GENETIC MUTATION AND DISORDERS

Subtopics:
A. What is Genetic Mutation and Causes

Genetic mutation:
A mutation is a change in genetic information. Since genetic information is encoded by the order of the nucleotide
bases of DNA, adenine (A), thymine (T), guanine (G), and cytosine (C), a mutation represents some sort of
change in that order. Mutations may occur in both somatic and sex cells.  Only mutations that occur in sex cells
can be passed from parent to offspring.

Causes:
1. Errors in DNA Replication
On very, very rare occasions DNA polymerase will incorporate a noncomplementary base into the
daughter strand. During the next round of replication the missincorporated base would lead to a mutation.
This, however, is very rare as the exonuclease functions as a proofreading mechanism recognizing
mismatched base pairs and excising them.

2. Errors in DNA Recombination

DNA often rearranges itself by a process called recombination which proceeds via a variety of
mechanisms. Occasionally DNA is lost during replication leading to a mutation.

3. Chemical Damage to DNA

Many chemical mutagens, some exogenous, some man-made, some environmental, are capable of
damaging DNA. Many chemotherapeutic drugs and intercalating agent drugs function by damaging DNA.

4. Radiation
Gamma rays, X-rays, even UV light can interact with compounds in the cell generating free radicals
which cause chemical damage to DNA.

Two types of
1. Somatic mutations take place in non-reproductive cells. Many kinds of somatic mutations have no obvious effect
on an organism, because genetically normal body cells are able to compensate for the mutated cells. Nonetheless,
certain other mutations can greatly impact the life and function of an organism. For example, somatic mutations
that affect cell division (particularly those that allow cells to divide uncontrollably) are the basis for many forms
of cancer.
2. Germ-line mutations occur in gametes or in cells that eventually produce gametes. In contrast with somatic
mutations, germ-line mutations are passed on to an organism's progeny. As a result, future generations of
organisms will carry the mutation in all of their cells (both somatic and germ-line).

B. Based on Chromosome Number

C. Based on Chromosome Number

a chromosomal mutation is the mutation of the chromosomal segments of the DNA strands. It involves the
alteration of longer stretches of DNA (ranging from multiple genes up to entire chromosomes)
c.1. deletion
A deletion mutation involves the loss of one or more nucleotides from a segment of DNA. A deletion can
involve the loss of any number of nucleotides, from a single nucleotide to an entire piece of a chromosome.
 Deletion mutations are actually the cause for a large number of genetic diseases, such as two-thirds of
cystic fibrosis cases and the cat cry syndrome, which is so-called because children with this syndrome often have
a cry that sounds similar to a cat meowing.

c.2. duplication
Duplication is a type of mutation in which one or more copies of a DNA segment (which can be as small
as a few bases or as large as a major chromosomal region) is produced. Duplications occur in all organisms. For
example, they are especially prominent in plants, although they can also cause genetic diseases in humans.
Duplications have been an important mechanism in the evolution of the genomes of humans and other organisms.

The type IA form of Charcot-Marie-Tooth disease is an example of an inherited human genetic disease
that's caused by a gene duplication. Individuals with Charcot-Marie-Tooth disease have damage to their peripheral
nerves, resulting in muscle weakness. The most common cause of this disease is duplication of the PMP22 gene,
located on chromosome 17. This particular gene duplication results in the production of too much PMP22 protein
which causes breakdown of the protective myelin sheath around the nerve, resulting in nerve damage and muscle
weakness.

c.3. translocation
Translocation occurs when a chromosome breaks and the (typically two) fragmented pieces re-attach to
different chromosomes. The detection of chromosomal translocations can be important for the diagnosis of certain
genetic diseases and disorders.
 The Philadelphia chromosome is an abnormal chromosome that causes chronic myelogenous leukemia
and a subset of other leukemias. It consists of a portion of chromosome 9 fused to a portion of chromosome 22, by
a translocation event between these two chromosomes. As a result, the BCR gene is fused to the ABL kinase gene
at the site of the translocation. The BCR-ABL gene produces an abnormal hybrid protein. Unlike the normal ABL
protein kinase, the hybrid kinase is always turned on and allows chronic myelogenous leukemia cells to grow and
survive. Importantly, there are targeted therapies that can turn the hybrid BCR-ABL protein off and kill the cancer
cells that contain the Philadelphia chromosome.

(Note: Summary only)

D. Based on Nucleotide Sequence

d.1. microlesion or point mutation
A point mutation occurs in a genome when a single base pair is added, deleted or changed. While
most point mutations are benign, they can also have various functional consequences, including changes
in gene expression or alterations in encoded proteins.
 Did you know that on any average day, the 37 trillion cells in your body will acquire trillions of point
mutations? These changes come from random errors in copying DNA as the cell divides or from environmental
exposures, like cigarette smoke or even sunshine. It sounds a little scary, but almost all of these changes are in
parts of your genome where it does not really matter. Your cells have also evolved ways to deal with some point
mutations and correct them back to your original genome. But the very rare point mutation in your somatic cells,
which are the cells that won't be sperm or eggs ultimately could lead to symptomatic disease.

d.2. frameshift mutation

A frameshift mutation in a gene refers to the insertion or deletion of nucleotide bases in numbers that are
not multiples of three. This is important because a cell reads a gene’s code in groups of three bases when making
a protein. Each of these “triplet codons” corresponds to one of 20 different amino acids used to build a protein. If
a mutation disrupts this normal reading frame, then the entire gene sequence following the mutation will be
incorrectly read. This can result in the addition of the wrong amino acids to the protein and/or the creation of a
codon that stops the protein from growing longer.

Imagine that you are reading a great mystery novel. When you get to an important part of the plot, you
find that a chapter of the book is missing, either torn from the book or not printed correctly. Because the chapter is
missing, none of the following parts of the book make much sense. For DNA, a missing segment can cause the
cell to effectively stop reading from that gene. The consequences depend upon the information stored in the part
of the genome where the problem occurred. If the gene performs a critical function, a significant medical problem
can result.

d.3. transverse mutation

Transition mutations occur when a pyrimidine base (i.e., thymine [T] or cytosine [C]) substitutes for
another pyrimidine base or when a purine base (i.e., adenine [A] or guanine [G]) substitutes for another purine
base.
 Transition versus Transversion mutations

    DNA substitution mutations are of two

types. Transitions are interchanges of two-
ring purines (A   G), or of one-
ring pyrimidines (C   T): they therefore involve
bases of similar shape. Transversions are
interchanges of purine for pyrimidine bases, which
therefore involve exchange of one-ring & two-
ring structures.

d.4. somatic mutation

An alteration in DNA that occurs after conception. Somatic mutations can occur in any of the cells of the
body except the germ cells (sperm and egg) and therefore are not passed on to children.

Somatic mutations are frequently caused by environmental factors, such as exposure to ultraviolet
radiation or to certain chemicals. Somatic mutations may occur in any cell division from the first cleavage of the
fertilized egg to the cell divisions that replace cells in a senile individual.

Somatic evolution has the potential to affect the disease progress of common complex diseases.
There is emerging evidence it can initiate disease, maintain disease once started, and possibly alleviate disease in
some cases. The strength of selection of mutations in particular genes appear to vary between individuals.
 d.5. sex cell mutation
Germline mutations are changes to your DNA that you inherit from the egg and sperm cells during
conception.

Note: Explain independent assortment process during gamete formation and recombination
during fertilization. These are natural mutation processes.

E. Genetic Disorders (Heritable or Non-heritable)

e.1. Tay-Sachs (Heritable)
Tay-Sachs disease is a rare genetic disorder passed from parents to child. It's caused by the
absence of an enzyme that helps break down fatty substances.

e.2. Sickle cell anemia (SCA) (Heritable)

 Sickle cell anemia (SCA) is a disease caused by production of abnormal hemoglobin, which
binds with other abnormal hemoglobin molecules within the red blood cell to cause rigid deformation of
the cell. This deformation impairs the ability of the cell to pass through small vascular channels;
sludging and congestion of vascular beds may result, followed by tissue ischemia and infarction.

e.3. Phenylketonuria (PKO) (HERITABLE)

Phenylketonuria (commonly known as PKU) is an inherited disorder that increases the levels of a
substance called phenylalanine in the blood. Phenylalanine is a building block of proteins (an amino
acid) that is obtained through the diet. It is found in all proteins and in some artificial sweeteners. If
PKU is not treated, phenylalanine can build up to harmful levels in the body, causing intellectual
disability and other serious health problems.

e.4. Hemophilia A (Heritable)

Haemophilia is an inherited bleeding disorder where blood doesn’t clot properly. It is caused
when blood does not have enough clotting factor. A clotting factor is a protein in blood that controls
bleeding.

e.5. Cystic Fibrosis (Heritable)

Cystic fibrosis (CF) is a chronic, progressive, and frequently fatal genetic (inherited) disease of
the body’s mucus glands. CF primarily affects the respiratory and digestive systems in children and
young adults.
e.6. Cri-du-chat Syndrome (Non-heritable)
Cri-du-chat (cat's cry) syndrome, also known as 5p- (5p minus) syndrome, is a chromosomal
condition that results when a piece of chromosome 5 is missing. Infants with this condition often have a
high-pitched cry that sounds like that of a cat. The disorder is characterized by intellectual disability and
delayed development, small head size (microcephaly), low birth weight, and weak muscle tone
(hypotonia) in infancy.

e.7. Duchenne Muscular Dystrophy (Heritable)

Is the most common form of muscular dystrophy. It is a genetic disorder characterized by
progressive weakness and degeneration of the skeletal muscles that control movement.
e.8. Down Syndrome (Non-heritable)
Down syndrome is a chromosomal condition that is associated with intellectual disability, a
characteristic facial appearance, and weak muscle tone (hypotonia) in infancy. All affected individuals
experience cognitive delays, but the intellectual disability is usually mild to moderate.

e.9. Edwards syndrome, etc., (Heritable)

Trisomy 18, known as Edwards Syndrome, is a rare condition resulting from genetic errors on
the 18th chromosome. The disorder occurs in approximately 1 in 5,000 live births and much more
commonly affects females than males. This disorder often results in physical deformities, defects in
internal organs, and severe intellectual and developmental disabilities.