toxic to Central
Nervous System)
-hydroxyphenylpyruvic acid
-hydroxyphenylpyruvic
Acid oxidase
Tyrosinemia
Melanin
(Dark pigment in skin and hair)
2,5 Dihydroxyphenyl pyruvic acid
(homogentisic acid)
Homogentisic
acid oxidase
Alkaptonuria
Acetoacetic acid + Fumaric acid
Co2 + H2O
Inherited human disorders with defects in phenylalanine – tyrosine metabolism
1- Phenylketonuria: (PKU) :
The Failure of Brain to develop in infancy .
PKU results from arecessive Mutation that causes aloss of
Phenylalanine Hydroxylase activity which converts
Phenylalanine to Tyrosine , the first step in the catabolism of
Phenylalanine .
As Protein is consumed Phenylalanine accumulates in the
blood of individuals with PKU , some times up to 100 times
the normal Level . as a result , metabolic derivatives of
Phenylalanine , such as Phenylpyruvic acid , are formed .
some of the derivatives are toxic to the Central Nervous
System and produce irreversible Brain damage .
2-Alkaptonuria :
Is caused by a recessive Mutation that results in the
Loss of activity of the Enzyme Homogentisic acid
Oxidase . In the presence of this enzyme ( in normal
people ) Homogentisic acid is normally oxidized and
eventually converted to carbon dioxide and water .
( Figure 33 ) .
In the absence of this enzyme Homogentisic Acid
accumulates and is excreted in the Urine and turns
urine black when exposed to air .
Alkaptonuria with many symptoms illustrated in
( Figure 34 ) .
Alkaptonuria
3- Albinism :
In certain types of Albinism , the enzyme Tyrosinase is
inactive or Lacking , resulting in ablock in the Pathway of
conversion of Tyrosine to the Dark-colored Pigment Melanin
4- Tyrosinosis :
Result from the lack of the Tyrosine Transaminase .
5- Tyrosinemia :
Result from the lack of the enzyme called
p- Hydroxyphenylpyruvic acid oxidase .
(Figure 35) Albinism