Mutation and genetic

variation
Dr.Baraa Maraqa MD
General pediatrician
Medical genetics
3rd year / 1st sem.
2020

Dr.Baraa Maraqa 2020

 Terms
 Mutation: a change in DNA sequence.
 Mutations can affect either germline cells or somatic cells (all cells
other than germline cells).
 Mutations in somatic cells can lead to cancer.
 Germline mutations can be transmitted from one generation to the
next.

In human genetics, the term mutation has often been reserved for DNA
sequence changes that cause genetic diseases and are consequently
relatively rare, with a population frequency less than 1%.

 DNA sequence variants that are more common in populations are

conventionally described as polymorphisms (“many forms,”
describing multiple alleles at a locus).
 Loci (plural of locus) that contain multiple alleles are termed
polymorphic.
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Alleles: different DNA sequences at the same loci on
homologos chromosome. (i.e a variant form of a given gene)
Locus (plural loci) :A gene’s location on a chromosome.

The
A person has If a person has combination
a certain the same allele
allele at the on both If the alleles of alleles
For β-globin members of a differ in DNA that is
example, locus on chromosome sequence, he or present at a
pair, he or she she is a given locus
chromosome
11. is said to be a heterozygote is termed
homozygote.
the
genotype

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Dr.Baraa Maraqa 2020
Dr.Baraa Maraqa 2020
 Types of Mutation
1. Base-pair substitution (point mutation) : one base pair is
replaced by another. This can result in a change in the amino acid
sequence. However, because of the redundancy of the genetic
code, many of these mutations do not change the amino acid
(silent substitutions).
o missense mutations: produce a change in a single amino acid.
o nonsense mutations: produce one of the three stop codons (UAA,
UAG, or UGA) in the mRNA, so>> premature end of polypeptide
chain.

Alterations of amino acid sequences can have profound

consequences, and many of the serious genetic diseases are the
result of such alterations.
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Types of Mutation
2. deletions or insertions of one or more base pairs. (eg. CF
gene mutation ΔF508).

 frameshift mutation : when the number of missing or

extra base pairs is not a multiple of three. Because codons
consist of groups of three base pairs, such insertions or
deletions can alter the downstream codons.

Dr.Baraa Maraqa 2020

 CF is caused by a mutation
in the gene cystic fibrosis
transmembrane
conductance
regulator (CFTR).
 The most common
mutation, ΔF508, is a
deletion of three
nucleotides that results in
a loss of the amino
acid phenylalanine (F) at
the 508th position on the
protein.
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Types of Mutation
3. duplications of whole genes can also lead to genetic
disease. Ex. Charcot–Marie–Tooth disease.

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Charcot–Marie–Tooth disease.

 peripheral nervous system condition that leads to

progressive atrophy of the distal limb muscles.
 1 in 2500 persons
 1.5 million-bp duplication on one copy of
chromosome 17.
 As a result, they have three, rather than two, copies of
the genes in this region. One of these genes, PMP22,
encodes a component of peripheral myelin. pes cavus
 The increased dosage of the gene product
contributes to the demyelination that is characteristic of
this form of the disorder.
 The pattern of inheritance varies with the type
of Charcot-Marie-Tooth disease. CMT1, most cases of
CMT2, and most intermediate forms are inherited in
an autosomal dominant pattern.

Dr.Baraa Maraqa 2020

Other types of Mutation
 promoter mutation can decrease the affinity of RNA
polymerase for a promoter site, often resulting in reduced
production of mRNA and thus decreased production of a
protein.
 Mutations of transcription factor genes or enhancer
sequences can have similar effects.
 Splice-site mutations, those that occur at intron–exon
boundaries, alter the splicing signal that is necessary for
proper excision of an intron.

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 Splice-site mutations can occur at the GT sequence that defines
the 5′ splice site (the donor site) or at the AG sequence that
defines the 3′ splice site (the acceptor site).

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 Other types of Mutation
Several types of DNA sequences are capable of propagating copies
of themselves; these copies are then inserted in other locations on
chromosomes (examples include the LINE and Alu repeats.
 Such insertions of mobile elements can cause frameshift
mutations.
 E.g. , isolated cases of type 1 neurofibromatosis, Duchenne
muscular dystrophy, β-thalassemia, familial breast cancer, and
others...

Dr.Baraa Maraqa 2020

 expanded repeats affects tandem repeated DNA
sequences that occur within or near certain disease-related
genes. The repeat units are usually 3 bp long, a typical
example is CAGCAGCAG.
Occasionally, the number of repeats increases during meiosis or
possibly during early fetal development, so that a newborn
might have hundreds or even thousands of tandem repeats.
When this occurs in certain regions of the genome, it causes
genetic disease.
It can be transmitted to the patient’s offspring.

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 Fragile X syndrome result of
a mutation of the fragile X mental
retardation 1 (FMR1) gene on the X
chromosome, most commonly an
increase in the number of
CGG trinucleotide repeats in the 5'
untranslated region of FMR1.
 In unaffected individuals, the FMR1 gene
contains 5–44 repeats of the sequence
CGG, most commonly 29 or 30 repeats.
Between 45-54 repeats is considered a
"grey zone", with a
premutation allele generally considered
to be between 55 and 200 repeats in
length.
 Individuals with fragile X syndrome have
repeat expansion greater than 200, there
is inactivation of the CGG repeat
expansion and FMR1 promoter, leading
to the silencing of the FMR1 gene and a
lack ofDr.Baraa
its product.
Maraqa 2020
 Molecular Consequences of Mutation
 Gain-of-function-mutation:
 Autosomal dominant (AD).
 Ex.:Charcot–Marie–Tooth disease,Huntington disease.
 Loss-of-function-mutation:
 Often AR. (e.g., CF)
 Can be AD if 50% of the protein (or enzyme) is not enough for normal
function (haploinsuffiency). E.g., Familial hypercholestrolemia.
 Dominant negative mutation:
 The protein product is not only abnormal but also inhibits the function of
the protein produced by the normal allele in the heterozygote.
 Typically, dominant negative mutations are seen in genes that encode
multimeric proteins (i.e., proteins composed of two or more subunits).
 E.g., Type I collagen , which is composed of three helical subunits. An
abnormal helix created by a single mutation can combine with the other
helices, distorting them and producing a seriously compromised triple-
helix protein. (Osteogenesis imperfecta , AD)
Dr.Baraa Maraqa 2020
 Causes of mutations
 Spontaneous : occurs spontaneously during DNA replication.
 Induced : due to environmental exposure (mutagens)

Examples of mutagens :
• Ionizing radiation (e.g., x-ray)
• Nonionizing radiation (e.g., UV light)
 chemicals (e.g., 5-bromouracil, acridine dyes, aflatoxin B1).

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DNA Repair
 DNA repair helps to ensure the accuracy of the DNA
sequence during DNA replication .
 DNA mismatch repair
 double-stranded DNA breaks repair.
 Nucleotide excision repair.

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 Xeroderma Pigmentosum: A Disease of
Faulty DNA Repair
 An inevitable consequence of
exposure to UV radiation is the
formation of potentially dangerous
pyrimidine dimers in the DNA of
skin cells.
 nucleotide excision repair (NER)
system removes these dimers in
normal persons.
 in xeroderma pigmentosum (A.R.),
NER does not work properly, and
the resulting DNA replication errors
lead to base-pair substitutions in skin
cells.
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Clinical Consequences of Mutation:
The Hemoglobin Disorders
 Genetic disorders of human hemoglobin are the most common
group of single-gene diseases: an estimated 7% of the world’s
population carries one or more mutations of the genes involved in
hemoglobin synthesis.

 Hemoglobin structure : The hemoglobin molecule is a

tetramer composed of four polypeptide chains, two labeled α and
two labeled β. The β chains are encoded by a gene on
chromosome 11, and the α chains are encoded by two genes on
chromosome 16 that are very similar to each other. Typically, an
individual has two normal β genes and four normal α genes.
 Each of these globin chains is associated with a heme group,
which contains an iron atom and binds with oxygen.

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Hemoglobin types

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Hemoglobin electrophoresis..
 During adult life the Hb fractions present in the normal
lysate are the major component HbA (α2β2 ≈ 96%), the
minor component HbA2 (α2δ2 ≈ 2.5-3.5%), and traces of
foetal HbF (α2γ2 <1%).
 The Hb fractions present at birth are mainly HbF (≈80%)
with some HbA (≈20%).
 Measurement of HbA, HbF and any abnormal fractions (HbS,
C, E, D, Bart’s etc.) which may be present supports the
correct interpretation of the results.

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The hemoglobin disorders
classified into two broad categories:
1. structural abnormalities, in which the hemoglobin
molecule is altered (e.g. Sickle cell disease)
2. The thalassemias, a group of conditions in which either the
α- or the β-globin chain is structurally normal but reduced
in quantity.

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Dr.Baraa Maraqa 2020
Sickle Cell Anemia
 Sickle cell disease is typically caused by a single missense
mutation that effects a substitution of valine for glutamic acid
at position 6 of the β-globin polypeptide chain.
 One particular HBB gene mutation produces an abnormal
version of beta-globin known as hemoglobin S (HbS). Other
mutations in the HBB gene lead to additional abnormal
versions of beta-globin such as hemoglobin C (HbC).
 AR inheritence ..
 HbAS : sickle cell trait (SCT).
Types:
 HbSS, HbSC, HbS/ß-Thalassemia

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“Sickiling” occurs at low
oxygen saturation

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Thalassemia
 divided into two major groups,
 α-thalassemia and β-thalassemia, depending on the globin chain
that is reduced in quantity.

α-thalassemia:
 Most cases are caused by deletions of the α-globin genes.
 The loss of one or two of these genes has no clinical effect.
 The loss or abnormality of three of the α genes produces
moderately severe anemia and splenomegaly (HbH disease, HbH
β-globin tetramer).
 Loss of all four α genes produces hypoxemia in the fetus and
hydrops fetalis.(Hb Barts : four gamma globins)

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 The β-thalassemias
 β-thalassemia minor: mutation in β-globin gene on one copy of
chromosome 11 (heterozygotes).
 Those in whom both copies of the chromosome carry a β-globin
mutation develop either β-thalassemia major (also called Cooley’s
anemia) or a less-serious condition, β-thalassemia intermedia.

 β0-thalassemia: β-globin gene completely absent.

 β+-thalassemia: globin amount reduced to about 10% to 30% of
the normal amount.

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 Name Description Alleles
Heterozygous form: Only one of β globin alleles bears a mutation.
Individuals will suffer from microcytic anemia. Detection usually
β+/β
Thalassemia minor involves lower than normal mean corpuscular volume value (<80 βo/β
fL).[15] (heterozygous)

Thalassemia Affected individuals can often manage a normal life but may need β+/β+ ( homozygous)
intermedia
occasional transfusions, e.g., at times of illness or pregnancy, βo/β+ (compound
depending on the severity of their anemia.[16] heterozygotes)

Homozygous form: Occurs when both alleles have thalassemia

mutations. This is a severe microcytic, hypochromic anemia.
Untreated, it causes anemia, splenomegaly and severe bone
Thalassemia major deformities. It progresses to death before age 20. Treatment consists βo/βo (homozygous)
of periodic blood transfusion; splenectomy for splenomegaly and
chelation of transfusion-related iron overload.[17]

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Dr.Baraa Maraqa 2020