1. LECTURE 6
Gene Mutation
(Chapter )

2. Words to know… Deleterious: (Adj) Causing harm or damage
Truncated: (Adj) Cut short
Restriction: The state of being limited in purpose or capacity

3. INTRODUCTION Mutation = heritable change to DNA
Wild type allele → mutant allele
Creates an unusual allele
If it occurs with a gene, it is usually deleterious
On the positive side, mutations are the foundation for evolutionary change
On the negative side, mutations are much more likely to be harmful than beneficial to the individual and often are the cause of diseases

5. Mutagen (e.g. UV light)
Gene

6. 16.1 CONSEQUENCES OF MUTATIONS
Mutations can be divided into three main types
1. Chromosome mutations
Changes in chromosome structure
2. Genome mutations
Changes in chromosome number
3. Gene mutations
Relatively small change in DNA structure that affects a single gene
Type 3 will be discussed in this chapter

7. Genome Mutation

8. Chromosomal Mutation

9. Gene Mutation
Small change in DNA sequence not visible on a karyotype

10. Point Mutations A Point mutation is a change of a single base pair
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
Is the above change a transition or a transversion?

11. Effects of Point Mutations
Point 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

12. Effects of Point Mutations
Missense mutations change the amino acid coded by the codon
May be deleterious, beneficial, or neutral
Deleterious example: Sickle-cell anemia Glu →Val

13. Beneficial Example: The sickle cell mutation is also beneficial!
Confers resistance to malaria in heterozygotes

14. Cystic fibrosis (severe) Cystic fibrosis (mild)
Neutral Example: Over 900 mutations have been documented in CFTR gene; many have no phenotypic effect
Cystic fibrosis (severe)
Cystic fibrosis (mild)

15. Nonsense mutations change an amino acid coding codon to a stop codon
Leads to a truncated polypeptide that is usually non-functional

16. Deletion of four base pairs Addition of four base pairs
Additions or deletions affect short sequences of DNA
5’ AACGCTAGATC 3’
3’ TTGCGATCTAG 5’
5’ AACGCTC 3’
3’ TTGCGAG 5’
5’ AACAGTCGCTAGATC 3’
3’ TTGTCAGCGATCTAG 5’
Deletion of four base pairs
Addition of four base pairs

17. Effects of Deletions and Insertions
Deletions and insertions can be divided into
Those that cause reading frame shifts
Number of base-pairs deleted or inserted is not divisible by 3 (e.g. 1, 2, 4, 5…)
Usually result in a truncated non-functional polypeptide with a deleterious phenotype
But can also be neutral of even beneficial
Those that don’t cause reading frame shifts
Number of base-pairs deleted or inserted is divisible by 3 (e.g. 3, 6, 9, 12…)
Usually less harmful than reading frame shift mutations

19. Beneficial Example: Mutation in CD4 receptor on lymphocytes
32 bp deletion results in a reading frame shift; receptor non-functional; prevents HIV virus entry into the cell

21. Gene Mutations outside of coding sequences can affect phenotype
Mutations in the core promoter can change levels of gene expression
Up mutations increase expression. Down mutations decrease expression
Other important non-coding mutations are in Table 16.2

22. Example: Replication error
FIRST OPPORTUNITY FOR DNA REPAIR
SECOND OPPORTUNITY FOR DNA REPAIR
MUTATION IS NOW “FIXED”

23. Other ways to Categorize Mutations
In a natural population, the wild-type is the relatively prevalent genotype. Genes with multiple alleles may have two or more wild-types (variations).
A forward mutation changes the wild-type genotype into some new variation
A reverse mutation changes a mutant allele back to the wild-type
It is also termed a reversion

24. As we’ve seen, they are often characterized by their phenotypic eddect
Mutations can also be described based on their effects on the wild-type phenotype
As we’ve seen, they are often characterized by their phenotypic eddect
Deleterious mutations decrease the chances of survival
The most extreme are lethal mutations
Beneficial mutations enhance the survival or reproductive success of an organism
The environment can affect whether a given mutation is deleterious or beneficial
Some mutations are conditional
They affect the phenotype only under a defined set of conditions
An example is a temperature-sensitive mutation

26. Mutations can also be divided into the type of cells affected
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

27. Copyright © The McGraw-Hill Companies, Inc
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Germ-line
mutation
Gametes
Somatic
mutation
The size of the patch will depend on the timing of the mutation
Embryo
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
Patch of
affected
area
Mutation is
found
throughout
the entire
body.
Mature
individual
Therefore, the mutation can be passed on to future generations
Therefore, the mutation cannot be passed on to future generations
Half of
the gametes
carry the
mutation.
None of
the gametes
carry the
mutation.
Figure 16.4
(a) Germ-line mutation
(b) Somatic cell mutation

29. 16.2 OCCURRENCE AND CAUSES OF MUTATION
Mutations can occur spontaneously or be induced
Spontaneous mutations
Result from abnormalities in cellular/biological processes
Errors in DNA replication, for example
Underlying cause originates within the cell
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

31. Spontaneous Mutations Are Random Events
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: Physiological adaptation theory
Proposed that physiological events (e.g. use and disuse) determine whether traits are passed along to offspring
Charles Darwin: Random mutation theory
Proposed that genetic variation occurs by chance
Natural selection results in better-adapted organisms

32. Random Mutations Can Give an Organism a Survival Advantage
Joshua and Ester Lederberg(1950s) devised an ingenious way to test these alterative theories experimentally
Studied the resistance of E. coli to infection by bacteriophage T1
tonr (T one resistance)
Hypothesis: E. coli cells that survive T1 infection were already resistant to the phage prior to exposure
Due to random mutations
"Replica plating"

33. The Lederbergs' experiment:
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Master plate containing
many colonies that were
grown in the absence of
T1 phage
A velvet cloth (wrapped over a
cylinder) is pressed gently onto the
master plate and then lifted. A little
bit of each bacterial colony adheres
to the velvet cloth, thereby creating
a replica of the arrangement of
colonies on the master plate.
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
Velvet cloth
The replica is then gently pressed
onto 2 secondary plates that
contain T1 phage.
Petri plate
with T1 phage
Petri plate
with T1 phage
Incubate overnight to
allow bacterial growth.
Figure Replica plating