Another example:
MLS 420: MOLECULAR BIOLOGY LEC.
MUTATIONS 
 by the anterior pituitary gland
Dr. Francis Ian Salaver, RMT, MD
Objectives:
• Discuss the importance of the sequences of
nucleotides in DNA in the formation of proteins
and expression of physical traits
• Differentiate spontaneous and induced mutations.
• Discuss the different causes of spontaneous
mutations
• Identify the mutagens and the mutations they can
induced.
• Differentiate germinal and somatic mutation.
• Differentiate point and frameshift mutation.
• This photo gives us an idea of the importance of
DNA to the formation of proteins and to the
expression of physical traits
• Phenylalanine (amino acid) acted upon by
phenylalanine hydroxylase —> produces Tyrosine
• Tyrosine: substrates for the pigment melanin
• Melanin: imparts brown color to the skin (one of our
physical traits)
• phenylalanine hydroxylase: enzyme, made up of
proteins and made up of amino-acids
• In some cases there are people; born with no
phenylalanine hydroxylase = they will have
PHENYL KETONURIA
- Phenylalanine will not be converted to
Tyrosine and thus there will be no substrate
for Melanin
PHENYL KETONURIA = NO Phenylalanine = NO
TYROSINE = NO Melanin = ALBINISM
Conclusion: The absence of a protein led to the
change in the color in the individuals. Thus, proteins
affect our physical traits. (Color)
• Growth Hormone produced
will act on the liver
• The liver responds to the
hormone by releasing Insulin-
like growth factor
• Insulin-like growth factor:
will act on the epiphyseal plates so that they can be
replaced eventually by bone
- When cartilage is replaced by bone, the
bone increases in length —> grow taller
(height)
Conclusion:
A protein can affect a particular trait (Height)
Estrogen and
Testosterone are
responsible for the
development of the female
and male secondary sexual
characteristics respectively
• The development of breasts in females and the
deepening of the voice in males are physical traits
• But estrogen and testosterone are NOT proteins but
rather STEROID HORMONES (derived from
cholesterol)
The hypothalamus senses a
drop in the blood levels of
estrogen and testosterone —>
and the hypothalamus responds
by producing (GnRH)
Gonadotrophin-releasing
hormone.
Gonadotrophin-releasing hormone : carried by the
blood to the anterior pituitary gland (APG)
The gonadotrophs of the APG will respond to
GnRH by producing 2 hormones:
• FSH Follicle-stimulating hormone - acts on
the follicles of the ovaries to produce estrogen
• LH Luteinizing hormone - acts on a cell in the
testes (Leydig cell) producing testosterone
GnRH. FSH & LH = are all considered to be
protein hormones. Thus absence/presence of these
proteins affect the production of estrogen and
testosterone production.
Conclusion: Proteins can affect the formation of
physical traits (breast formation and voice change)

PROTEINS
• Proteins are made up of specific sequence of amino
acids
replacing the amino
acids (even if it’s only one)
in the sequence changes
the entire protein (to
become abnormal or
misfolded)
rearranging the
sequence of the same
amino acids will still
change the entire protein
GENE
• The sequence of the amino acids in proteins are
encoded in the gene (Central Dogman of Life )
• Genes are small portions of the DNA
- If you want to form the protein and have
the correct sequence of the amino acids,
always transcribe the gene
DNA
DNA is found in the nucleus while the ribosomes
(site for protein synthesis) are found in the
cytoplasm
Ribosome - found in the cytoplasm and is the site
for protein synthesis
• DNA of Eukaryotes is enclosed in the nucleus to
protect it from the chemicals in the cytoplasm that
can cause its mutation.
• Transcribed DNA into mRNA and the mRNA goes
out of the nucleus to be translated in the
ribosomes for protein synthesis
Gene found in DNA —> DNA found in Nucleus 
 U ——-—-> A
But in protein synthesis you cannot let the DNA exit
the nucleus or else it will become mutated.
• Instead, copy the sequence of the nucleotides in
the gene of the DNA in the form of mRNA
• mRNA will go into the nuclear pore of the cell and
the mRNA will go to the ribosomes
how is the sequence of the amino acids are
derived from the gene?
• DNA is composed of 2 strands linked at the
center by their bases.
- each of the strand of the DNA has a gene
that encodes for specific proteins
ex. Polypeptide - has to have a Methionine,
Isoleucine and Serine sequence
- To have this sequence you have to copy
the sequence of the gene bases
- in this case the Blue strand contains the
portion of the DNA or gene that encodes
for the polypeptide.
- The two strands separate to expose the
bases to be able to copy the bases on the
blue strand complementarily to form
messenger RNA (mRNA)
- Adenine copied complementarily to Uracil
- Cytosine copied complementarily to
Guanine
- mRNA will go out of the nucleus towards
the ribosome
Codon = group of 3 mRNA bases; codes for a
particular amino acid
- AUG = Methionine
- AUC = Isoleucine
The sequence of the codons have been copied
from the DNA and predicts the amino acid
sequence
How are codons read by the ribosomes?
Ribosomes has a large subunit and
a small subunit
Sandwiched between these
subunits is the mRNA
Translation= the process that
happens in the ribosomes; and
starts at the 5’ end of the mRNA
tRNA (transfer RNA) - has an amino acid attached to
one end of the tRNA and will come close to the
ribosome bringing anti-codons
codons of mRNA and tRNA are complementary to
each other.
mRNA tRNA
A ——-—> U
G ——-—-> C
C ——-—-> T
• codon AUG is bound to UAC anticodon and the
tRNA will carry Methionine
• codon UGG is bound to ACC anticodon and will
carry Tryptophan
What will happen to the amino acids if you will
change even only ONE of the bases in the gene?
protein produced/encoded becomes abnormal and
mutated
MUTATIONS
• Alteration in the nucleotide sequence of the genome
of an organism
• Mutations result from:
(1) errors during DNA replication or
(2) caused by damages to DNA caused by
viruses, chemicals, or exposure to ionizing
radiation
• Mutations may or may not produce detectable
changes in the observable characteristics or
phenotype of an organism.
- that is why there are “silent” mutations
• Mutations can lead to changes in the structure of an
encoded protein or to a decrease or complete loss
in its expression.(protein may not be produced at
all)
• Because a change in the DNA sequence affects all
copies of the encoded protein, mutations can be
particularly damaging to a cell or organism.
Mutations can also affect the physical trait of the
organism.
Height is influenced by growth hormones; 
 bladder cancer
GH acts on liver releasing (Insulin-like growth
factor) IGF-1 acts on chondrocytes so that
cartilage to replace by bone.
• Epiphyseal plates found at the proximal and
distal parts of the bone and composed of
hyaline cartilage, and chondrocytes
• The EP has 5 zones.
- The 5th zone - (Zone of bone deposition)
the portion of the cartilage that is slowly
replaced by bone
• The chondrocyte occurs singly but when acted
upon by IGF-1 causes the proliferation of
chondrocytes to maintain the size of the EP
so that the bone can expand = taller
individual
- Chondrocytes in the Epiphyseal plate can
develop mutaion = affecting the protein
receptor
• GGG for Glycine is changed to AGG for
Arginine
- FGFR3 receptor found on the cell
membrane of chondrocytes
• GGG to AGG mutation= causes the over
activated of the receptor = suppression of the
chondrocytes and differentiation
Achondroplasia
- people with Achondroplasia will not
respond to the GH medication
CAUSES OF MUTATIONS
• Mutations arise spontaneously (SPONTANEOUS
MUTATION )at low frequency owing to the chemical
instability of purine and pyrimidine bases and to
errors during DNA replication
- Spontaneous mutation - we have no control
over when it will appear and will not cause
significant problems
When a cell divides, it makes a copy of its
DNA — and sometimes the copy is not quite
perfect. That small difference from the original
DNA sequence is a mutation.
• Mutations can also be caused by exposure to
specific chemicals, microorganism or radiation.
(Mutagens) = INDUCED/ ACQUIRED MUTATIONS
These agents cause the DNA to break
down. When the cell repairs the DNA, it
might not do a perfect job of the repair. So
the cell would end up with DNA slightly
different than the original DNA and hence, a
mutation.
CHEMICAL MUTAGENS
cancers: caused by mutations
• Tobacco - lung, stomach, intestinal and urinary
• Alcohol - hepatocellular (liver) carcinoma
• Benzene – Leukemia
- The use of benzene as a clearing agent has
been abandoned because it can cause acute
myelogenous leukemia (Leukemias are
caused by mutations)
• Asbestos – lung, larynx, esophagus cancer
• Aflatoxin – Aspergillus flavus – hepatocelluar
(liver) cancer
- Mycotoxicosis = diseases caused by fungus
Aspergillus flavus manifesting Liver cancer
Aspergillus flavus : produces the toxin
Aflatoxin, and is seen in peanuts and corn
• Processed meats - 

Since the meat is already processed, the “heme” is
already chemically modified to form Nitric Oxide

Once ingested Nitric Oxide will be converted to N-
nitroso compounds.
Nitroso compounds can cause damage
to the epithelium; 

when there is constant damage to the
epithelium = mutation can occur —>
Stomach and colon cancer
A high fiber diet lowers the chance of
developing colon cancer
PHYSICAL MUTAGENS
IONIZING RADIATION
• INDIRECT ACTION casued by ionizing radiation: 

X-rays, gamma rays, cosmic rays are ionizing
radiation which ionizes water of the cell to release
hydroxyl free radical (OH).
The hydroxyl radical is a powerful
oxidizing agent. 

Hydroxyl radical oxidises the
phosphodiester bond of DNA leading to
damage
• DIRECT ACTION caused by Ionizing radiation:
Sometimes the ionizing radiation does not need
the Hydroxyl radical to cause damage to the DNA;
since the ionizing radiation can directly cause
damage to the DNA.
 Regardless of outcome; the possible outcome of
Ionizing reagents is a break in one or both the
DNA strands —> not able to produce the protein
—-> mutation.
NON IONIZING RADIATION (UV LIGHT)
• UV light is a non-ionizing radiation. It causes the
formation of thymine dimer.
• If two thymine occur together in one strand of DNA
= UV light causes fusion to form thymine dimer;
instead of the usual bond formation of the bases
• At the site of thymine dimer confirmation of DNA is
changed, so rate of error during DNA replication is
high, since the are of thymine dimers can no
longer be transcribed to form mRNAs
BIOLOGICAL MUTAGENS
VIRUSES
• Helicobacter pylori – Gastric cancer
Those with chronic ulcers are advised to be
tested with H.pylori antigen test
• Hepatitis B, C and D – can cause chronic form of
hepatitis leading to Hepatocellular carcinoma
Hepatitis D cannot occur without Hepatitis B
• Human herpesvirus 8 – Kaposi sarcoma
Kaposi sarcoma: malignant tranformation of
the lining of the blood vessels of the lymphatic
capillaries or blood vessels
- 90% of humans have already been
exposed to Herpes Virus 8 and since we
are immunocompetent we do not develop
the symptoms of the disease
- but if your immune system is down; this
virus can cause lesions on the skins, and
other places.
• Human papillomavirus – Cervical cancer
There are alot of HPV serotypes:
- those that cause benign warts
- predispose a woman to develop cervical
cancer
- predispose a man to develop penis cancer
Serotypes 16 & 18 (HPV16 & HPV18) = are the
ones that cause malignancies in the cervix
 TYPES OF MUTATIONS
Thus women of reproductive age must have
annual Pap-smears for early detection of
malignancies
• Epstein-Barr virus – Burkitt’s lymphoma and
Nasopharyngeal carcinoma
EBV is transmitted by kissing and will initially
affect the epithelial cells of the oral cavity —>
affecting the B-cells —-> Once the B-cells are
infected they will become plasma cells that
produce the heterophil antibodies leading to
cancer
PARASITES
• Clonorchis sinensis and Opisthorchis felineus :
these are hepatic flukes that are found in the bile
duct
- The eggs of the parasite are flushed out in the
bile and are found in the stool of the individual
Eating raw fish will predispose us to developing
the infection with C. sinensis and O. felineaus 

-> leading to bile duct obstruction and gallstone
formation
Worms are capable of producing N-nitroso
compounds = Cholangiocarcinoma (Cancer of
the bile duct)
• Schistosoma haematobium – Bladder cancer
Male and female S. haematobium adults found
in the venous plexus of the urinary bladder 

When they will mate the eggs will be passed out
to the lumen of the urinary bladder and the
urine
Cercaria of the parasite will penetrate the
human skin causing the infection
The eggs of the parasite are identified by the
terminal spine = once these eggs crowd the
urinary bladder; the terminal spines will cause
injury to the wall of the bladder
constant injury = constant mutation of
cells = urinary bladder cancer
QUIZ TIME!!!
Answers:
1. G
2. F
3. E
4. D
5. C
6. B
7. A
Induced vs. Spontaneous
SPONTANEOUS MUTATIONS: Mutations
that have been occurring in nature without a
known cause. These are mutations that occur
naturally, without human interference. (NO
associated mutagen)
• Mutations arise spontaneously at low frequency
owing to the chemical instability of purine
and pyrimidine bases and to errors during
DNA replication
Spontaneous mutations usually caused by
the following:
- Tautomeric shifts
- Wobble base pairing
- Strand slippage
- Unequal crossing over
- Spontaneous Chemical changes
1. Tautomeric Shifts
Review on Watson and Crick Principle:
- Thymine complement of Adenine
- Cytosine complement of Guanine
• Tautomeric shifts can be caused by the change of
Adenine and Cytosine from amino form to imino
form
• Can be caused by the change of Thymine and
Guanine from keto forms to enol forms
• Adenine is a purine with 2 fused rings and Cytosine
is a pyrimidine since it only has 1 ring
• Blue circles: highlights the amino groups attached
to the rings of Adenine and Cytosine
 there are Oxygen molecules forming a double
Thus when they have this amino groups they are in
the AMINO form
• In some situations the amino group of Adenine and
Cytosine will lose its hydrogen.
• Instead, the nitrogen will form a double bond with
the carbon of the rings in Cytosine
• Adenine and Cytosine are in IMINO form = causing
a Tautomeric Shift
• Spontaneous mutations occur at low frequency

Why? One of the causes is Tautomeric shift
• Look at the encircled arrows: The longer arrows
show us that Adenine and Cytosine are usually in
the Amino form and it is very rare that they exist in
Imino form
• And since this occurrence is rare; spontaneous
mutations occur at low frequency
• Tautomeric shift also occurs when Guanine and
Thymine will transform from their Keto forms to the
Enol forms
What are Keto forms?
• On the left side of the screen you can see that
bond with the carbon of the rings - these are
referred to as KETONES
• Since there are ketones in the structural formula
you refer to the structure as KETO FORMS
What are ENOL forms?
• Look at the right side of the picture - see that
oxygen has lost on of the bonds (from the double
bond) with carbon and instead forms a bond with
hydrogen = ENOL FORMS
• Look at the arrows: it tells us that is is very rare
for Thymine and Guanine to exist in ENOL forms
Hi ☺ Before proceeding to the continuation of
the notes, maybe take a mini break first?
Stretch a bit and get some snacks. 

Remember to take care of yourself despite the
hustle
🔅🔅🔅
Good luck and God Bless!
Cont… Tautomeric Shift
 The one that follows Watsons and Crick:
 Thymine + Adenine
 But if there is tautomeric shift: Thymine + Guanine
 Pic above (keto form)
o Thymine has ketone group
o Expected to bind with adenine
 Pic below (enol form)
o Pair up with guanine
 Tautomeric Shift: a mutation that can occur if the
thymine and guanine will transfrom from keto form to
enol form; changing its complementary base
Spontaneous Mutations
2. Wobble Base Pairing
 Cytosine (amino form) + Guanine
 Cytosine (imino form) + Adenine
Effect of Tautomeric Shift to DNA?
 Left side of screen: DNA molecule with 2 strands
 Middle: strands separated in attempt to duplicate
DNA in DNA replication
 One of the adenine bases will undergo
transformation from amino form to imino form
o Particular strand will be replicated but the
letter (A) is existing in imino form and will not
pair up with Thymine but will bind to cytosine
o The newly formed DNA will have cytosine on
the newly replicated/formed strand
 What will happen if this DNA will undergo another
round of replication?
o Adenine that has undergone TS will now
revert back to its amino form (A+T)
o Blue strand has letter (C) instead of T (C+G)
o AAG but (AGG-mutation)
 If the gene is found on the red strand, codons will be
red
o AAG –lysine
o AGG –Arginine (replacement -mutation)
 Tautomeric shift can cause spontaneous mutation
and it occurs because of chemical instability among
purine and pyrimidine bases bec they can undergo
transformation from keto to enol and amino to imino
form
• Are usually caused by the following:
• Tautomeric shifts
• Wobble base pairing
• Strand slippage
• Unequal crossing over
• Spontaneous Chemical changes
 Green (large and small subunits of ribosomes)
 mRNA (5’-3’)
o reading bases in groups of 3 = codon
 for that amino acid to be loaded to form proteins =
tRNA
 tRNA must have complementary anti-codon
 AUG = UAC
 GGU = CCA; GGC = ___
 Scientists found out that the same tRNA will also
bind to GGC even if its anticodon is CCG = wobble
base pairing
 Pairing between two nucleotides in RNA molecules
that does not follow Watson-Crick base pair rules
 Occur at a high frequency in tRNAs and rare with
other types of nucleic acids
o Takes place on 3rd position codon and 1st
position of anticodons
 See photo above.
o mRNA = UCC
 expected anticodon should be AGG
 if the codon is UCU
 tRNA with the anticodon of AGG can
also bind to UCU bec 1st osition and
3rd position will not follow the
Watson-Crick rule = wobble base
pairing
 GCU – good to c u
 I –hypoxantine
o Can bind to any base in 3rd position of codon
(CAU)
Reason behind Wobble base pairing
 The smaller ribosomal subunit possesses a means
of examining whether the standard Watson-Crick
base pairs have formed between the 1st codon base
and the 3rd anticodon base, as well as between the
2nd codon base and the 2nd anticodon base.
o However, there is no system to check
whether the 3rd codon base and the 1st
anticodon base are complimentary to one
another and this amounts to the more lenient
base-pairing that is witnessed exclusively at
the 3rd position
 1 AA can be coded by more than 1 codons
 Analyze:
o UCC encodes for Serine
o UCU encodes for Serine
 WBP is not harmful bec even if the
1st position of anticodon in tRNA will
WBP, the AA added to the growing
protein will be the same
 Silent mutation
o CGA for arginine
o CGC for arginine
o CGU for arginine
 WBP:
 Redudant characteristics of codon
 The Wobble Hypothesis explains why multiple
codons can code for a single amino acid.
 One tRNA molecule (with one amino acid attached)
can recognise and bind to more than one codon,
due to the less-precise base pairs that can arise
between the 3rd base of the codon and the base at
the 1st position on the anticodon
3. Strand slippage
 In some cases, DNa can have repeating sequences

 Once repeating seq will be encountered by DNA
polymerase due to unknown reason
o DNA polymerase will temporarily dissociate
from the site of replication site = allowing 2
strands to separate from each other where
mutation can happen
 Gray –being replicated
Orange –newly formed strand
 During replication, the DNA sequences are
associated, and the DNA polymerase can recognise
and bind to the 3’ end of the DNA strand, allowing it
to synthesise an identical complementary copy (1).
 Sometimes the strands will dissociate, the DNA
polymerase complex falls off, and replication stops
(2).
 When the two DNA strands pair up again, they will
align correct most of the time (1).
o But there are problems that could arise!!!
o 2 blue arrows: pointing the portion of the
strands that the DNA polymerase encounter
the repeating or repeated seq
o Red arrow: bases are complementary to the
portion pointed by the blue arrow
 if the strands will try to reunite after
DNA polymerase dissociated from
them
 there’s a chance that the portion
pointed by red arrow will form bonds
or will pair up with the portion
pointed by the blue arrow
 consequence? There will be portion
on the newly formed strand now that
will not bind to the template strand
 Sometimes, because of the repeated sequences
(GATA), the strand will mispair to create a shorter
’copy’ (3) or more rarely a longer ’copy’ (4).
o Slippage on newly formed strand: longer
than template strand
 These faulty copies are called stutters in general,
and back stutter (3) and forward stutter (4) in
particular.
o If the slippage happens on the TS, NFS will
be shorter than the TS
How does strand slippage cause spontaneous mutation
in DNA?
 Blue –repeated seq = DNA poly will dissociate
strand slippage
o Fold in NFS –at the end of the replication,
the NFS will be longer than template strand
 Orange –repeated seq = strand slippage happens on
TS = shorter NFS and TS will be longer
 2nd gen NF DNA is no longer similar to the DNA in
initial generation
True or False?
 Mispairing on the synthesis/replicated strand
generates addition events. ______
 Slipped-strand mispairing on the template strand
results in deletions. _________
4. Unequal crossing over
 46 chromosomes
 One (father); the other one (mother)
 Should the cell decide to undergo replication, all of
the cells should be duplicated so that once the cell
will divide = daughter cells will have equal copies of
chromosome
 Chromosome 1 : duplicated chromosome
Unequal CO = chromosomes are not properly aligned
 Mitosis: all of the duplicated chromosomes align
singly at the equatorial plate; that’s why when they’re
pulled at opposite poles during anaphase –the
chromosomes will be equally divided among
daughter cells
 Meiosis: homologous chromosome do not separate
o Do not align singly in EP; they go to the
center as pair
o Blue arrow –duplicated chromosomes of
Chromosome 1 (blue –father; brown-
mother)
o Meiosis is a cellular division of gametes
(egg and sperm cell) ….anaphase
 The whole chromosome of father
will be pulled towards the left side or
to the left daughter cell
 The whole chromosome of father
will be pulled towards the right
daughter cell
o Sperm cell and egg cell –responsible for
passing on the DNA from 1 gen to another
 So, what must happen to have
combination of genes from grandpa
and grandma? = CROSSING OVER
 Paired homologous chromosomes, before they are
pulled toward the opposite poles –they exchange
DNA/genes
 If chromosomes are properly aligned = equal sharing
of genes and DNA = no mutation
 During normal crossing over, the homologous
sequences of the two DNA molecules align and
crossing over produces no net chance in the
number of nucleotides in either molecule.
 Misaligned pairing may cause unequal crossing
over which results in one DNA molecule with an
insertion and the other with a deletion
o Some of the portions of 1 chromosome will
be transferred to the other chromosome
without a corresponding exchange
o 1232345 are only left with 145 :<<
 1 C will have lesser number of genes = DELETION
 1 C will have extra copy of genes = DUPLICATION
5. Spotaneous Chemical changes
2 processes:
 Depurination –removal of purine bases
 Deamination –removal of amino group
DEPURINATION
 Release of adenine or guanine bases
 Removal of purine base from nucleotide
 There is chemical instability between the bonds of
guanine and 1st carbon of sugar molecule
o Bec if there’s reaction with water
 (H20 will destroy the bond between
guanine and the 1st carbon of the
sugar and will cause removal of
guanine base from nucleotide)
 and since guanine is removed
 and guanine is a purine =
DEPURINATION
 L side photo: if these nucleotide will react with water
= release of guanine = phosphate and sugar
molecule left
 The portion of nucleotide with the absence of
guanine is called APURINIC SITE
o REMOVAL OF PURINE
o No purine base attached to it
 The bond between deoxyribose and guanine bases
can be destroyed by addition of water
**slide 108
 Apurinic site in TS of DNA are usually paired with
adenine
 TGGC = TTGC
 Mutation!!! –consequence of depurination
 Guanine was removed; if replicated it should be
paired with adenine
 Apurinic site can still be coupled with T, G, C
o But usually: A!!!!!
DEAMINATION
 USUALLY HAPPENS TO CYTOSINE!!!
o Deamination = replaced by ketone
o Cytosine become uracil
 Spontaneous Chemical change
 Amino group is removed from the cytosine base
and converting it into uracil
 Eventually, a CG base pair will have transition
mutation to TA
 Red arrow –normal DNA –deamination –cytosine
will become uracil –replication –separate blue
strand from yellow strand
 Yellow arrow –normal seq of nucleotide
 Blue arrow –undergone deamination of cytosine
o If replicated, uracil will be paired with
adenine
o Looking back, in normal dna, the position of
adenine is occupied by guanine
o G will be replaced by A = mutation!!
o If replicated = A will be paired with T!!!
o CG to TA Base pair!!
PART 2 - For the mutation to be passed on to one
Types of Mutations generation to another or the mutation that cause
• Induced vs. Spontaneous. the cancer must be germinal or germ line.
• Germinal vs. Somatic - If you know someone with breast cancer, must
• Point mutations likely that person has family member who has
• Substitution, Insertion, and Deletion breast cancer.
• Frameshift mutation o Breast cancers
o Ovarian cancers
SOMATIC CELLS vs. GAMETES o Colon cancers
• Somatic – body cells o Melanomas – usually mistaken as moles.
o All the cells of the body except the sperm ▪ Continuously growing in size.
and the egg. ▪ To assess suspected melanomas
o Ex. Skin, liver, eyeballs (ABCD)
o Mutation in the DNA of somatic cells → • Asymmetrical in shape
SOMATIC MUTATION • Uneven Border
• Gametes (Germ cells) – sex cells • Multiple Colors
o Cells responsible for transmitting the DNA to • Diameter of more than 6
one generation to another. mm
o Ex. Egg or Sperm (DNA here gets passed on • Cystic fibrosis
to kids!)
o Mutation that will happen on sperm and the
egg cell → GERMINAL / GERM LINE
MUTATION

Types of Mutations: Germinal vs Somatic Mutations

Germinal mutations
• Occurs in the DNA of gametes or reproductive cells
(sperm and oocyte)
• Also known as germline mutations
- affects the DNA of
either the sperm or the
egg
- so, expect if the
affected sperm or egg
will form the zygote the
offspring will be
inheriting the mutation.
- after fertilization, the
germ cells will multiply
in number, so they can
form all the cell in the
body → it is expected
that the germ cell and
the somatic cells of the
offspring will bare the
mutation
- if the offspring will
become an adult, he or she will be passing the mutation to
the next generation. • Do you know that melanoma can also affect the
• Can be passed on to offspring especially when eyes?
either a mutated sperm or oocyte come together to • Melanomas – are cancer involving the melanocytes
form a zygote. (the cells that are responsible for the production of
▪ Main reason why genetic diseases the brown pigment of the skin)
run in families. • *See the image of the flower on the photo above.
• After fertilization event occurs, germ cells divide ➔ The image will enter the hole of the pupil (the area of
rapidly to produce all the cells in the body, causing the lens that is not covered by the iris)
this mutation to be present (distributed) in ➔ Then into the lens, then the role of the lens is to direct
every somatic and germ cell in the offspring. the light or the image towards the retina.
➔ So, the retina can perceive the light or the image
Example of Germline mutation • The lens is partially covered by the iris of both
• Cancers – inherited or hereditary cancers (run in the side, the area not covered by the iris is called
family) pupil.
 • Unlike germline mutations, which can be passed on
to the descendants of an organism, somatic
mutations are not usually transmitted to
descendants.
Example of Somatic mutation
• Cancers – sporadic cancers
o Acquired, need to be exposed to physical
mutagens before you will develop the
cancer.
o Not passed on from one generation to
another.
o If the younger generation has a cancer, most
likely the person was exposed to the same
cause of cancer not because he inherited it
• Cut section of the eye.
from previous generation.
• The lens is partially covered by the iris on both
o tobacco use, ultraviolet radiation, viruses,
sides.
parasites, chemical exposures, and aging.
• The posterior portion of the iris have the brown
• Somatic mutation in red delicious apple
color pigmentation → melanin pigments.
• Example this apple, it
• For the iris to have pigments, there must have a undergoes mutation that causes
presence of melanocytes. some of it became yellow.
• The purpose of melanin on the iris, is to block the • If you want to plant the seed
light from entering the eye and the light will enter of this apple → the apple would not
through pupil. have red delicious apple with
• Iris – regulate the amount of light entering the eye. yellow color because it is not
• If the iris has melanin pigment and it has germinal mutation. (Newly formed
melanocytes, and the person has melanoma → fruits would not have somatic
expect that the cells in eye will also undergone mutation)
malignant transformation.
Types of Mutations:
Point mutation
• Type of mutation caused by a change in a single
nucleotide.
o The mutation will only involve one
nucleotide.
• Mutation results when a DNA nucleotide is added,
removed, or replaced by a different nucleotide.

• Example of melanoma affecting the eye.

• The location of melanoma → IRIS

Somatic Mutation
• Any mutation that occurs in a cell other than the
gametes
• Also known as acquired mutation.
o Because the zygote was formed by a normal
sperm and egg cell. ➔ The first example is the correct sequences to have a
o To develop somatic mutation, you probably normal product. (CATCATCAT…)
exposed to a chemical, physical mutagen, ➔ As you can see on 2nd example one of the sequences
and a biological mutagen. is change into G from C. (CATGATCAT)
• Mutation is not found in in every cell in the body. ➔ The change of one nucleotide will have an impact in
o Only the affected cells will have a mutation. the transcription of mRNA → have different codon
o In germinal mutation, since the germ cells and insert a different type of protein.
will give rise to almost cells of the body → if ➔ There is still production of AA but in a certain area
they are mutated then almost cells of the there is a change in a single mutation.
body will have mutation.
o In somatic mutation, only those cells that are
exposed to the mutagen will develop the
mutation.
 Beta-thalassemia (example of nonsense mutation)

➔ At the 39th codon, cytosine was replaced by uracil.

➔ CAG (glutamine)
➔ In beta-thalassemia, it is a replacement of cytosine
to uracil.
• Point mutation has 3 possible outcomes. ➔ CAG → UAG (STOP)
➔ Once the ribosome will read the stop codon it will not
Silent Mutation add glutamine → the ribosome will stop the
• DNA mutation that do not result in a change to the production of beta-globin
amino acid sequence of a protein. ➔ People with beta-thalassemia will have shorter beta-
• It is due to code redundancy. globin chain compared to normal individuals.
• New codon by mutation specifies the same amino
acid as the unmutated codon. - the globin chain of
• +) in molecule cloning experiments, silent mutation hemoglobin is composed of
can control the effect of restricted enzyme. 2 identical chains.

- Example on the photo: The - Adult hemoglobin → 2

GAA (Glutamine) codon is
change into GAG (change in
one nucleotide – point
mutation)
- What makes it silent is that
even if the adenine was
replaced with guanine GAG
still encode for the same
amino acid. → no change in
the sequence or type of amino acid in the protein.
- The mutation is silent because no detectable change
in the protein or the physical trait of individual, but it
is still a mutation because there is a change of
nucleotide.
beta-chains and 2 alpha-
chains
- if the person was born with beta-thalassemia, they
can produce beta-chain but shorter than the normal
individual.
- they would always a consequence in the production
of the globin chain
- if the formation of beta-chain is affected therefore the
person cannot form hemoglobin → anemia

• Mutation characterized by a change in the sequence

of nucleotide bases which constitutes DNA, without
a subsequent change in the amino acid or the
function of the overall protein.
o Thanks to the redundancy change of codon,
because amino acid can be encoded more
than one codon.
Nonsense mutation
• Mutation characterized by a change in the
sequence of nucleotides
in DNA that causes a
protein to terminate or
end its translation earlier
than expected.
o If the change of
nucleotide would cause
the formation of STOP
CODON
• Fetal Hb: Alpha and Gamma (fetal Hb is not affected
by beta-thalassemia)
• The Hb A1 (Alpha and Beta) – most abundant Hb in
adult.
• People with beta-thalassemia will have low levels of
hemoglobin.
• A2 (Alpha and delta)
• People born with beta-thalassemia cannot form their
own adult Hb.
• After birth, the fetal Hb will try to compensate the lack
of adult hemoglobin.
• These children will have fetal Hb even though they
are already growing.
• A2 will also compensate but most of the time fetal Hb
will compensate.
• Since these children will always have episodes of
anemia, the response of the body is to expand the
bone marrow.
 • As the bone marrow expand, it will have more areas - pumping out
for RBC production. chloride ions out of
• PROBLEM: bone marrow will be replacing the bone the cell.
→ it will lead the bone to become soft. (Possibility of
fracture)
• To avoid bone expansion, it is advisable to have
blood extraction for beta-thalassemia px.
• However, if the patient has transfusion ever now and
then → it will lead to IRON OVERLAOD.
- transporters are
made up of protein
(yellow color on the
phot)
- For the transporter
to be functional,
protein need to be
part of their
structures.
- Any change of DNA/mRNA will cause abnormality in
the formation of proteins.
- If proteins will become abnormal → transporters will
not also function.

➔ The areas in red marrow will expand if the person

has beta-thalassemia.

➔ In the case of cystic fibrosis, the point mutation

causes the codon to become a stop codon. Instead
➔ A. radiologic picture of vertebral column – white
of creating a full-length protein that will become
because they have calcium ion deposited in their
transporter.
boney matrix.
➔ The CFTR protein → shorter protein or Truncated
➔ B and C radiologic image of people with beta-
thalassemia (untreated) – lost its white color
(because red BM expanded and destroy boney
matrix)
➔ If the boney matrix is destroyed calcium will be
release into the blood.

➔ The role of CFTR is to pump out chloride ions from

➔ The bone now will have less matrix and more on BM
→ prone to fracture.
➔ Person with beta-thalassemia → Vertebral fracture
→ damage to spinal cord → paralysis
CYSTIC FIBROSIS
• Caused by mutations in the gene that produces
the cystic fibrosis transmembrane conductance
regulator (CFTR) protein. This protein is responsible
for regulating the flow of salt and fluids in and out of
the cells in different parts of the body.
intracellular to extracellular area.
➔ Salts (NaCl) – can loosen secretion in the airway.
➔ If you have Mutated CFTR because of point-
nonsense mutation → the cells in the airway cannot
release chloride → the mucus will not become
loosen → the mucus will build up → narrowing of
the airway passage → difficulty of breathing.
 - airway of
normal
individual and
with cystic
fibrosis
- With cystic
fibrosis: build
up of sputum
(because
sputum is not
mixed with chloride) ➔ at the 6th AA glutamic acid is replaced by valine.
- Since they have mucus lining in their airway → they ➔ Sickle cell anemia – single base substitution
can trap pathogenic organisms. → can easily (Thymine → Adenine)
transmit it to another individual. ➔ So, if to transcribe CAC you will have a mRNA with
- In the movie ‘Five Feet Apart’ the couple need to be a codon of GUG (valine).
5 ft apart because they could infect one another.

- The reason it is called sickle cell anemia because

➔ Sinuses: build up of mucus → trapped bacteria →
infection Sinusitis
➔ The bile duct and pancreatic duct can also clog or
obstructed by mucus → the enzyme (digest
something) of pancreas will no longer reach the
duodenum.
➔ If the amylase and lipase will no longer digesting
sugar and lipid in duodenum, since they cannot
pass through the mucus layer of pancreatic duct →
the enzyme will start digesting pancreas.
➔ Intestine: if a lot of mucus → cannot fully absorb
nutrients.
Missense mutation
• Remember silent mutation.
• The change of nucleotide will cause the addition of
another type of amino acid → it will cause to have
another type of protein (abnormal or non-functional)
• Occurs when the change of a single base pair
causes the substitution of a different amino acid in
the resulting protein.
• This amino acid substitution may have no effect, or
it may render the protein non-functional.
SICKEL CELL ANEMIA
• Problem with beta globin
chain
• Beta globin chain is
composed of 147 amino
acids.
• The gene for beta globin is
mutated.
o Single-base mutation
o the sixth amino acid in the chain is valine,
rather than glutamic acid.
the RBC will become in sickle or irregular in shape.
- These RBCs cannot anymore carry oxygen and
they can cause occlusion of small blood vessels.
• The valine will cause the Hb to form rigid rods.
• Molecules of sickle-cell haemoglobin stick to one
another, forming rigid rods.
• These rods cause a person's red blood cells to take
on a deformed (sickling), sickle-like shape, thus
giving the disease its name.
o The rigid, misshapen blood
cells do not carry oxygen well, and
they also tend to clog capillaries
(occlusion), causing an affected
person's blood supply to be cut off to
various tissues, including the brain
and the heart. (acute myocardial
infraction and stroke)
Types of Mutations:
Substitution Mutation
 Mutation that exchanges one base for another
 Basically, point mutation → Mutation that
exchanges one base for another
o Missense, nonsense, silent mutation
 3 possible things can happen
o (1) change a codon to one that encodes a
different amino acid and cause changes in
the protein produced = MISSENSE
MUTATION (Sickle Cell Anemia)
 o (2) change a codon to ➢ In hemophilia A, there is an insertion of genes in the
one that encodes the normal factor VIII gene → will cause problems in
same amino acid and formation of mRNA → formation of codons →
causes no change in the produce different type of protein
protein produced. These ➢ Factor VIII is abnormal → prone to bleeding →
are called SILENT why?
MUTATIONS.

o (3) change an amino-

acid-coding codon to a
single "stop" codon
and cause an
incomplete protein =
NONSENSE
MUTATION

Types of Mutations:
Insertion Mutation
 One or more extra nucleotides are inserted into
replicating DNA, often resulting in a frameshift
mutation
 Do not just change one of the bases in the
nucleotide sequence instead you insert new
nucleotide bases
➢ On the replicating DNA, there is an insertion of the
base pairs A-T
➢ Expect that if you are going to form an mRNA from
this DNA molecule, sequence of codons will also
change → frameshift mutation
➢ These are the responses of our body whenever
there is an injury
➢ (1) Vasoconstriction – limit blood flow to the site of
injury → there will be no further blood loss
➢ (2) Primary hemostasis – ends up with platelet
plug formation
o Depends on the fxn and number of PLT
o Plt adhesion, release, aggregation
➢ (3) Secondary hemostasis – end point: formation
of fibrin clot
o Fibrin clot is formed by the help of
coagulation factors
▪ Ex: Factor VIII (if absent, affect
secondary hemostasis) → episodes
of uncontrolled bleeding
➢ (4) Fibrinolysis – removal of fibrin after the tissue
has completed repair
o Fibrin is not allowed to stay because it
might cause occlusion of blood vessel

Hemophilia A

➢ Recall 2 pathways of coagulation cascade –

➢ Extrinsic Pathway
➢ good example of insertion mutation
➢ Hemophilia A is the absence of Factor VIII (“A”ight
→ eight)
➢ Hemophilia B – absence of Factor IX (b → invert it
will look like 9)
Intrinsic and Extrinsic
o Activator is tissue factor (III) → produced
by damaged tissues → go inside the blood
vessel and interact with the coagulation
proteins
o Came from outside blood vessel →
extrinsic
 FIII → will activate FVII →will activate FX
(3+7=10)
 ➢ Intrinsic Pathway
o Activator of FXII – exposed collagen or
basement membrane of the blood vessel
→ found within the blood vessel → intrinsic
 FXII will be activated by the exposed collagen
or BM → will activate FXI → activate FIX →
with the help of FVIII (cofactor), activate FX
 12-11-9-8-10
Factor X
- Where 2 pathways merge = COMMON PATHWAY
- FX with the help of FV → activate FII (10/5 = 2) →
thrombin → cause fibrinogen to become fibrin ➢ Hemoglobin Gun Hill
o Affects B-globin gene
So, if FVIII is not present because of insertion of o 92nd to 97th codons are deleted
mutation… o Globin chain will lose 6 AA
- FIX will not have any way of activating FX o B-globin chain is shorter than normal

Signs and Symptoms ➢ Hemoglobin – composed of 4 globin chains

- Dizziness – low Hgb level secondary to blood loss ➢ Globin chains – composed of 2 identical types of
- Epistaxis – nose bleed chains
- Bleeding – not stop even if the site of bleeding has ➢ Adult Hgb: 2 beta chains and 2 alpha chains
been applied with pressure ➢ Heme + globin chains = hemoglobin
- Headache – warning to the physician; bleeding in ➢ For the heme to be incorporated in the central
the brain portion of globin chains, heme must have a bond to
- Pain and stiffness in the joints – accumulation of the AA that are part of the globin chains
blood
- Blood in urine or stool

Types of Mutations:
Deletion Mutation
 Mistake in the DNA replication process which
removes nucleotides from the genome.
 A deletion
mutation can
remove a single
nucleotide, or entire
sequences of
nucleotides. ➢ (Pic B) Heme is in the center of the globin chain →
 Opposite of for it to be positioned in that area, heme must bind
insertion mutation to the histidine at the 93rd position of the globin
chain
➢ If you have Hgb Gun Hill → His at 93rd position will
go missing (deleted) → heme will not attach to the
globin chain
➢ This results in impaired heme binding, and the
abnormal molecule lacks half the expected number
of heme groups. These structural alterations are
probably responsible for the instability of the
abnormal hemoglobin. →ANEMIA
Types of Mutations:
Frameshift Mutation

➢ Upper part: Normal HEXA gene

➢ Tay-Sachs disease: there is an insertion of 4
nucleotide bases after the TC bases in the normal
HEXA gene → changed reading frame
➢ Upper part: normal DNA
➢ Reading frame: every codon that will be read
➢ Point mutation
o 2nd pic: C is changed to G
o Will not affect the reading frame
o Even if the 2nd codon is affected, the
reading of the succeeding codons will still
be the same
➢ Lower part
o Thymine was removed from the DNA
o C & A from the 2nd reading frame will not
have a 3rd member → C from the 3rd
reading frame will now be a part of the 2nd
reading frame → 2nd reading frame: CAC ➢ Food particles engulfed by the cell → enclosed in a
o Next reading frame will not be CAT → but food vacuole → fuse with lysosomes (for the
ATC particles to be exposed to the digestive enzymes of
o Reading frame is disrupted/ change in the lysosomes)
reading frame = FRAMESHIFT MUTATION ➢ If particle inside the vacuole is ganglioside, the
lysosome is expected to digest it using
 Type of mutation involving the insertion or hexosaminidase enzyme → if you have Tay-Sachs,
deletion of a nucleotide that disrupts this you cannot digest the gangliosides
reading frame
 The entire DNA sequence following the mutation
will be read incorrectly. A frameshift mutation will in
general cause the reading of the codons after the
mutation to code for different amino acids.

TAY-SACHS DISEASE
 Lysosomal storage disease
o Lysosomes contains numerous
digestive enzymes; to digest anything
that the cell engulfed/ eaten
 Genetic disorder that results in the destruction
of nerve cells in the brain and spinal cord. It is ➢ Left: normal neuron (lots of dendrites; cytoplasm is
caused by the absence of a hexosaminidase dark because of Nissl bodies)
enzyme that helps break down fatty ➢ Right: neuron of someone with Tay-Sachs disease
substances. These fatty substances, called o Large space within the cytoplasm that
gangliosides, build up to toxic levels in the appears clear = gangliosides
child's brain and affect the function of the nerve o Build up of gangliosides → death of
cells (neurons) → mental retardation neurons
 hexosaminidase enzyme – protein → made up
of specific sequence of amino acids →
changing the reading frame → change the type
of AA in the hexosaminidase enzyme → non
functional
Types of Mutations:
Chemokine receptor (CCR5) mutation

➢ another example of frameshift mutation

➢ Retrovirus with GP120 → targets cells in the body
that have CD4 receptors → binding is not enough
for the virus to enter the cell → because there are
co receptors (CCR5)

➢ GP120 is used to bind with

CD 4
➢ Some of the GP120 will
bind to co-receptors (CCR5,
CXCR4)
➢ After binding to both CD4
and CCR5, virus will invade
CD4+ T cell

➢ There are people born with frameshift mutation

affecting their chemokine receptor CCR5 →
resistant to HIV infection → virus can’t invade their
T helper cells
➢ Not all mutations can cause diseases → some can
provide benefits
➢ Sickle Cell anemia
o Short lifespan of RBCs → can’t serve as
host cell for the development of
Plasmodium species → do not suffer from
severe infection with Malaria