Ch7_Mutation- types and its effects.ppt

SBB 1054 Genetics
Prepared by Pratheep Sandrasaigaran
Lecturer at Manipal International University
1

Lecturer at Manipal International University
7.0 Mutation- types
and its effects
2

By the end of this chapter
you should be able to:
• Getting to the root of mutation
• Grasping how mutations occur
• Realise the consequences of mutation
and repair mechanism
Diagram adopted from Internet Sources
3

7.1 Introduction
4

Mutation
• Simply genetic change, is responsible for all
phenotypic variation.
– Variation in flower colors and plant height
– The flavor of different varieties of apples
– The differences among dog breeds
5
Mutation is good..!!???

Mutation
• Mutation occurs all the time, spontaneously
and pretty much randomly.
• Mutation can also be bad. It can disrupt
normal gene activity and cause disease such
as cancer and birth defects.
6

7.2 Types of Mutations
7

Somatic mutations
Germ-cell mutations
Mutation
• Somatic cell
• Not heritable
• Affect the person with the
mutation
• Mutations in the sex cells
• Heritable
• No affect on parents
8

General sense in Mutations
• Substitutions of one base for another: Point
mutations.
– Two categories
• Transition mutation
• Transversion mutation
• Insertions and deletions of one or more
bases
9

• Purine base is substituted for
the other purine
• Pyrimidine is substituted for
the other pyrimidine
• Most common form of
substitution errors
• Purine replaces a pyrimidine
• Pyrimidine replaces a purine
Transition mutation
Transversion mutation
Point mutations
10

Insertions and deletions of one
or more bases
• Insertion- an extra base is added to a strand.
• Deletion- dropping a base from a strand.
• Insertions and deletions can lead to a shift in the
reading frame in the genetic code during
translation… WHY?
• Frameshift mutation results in a completely
different interpretation of what the code and
produces an entirely different amino acid strand
11

Insertions and deletions of one
or more bases
• What happen if three bases are added or
deleted, will the reading frame be affected?
• The result of a three-base insertion or deletion,
called an in-frame mutation, is that one amino
acid is either added (insertion) or lost (deletion).
• In-frame mutations can be just as bad as
frameshift mutations.
12

TEST YOUR KNOWLEDGE 1
13

1. Discuss the importance of mutations in genetic
studies.
2. Most mutations are thought to be deleterious.
Why, then, is it reasonable to state that
mutations are essential to the evolutionary
process?
14

7.3 Uncovering Causes of
Mutation
15

• Mismatches during
replication
• Strand slipups
• Spontaneous chemical
changes
• Chemical mutagens
• Radiation
Spontaneous mutations
Induced mutations
Causes of mutations
16

Spontaneous mutations
• It’s a natural, normal occurrence.
• Because the vast majority of your DNA doesn’t
code for anything, most spontaneous mutation
goes unnoticed…. WHY?
• But when mutation occurs within a gene, the
function of the gene can be changed or
disrupted.
17

Most
spontaneous
mutation
goes
unnoticed….
WHY
18

• Most DNA is not
part of the gene
• App 41% are genetic
parasite repeats
• 8% have similar
characteristics of
genetic parasite
repeats.
• 20% no idea what is
their funtion
• 28% of DNA is gene
inclusive of introns
19

20

a. Mismatches during
replication
• Usually, mistakes made during DNA replication are
fixed by DNA polymerase.
• Three task of DNA polymerase:
– Reading the template.
– Adding the appropriate complementary base
to the new strand.
– Proofreading the new base before moving to
the next base on the template.
21

replication
• DNA polymerase can snip out erroneous bases
and replace them, but occasionally, a wrong
base escapes detection.
• Such an error is possible because non-
complementary bases can form hydrogen
bonds through wobble pairing.
22

Wobble base pairing allows mismatched bases to form bonds.
Diagram adopted from Genetics for Dummies. Tara. R.R
replication
23

replication
1. A mismatched base pair
creates a permanent change
in the DNA with one round of
replication.
2. Mistake is perpetuated
after the next round of
replication
3. The mistaken base is read as
part of the template strand,
and its complement is added
to the newly replicated strand
opposite
4. Mutation is
permanently added to
the structure of the DNA
24

b. Strand slipups
• Strand slippage is associated with repeating bases,
e.g. AAAAAA or AGTAGTAGT.
• Normally both strands of DNA are copied more or
less at the same time during replication.
• Either the template or the newly synthesized
strand can form a loop in a process called strand
slippage
25

b. Strand slipups
Strand slippage causes loops to form during replication, resulting
in deletions or insertions
26

b. Strand slipups
• If strand slippage occur at the noncoding region
(junk DNA), and the variation’s useful for
determining individual identity; the basis for DNA
fingerprinting.
• However If strand slippage occur within genes may
leads to a stronger effect of the genetic disorders.
• Strand slippage result into repeated bases which
may lead to unequal crossing-over due to many
similar bases that match.
27

c. Spontaneous chemical
changes
• DNA can undergo spontaneous changes in its
chemistry that result in both deletions and
substitutions.
• Cause of the deletions and substitutions:
– Apurination
– Deamination
28

i. Apurination
• DNA naturally loses purine bases at times in a
process called apurination.
• Most often, a purine is lost when the bond
between adenine and the sugar, deoxyribose, is
broken.
• When a purine is lost, replication treats the spot
occupied by the orphaned sugar as if it never
contained a base at all, resulting in a deletion.
29

ii. Deamination
• An amino group is lost from a base.
30

ii. Deamination
• When cytosine loses its amino group, it’s
converted to uracil.
• If uracil appears in a DNA strand, replication
replaces the uracil with a thymine, creating a
substitution error.
• What happen when this strand undergoes DNA
replication?
31

32

33
1. Somatic mutation is the mutations that happen
in the sex cells.
2. Two type of point mutation; Transition mutation
and Transversion mutation.
3. Induced mutation may happen due to
mismatches during replication and during
strand slipups.
4. DNA polymerase functions to proofread the
new base before moving to the next base on the
template.
5. Strand slipups may happen both in new strand
and the template strand.

1. Why are X rays more potent mutagens than UV
radiation?
2. Speculate on how improved living conditions and
medical care in the developed nations might affect
human mutation rates, both neutral and deleterious.
3. What is a spontaneous mutation, and why are
spontaneous mutations rare?
4. Differentiate apurination and deamination.
34

Induced mutations
• A mutagen is any factor that causes an increase
in mutation rate.
• Mutagens may or may not have phenotypic
effects
• It depends on what part of the DNA is affected.
35

Induced mutations
Chemical mutagens
Base analogs
Alkylating agents
Unusually reactive
forms of oxygen
Intercalating
agents
Radiation
36

a. Chemical mutagens- Base
analogs
• Base analogs are chemicals that are
structurally very similar to the bases
normally found in DNA.
• Base analogs can get incorporated into
DNA during replication.
• 5-Bromouracil (5BU), is almost identical
to the base thymine pairs with adenine
during replication.
37

analogs
• The problem arises when DNA replicates
again with 5BU as part of the template
strand; 5BU’s mistaken for a cytosine and
gets miss-paired with guanine.
• Can you comprehend the whole event?
38

analogs
1. 5BU is incorporated where thymine used to be.
2. So instead T-A, it becomes 5BU-A.
3. After one round of replication, the pair is 5BU-G
because 5BU is prone to chemical changes that
make it a mimic of cytosine and paired to
guanine.
4. After a second round of replication, the pair ends
up as C-G because 5BU isn’t found in normal
DNA.
A-T
C-G
39

analogs
40
Diagram adopted from Benjamin A. Pierce

analogs
• Another class of base analog chemicals that
foul up normal base pairing is deaminators.
• Where do you see deamination happens?
• Deamination can get speeded up when cells
are exposed/ induced to certain chemicals
• What the effect of deamination?
41

b. Chemical mutagens-
Alkylating agents
• Like base analogs, alkylating agents induce
miss-pairings between bases.
• Alkylating agents, such as the chemical
weapon mustard gas, add chemical groups to
the existing bases that make up DNA.
• As a consequence, the altered bases pair with
the wrong complement, thus introducing the
mutation.
• Hence Alkylating agents are good or bad?
42

b. Chemical mutagens-
Alkylating agents
• Surprisingly, alkylating agents are often used to
fight cancer as part of chemotherapy.
• Therapeutic versions of alkylating agents may
inhibit cancer growth by interfering with the
replication of DNA in rapidly dividing cancer
cells.
43

c. Chemical mutagens- Unusually
reactive forms of oxygen
• Some forms of oxygen, called free radicals, are
unusually reactive, meaning they react readily with
other chemicals.
• Free radicals can damage DNA directly (by causing
strand breaks)
• Free radicals can convert bases into new unwanted
chemicals that, like most other chemical mutagens,
then cause miss-pairing during replication.
44

c. Chemical mutagens- Unusually
reactive forms of oxygen
• Free radicals of oxygen occur normally in your body
as a product of metabolism, but most of the time,
they don’t cause any problems.
• How to increase free radicals in your system (If you
keen to)?
– Cigarette smoking
– High exposure to radiation
– Pollution
– Weed killers
45

d. Chemical mutagens-
Intercalating agents
• Many different kinds of chemicals wedge
themselves between the stacks of bases in double
helix .
• This disrupting the shape of the double helix.
• Chemicals with flat ring structures, such as dyes,
are prone to intercalate themselves between
bases.
46

d. Chemical mutagens-
Intercalating agents
• Intercalating agents create bulges in the
double helix that often result in insertions
or deletions during replication, which in
turn cause frameshift mutations
47

Radiation Exposure in Humans
48

• People are routinely exposed to low levels of
radiation from cosmic, medical, and environmental
sources.
• On August 6, 1945, a high-flying American plane
dropped a single atomic bomb on the city of
Hiroshima, Japan.
• The explosion devastated 4.5 square miles of the
city, killed from 90,000 to 140,000 people, and
injured almost as many

• Three days later, the United States dropped an
atomic bomb on the city of Nagasaki, this time
destroying 1.5 square miles of city and killing
between 60,000 and 80,000 people.
• Huge amounts of radiation were released during
these explosions and many people were exposed.
• After the war, a joint Japanese–U.S. effort was made
to study the biological effects of radiation exposure
on the survivors of the atomic blasts and their
children.

• Somatic mutations were examined by studying
radiation sickness and cancer among the survivors.
• Germ-line mutations were assessed by looking at
birth defects, chromosome abnormalities, and gene
mutations in children born to people that had been
exposed to radiation.

Radiation
• Mechanism of radiation DNA damage:
– Radiation can break the strands of the double
helix by knocking out bonds between sugars
and phosphates.
– Radiation causes mutation through the
formation of dimers (di- meaning two, mer
meaning thing).
53

Mutation through the
formation of dimers
Adjacent thymine can bond together to form dimers, which damage the
double helix
54

formation of dimers
• Dimers are unwanted bonds between two
bases stacked on top of each other.
• They’re most often formed when two
thymine in a DNA sequence bind together.
• Thymine dimers can be repaired, but if
damage is extensive, the cell dies.
55

formation of dimers
• When dimers aren’t repaired, the machinery
of DNA replication assumes that two
thymine are present and puts in two
adenines.
• Good or Bad?
• Unfortunately, cytosine and thymine can also
form dimers, so the default repair strategy
sometimes introduces a mutation instead.
56

57

58
1. Base analogs are chemicals that are structurally
very similar to the bases normally found in DNA.
2. Alkylating agents induce miss-pairings between
bases that always have bad implications.
3. Free radicals of oxygen occur normally in your
body as a product of metabolism.
4. Radiation causes mutation through the
formation of dimers.
5. Dimers may only happen between two thymine
bases.

1. Why would a mutation in a somatic cell of a multicellular
organism escape detection?
2. Contrast and compare the mutagenic effects of
deaminating agents, alkylating agents, and base analogs.
3. Contrast the various types of DNA repair mechanisms
known to counteract the effects of UV radiation.
4. What is a mustard gas?
59

7.4 Realizing the consequences of
mutation and repair mechanism
60

Consequences of Mutation
• If the mutation happen and bring no effect,
it’s considered silent.
• Mutations that actually alter the code are
called missense mutations
• A nonsense mutation occurs when a message
to stop translation (called a stop codon) is
introduced into the middle of the sequence
• The introduction of the stop codon usually
means the gene stops functioning altogether
2 Types
Neutral
Functional
change
61

Consequences of Mutation
Silent
Mutation that happen at non-coding region
Missense mutations
Mutation at coding region that cause anomalies
Nonsense
Mutation that stop translation when it introduce a stop codon in the sequence. E.g.
AAG mutated to UAG
62

Consequences of Mutation-
Neutral
• When the amino acid produced from the mutated
gene still creates a fully functional, normal protein.
• E.g. Consider the following sequence in genetic
code.. ‘ACA AGC GGA GAA’ suppose to result into
“Thr-Ser-Gly-Glu”.
• If mutation happen in the second codon .. ‘ACA
AGU GGA GAA’ will still translate as “Thr-Ser-Gly-
Glu”.
• The above is just an example as protein function is
depends on the protein folding.
63

Functional change
• When a new protein is created changes in function
either result gain or loss.
• A gain-of-function mutation creates an entirely new
trait or phenotype; harmless, like a new eye color.
• In other cases, if the gain is decidedly harmful and
usually the effect is autosomal dominant.
• If a mutation causes the gene to stop functioning
altogether or vastly alters normal function, it’s a
loss-of-function mutation.
64

Functional change
• All nonsense mutations are loss-of-function
mutations, but not all loss-of-function mutations
are the result of nonsense mutations.
• loss-of-function mutations is due to frameshift
apart from nonsense mutations.
• Loss-of-function mutations are usually recessive as
unmutated allele is still producing product and they
are able to compensate the mutated allele.
65

Options for DNA Repair
Mismatch
repair
Direct repair Base-excision
repairs
Nucleotide-
excision repair
66

DNA Repair- Mismatch repair
• Incorrect bases are found, removed, and replaced
with the correct complementary base by DNA
polymerase.
• DNA polymerase can back up and correct the error
without missing a beat.
• The mismatch repair enzymes can detect any
differences between the template and the newly
synthesized strand.
• Hence they clip out the wrong base and, using the
template strand as a guide, insert the correct base.
67

DNA Repair- Direct repair
• Bases that are modified and converted back to
their original states.
• Direct repair enzymes look for bases that have
been converted to some new chemical, usually by
the addition of some unwanted group of atoms.
• The enzymes then clip off the atoms that don’t
belong, converting the base back to its original
form.
68

DNA Repair- Base-excision
repairs
• Base-excisions and nucleotide-excisions work in the
same way.
• When an unwanted base (such as uracil) is
recognize by a specialized enzymes, the damage
base is snipped out and replaced with the correct
one.
69

DNA Repair- Nucleotide-
excision repair
• When intercalating agents or dimers distort the
double helix, nucleotide-excision repair
mechanisms step in to
– Snip part the entire nucleotide in the strand
– Remove the damage
– Synthesize fresh DNA (DNA polymerase) to
replace the damaged section.
– DNA ligase seals the breaks in the strand to
complete the repair process
• The mechanism is aided by specialized enzymes
recognizing the damaged section of the DNA
70

DNA Repair-
Nucleotide-
excision repair
71

DNA Repair-
Nucleotide-
excision repair
72

Ch7_Mutation- types and its effects.ppt

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