2. INTRODUCTION
The term mutation refers to a heritable change in
the genetic material
Mutations provide allelic variations
On the positive side, mutations are the foundation for
evolutionary change
E.g. Light skin in high latitude human populations
On the negative side, mutations are the cause of many
diseases
E.g. Hemophilia
4. Mutations can be divided into three main types
1. Chromosome mutations
Changes in chromosome structure
2. Genome mutations
Changes in chromosome number
3. Single-gene mutations
Relatively small changes in DNA structure that occur within a
particular gene
Types 1 and Type 2 had discussed in aberration
Type 3 will be discussed in this set of lecture notes
16.1 CONSEQUENCES OF
MUTATIONS
5. A point mutation is a change in a single base pair
It involves a base substitution
Gene Mutations Change the DNA
Sequence
5’ AACGCTAGATC 3’
3’ TTGCGATCTAG 5’
5’ AACGCGAGATC 3’
3’ TTGCGCTCTAG 5’
A transition is a change of a pyrimidine (C, T) to
another pyrimidine or a purine (A, G) to another purine
A transversion is a change of a pyrimidine to a purine
or vice versa
Transitions are more common than transversions
6. Mutations may also involve the addition or deletion
of short sequences of DNA
Gene Mutations Change the DNA
Sequence
5’ AACGCTAGATC 3’
3’ TTGCGATCTAG 5’
5’ AACGCTC 3’
3’ TTGCGAG 5’
5’ AACGCTAGATC 3’
3’ TTGCGATCTAG 5’
5’ AACAGTCGCTAGATC 3’
3’ TTGTCAGCGATCTAG 5’
Deletion of four base pairs
Addition of four base pairs
7. Mutations in the coding sequence of a structural
gene can have various effects on the polypeptide
Silent mutations are those base substitutions that do
not alter the amino acid sequence of the polypeptide
Due to the degeneracy of the genetic code
Missense mutations are those base substitutions in
which an amino acid change does occur
Example: Sickle-cell anemia
If the substituted amino acid does not affect protein function (as
measured by phenotype), the mutation is said to be neutral
Gene Mutations Can Alter the
Coding Sequence Within a Gene
8. Mutations in the coding sequence of a structural
gene can have various effects on the polypeptide
Gene Mutations Can Alter the
Coding Sequence Within a Gene
Nonsense mutations are those base substitutions that
change a normal codon to a termination codon
Frameshift mutations involve the addition or deletion of
nucleotides in multiples of one or two
This shifts the reading frame so that a completely different amino
acid sequence occurs downstream from the mutation
Table 16.1 describes all of the above mutations
9.
10. In a natural population, the wild-type is the most
common genotype (may be encoded by a
dominant or recessive allele)
A forward mutation changes the wild-type
genotype into some new variation
If it is beneficial, it may move evolution forward
Otherwise, it will be probably eliminated from a
population
A reverse mutation has the opposite effect
It is also termed a reversion
Gene Mutations and Their Effects on
Genotype and Phenotype
11. Mutations can also be described based on their
effects on the wild-type phenotype
When a mutation alters an organism’s phenotypic
characteristics, it is said to be a variant
Variants are often characterized by their differential
ability to survive
Deleterious mutations decrease the chances of survival
The most extreme are lethal mutations
E.g. Homozygous polydactyly in cats
Beneficial mutations enhance the survival or
reproductive success of an organism
Some mutations are called conditional mutants
They affect the phenotype only under a defined set of
conditions
12. A second mutation will sometimes affect the
phenotypic expression of another
These second-site mutations are called
suppressor mutations or simply suppressors
Suppressor mutations are classified into two types
Intragenic suppressors
The second mutant site is within the same gene as the first
mutation
Intergenic suppressors
The second mutant site is in a different gene from the first
mutation
13. Several human genetic diseases are caused by an
unusual form of mutation called trinucleotide repeat
expansion (TNRE)
The term refers to the phenomenon that a sequence of 3
nucleotides can increase from one generation to the next
Mutations Due to Trinucleotide
Repeats
14. Certain regions of the chromosome contain
trinucleotide sequences repeated in tandem
In normal individuals, these sequences are transmitted
from parent to offspring without mutation
However, in persons with TRNE disorders, the length of a
trinucleotide repeat increases above a certain critical size
It also becomes prone to frequent expansion
This phenomenon is shown here with the trinucleotide repeat
CAG
CAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG
CAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG
n = 11
n = 18
15. In some cases, the expansion is within the coding
sequence of the gene
Typically the trinucleotide expansion is CAG (glutamine)
Therefore, the encoded protein will contain long tracks of
glutamine
This causes the proteins to aggregate with each other
This aggregation is correlated with the progression of the disease
In other cases, the expansions are located in
noncoding regions of genes
These expansions are hypothesized to cause abnormal
changes in RNA structure
Thereby producing disease symptoms
16. A chromosomal rearrangement may affect a gene
because the break occurred in the gene itself
A gene may be left intact, but its expression may be
altered because of its new location
This is termed a position effect
There are two common reasons for position effects:
1. Movement to a position next to regulatory sequences
Refer to Figure 16.2a
2. Movement to a position in a heterochromatic region
Refer to Figure 16.2b AND 16.3
Changes in Chromosome Structure
Can Affect Gene Expression
18. Geneticists classify the animal cells into two types
Germ-line cells
Cells that give rise to gametes such as eggs and sperm
Somatic cells
All other cells
Germ-line mutations are those that occur directly in a
sperm or egg cell, or in one of their precursor cells
Refer to Figure 16.4a
Somatic mutations are those that occur directly in a
body cell, or in one of its precursor cells
Refer to Figure 16.4b AND 16.5
Mutations Can Occur in
Germ-Line or Somatic Cells
19. Figure 16.4
Therefore, the
mutation can be
passed on to future
generations
The size of the patch
will depend on the
timing of the mutation
The earlier the mutation,
the larger the patch
An individual who has
somatic regions that are
genotypically different
from each other is called
a genetic mosaic
Therefore, the mutation cannot be
passed on to future generations
20. Mutations can occur spontaneously or be induced
Spontaneous mutations
Result from abnormalities in cellular/biological processes
Errors in DNA replication, for example
Induced mutations
Caused by environmental agents
Agents that are known to alter DNA structure are termed
mutagens
These can be chemical or physical agents
Refer to Table 16.4
16.2 OCCURRENCE AND CAUSES
OF MUTATION
21.
22. Are mutations spontaneous occurrences or
causally related to environmental conditions?
This is a question that biologists have asked
themselves for a long time
Jean Baptiste Lamarck
Proposed that physiological events (e.g. use and disuse)
determine whether traits are passed along to offspring
Charles Darwin
Proposed that genetic variation occurs by chance
Natural selection results in better-adapted organisms
Spontaneous Mutations Are Random
Events
23. These two opposing theories of the 19th century
were tested in bacteria in the 1940s and 1950s
Salvadore Luria and Max Delbruck studied the
resistance of E. coli to bacteriophage T1
tonr
(T one resistance)
They wondered if tonr
is due to spontaneous mutations
or to a physiological adaptation that occurs at a low
rate?
The physiological adaptation theory predicts that the number of
tonr
bacteria is essentially constant in different bacterial
populations
The spontaneous mutation theory predicts that the number of
tonr
bacteria will fluctuate in different bacterial populations
Their test therefore became known as the fluctuation test
24. Joshua and Ester Lederberg were also interested in
the relation between mutations and the environment
At that time (1950s), there were two new theories
Directed mutation theory
Selected conditions could promote the formation of specific
mutations allowing the organism to survive
This was consistent with Lamarck’s viewpoint
Random mutation theory
Environmental factors simply select for the survival of those
individuals that happen to possess beneficial mutations
This was consistent with Darwin’s viewpoint
Random Mutations Can Give an
Organism a Survival Advantage
25. Figure 16.7 Replica plating
A few tonr
colonies were
observed at the same
location on both plates!!!
This indicates that mutations
conferring tonr
occurred
randomly on the primary
(nonselective plate)
The presence of T1 in the
secondary plates simply
selected for previously
occurring tonr
mutants
This supports the random
mutation theory
The Lederbergs developed
a technique to distinguish
between these two theories
26. Spontaneous mutations can arise by three types
of chemical changes
1. Depurination
2. Deamination
3. Tautomeric shift
Causes of
Spontaneous Mutations
The most common
27. Depurination involves the removal of a purine
(guanine or adenine) from the DNA
The covalent bond between deoxyribose and a purine
base is somewhat unstable
It occasionally undergoes a spontaneous reaction with water
that releases the base from the sugar
This is termed an apurinic site
Fortunately, apurinic sites can be repaired
However, if the repair system fails, a mutation may result
during subsequent rounds of DNA replication
Causes of Spontaneous Mutations
29. Deamination involves the removal of an amino
group from the cytosine base
The other bases are not readily deaminated
Figure 16.9
DNA repair enzymes can recognize uracil as an
inappropriate base in DNA and remove it
However, if the repair system fails, a C-G to A-T mutation will result
during subsequent rounds of DNA replication
30. Deamination of 5-methyl cytosine can also occur
Thymine is a normal constituent of DNA
This poses a problem for repair enzymes
They cannot determine which of the two bases on the two DNA
strands is the incorrect base
For this reason, methylated cytosine bases tend to create
hot spots for mutation
Figure 16.9
31. A tautomeric shift involves a temporary change in
base structure (Figure 16.10a)
The common, stable form of thymine and guanine is the
keto form
At a low rate, T and G can interconvert to an enol form
The common, stable form of adenine and cytosine is the
amino form
At a low rate, A and C can interconvert to an imino form
These rare forms promote AC and GT base pairs
Refer to Figure 16.10b
For a tautomeric shift to cause a mutation it must
occur immediately prior to DNA replication
Refer to Figure 16.10c
35. An enormous array of agents can act as mutagens
to permanently alter the structure of DNA
The public is concerned about mutagens for two
main reasons:
1. Somatic mutagens are often involved in the
development of human cancers
2. Germ-line mutations may have harmful effects in
future generations
Mutagenic agents are usually classified as
chemical or physical mutagens
Refer to Table 16.5
Types of Mutagens
37. Chemical mutagens come into three main types
1. Base modifiers
2. Intercalating agents
3. Base analogues
Mutagens Alter DNA Structure in
Different Ways
38. Base modifiers covalently modify the structure of
a nucleotide
For example, nitrous acid, replaces amino groups with
keto groups (–NH2 to =O)
This can change cytosine to uracil and adenine to
hypoxanthine
Refer to Figure 16.1
39. Mispairing of modified basesFigure 16.13
These mispairings
create mutations in the
newly replicated strand
40. Intercalating agents contain flat planar structures
that intercalate themselves into the double helix
This distorts the helical structure
When DNA containing these mutagens is replicated, the
daughter strands may contain single-nucleotide additions
and/or deletions
Examples:
Acridine dyes
Proflavin
Ethidium bromide
41. Base analogues become incorporated into
daughter strands during DNA replication
For example, 5-bromouracil is a thymine analogue
It can be incorporated into DNA instead of thymine
Figure 16.14
Normal pairing
This tautomeric shift
occurs at a relatively
high rate
Mispairing
42. Figure 16.14
In this way, 5-bromouracil can promote a change
of an AT base pair into a GC base pair
43. Physical mutagens come into two main types
1. Ionizing radiation
2. Nonionizing radiation
Ionizing radiation
Includes X rays and gamma rays
Has short wavelength and high energy
Can penetrate deeply into biological molecules
Creates chemically reactive molecules termed free
radicals
Can cause
Base deletions
Single nicks in DNA strands
Cross-linking
Chromosomal breaks
44. Nonionizing radiation
Includes UV light
Has less energy
Cannot penetrate deeply
into biological molecules
Causes the formation of
cross-linked thymine
dimers
Thymine dimers may
cause mutations when that
DNA strand is replicated
Figure 16.15
45. Gene recombination originate as a result of
Crossing over
Orientation of chromosome during cell division
Random fusion of male and female gametes
during fertilization
Read detail from book Pinciples of botany
pg#472
Gene recombination
46. The rate of cancer increases with age
Diseases caused by new point mutations usually
come from the father
Testicular tissues undergoes many more rounds of DNA
replication than ovarian tissue prior to meiosis
Cancers develop when one mutation promotes
DNA replication and cell division
This promotes additional mutations
Some of the new mutations further promote DNA replication and
cell division (or mutate genes that down-regulated replication
and cell division)
This process continues to produce a malignant tumor
DNA Replication itself is mutagenic