Human Genetics

Concepts and Applications

Tenth Edition
RICKI LEWIS

Gene
12 Mutation
PowerPoint® Lecture Outlines
Prepared by Johnny El-Rady, University of South Florida

Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display
 The Nature of Mutations
A mutation is change in a DNA sequence
that is present in < 1% of a population
May occur at the DNA or chromosome level
A polymorphism is a genetic change that
is present in > 1% of a population
The effect of mutations vary
“Loss-of-function” mutations – Recessive
“Gain-of-function” mutations – Dominant
2
 The Nature of Mutations

The term mutant refers to phenotype

- Usually connotes an abnormal or
unusual, or even uncommon variant that
is nevertheless “normal”
Mutations are important to evolution
Our evolutionary relatedness to other
species allows us to study many
mutations in non-human species
3
Figure 12.1
4
 The Nature of Mutations
Germline mutations
- Originate in meiosis
- Affect all cells of an individual

Somatic mutations
- Originate in mitosis
- Affect only cells that descend from
changed cell
5
 Mutations Alter Proteins

Identifying how a mutation causes

symptoms has clinical applications

Examples of mutations that cause

disease:
- Beta globin gene
- Collagen genes

6
 Sickle Cell Anemia
Results from a single DNA base change in the
b-globin gene, which replaces glutamic acid
(6th position) with valine
Phenotype associated with homozygotes
Altered surface of hemoglobin allows molecules
to link in low oxygen conditions
Creates sickle shape of RBC
Sickling causes anemia, joint pain, and organ
damage when RBC become lodged in small
blood vessels
7
Figure 12.2

8
 Thalassemia
Caused by another beta hemoglobin mutation
Too few beta globin chains
Excess of alpha globin prevents formation of
hemoglobin molecules
So RBCs die
Liberated iron slowly damages heart, liver, and
endocrine glands
Thalassemia minor (heterozygous)
Thalassemia major (homozygous for mutation
and more severe)
9
 Collagen
A major component of connective tissue
- Bone, cartilage, skin, ligament, tendon,
and tooth dentin

More than 35 collagen genes encode more

than 20 types of collagen molecules

Mutations in these genes lead to a variety

of medical problems
10
Collagen Disorders

11
Collagen has a precise structure
- Triple helix of two a1 and one a2
polypeptides
- Longer precursor, procollagen is
trimmed to form collagen Figure 12.3

12
 Ehler-Danos Syndrome
A mutation prevents procollagen chains
from being cut
Collagen molecules cannot assemble, and
so skin becomes stretchy

Figure 12.4
Figure 12.4

13
How Mutations Cause Disease

Mutations in a gene may cause either

different versions of the same disease
or distinct illnesses

Table 12.2 lists several examples of

mutations and the diseases theyFigure 12.4
produce

14
How Mutations Cause Disease

15
 Causes of Mutations

Mutations may occur spontaneously or by

exposure to a chemical or radiation

An agent that causes a mutation is called

a mutagen
Figure 12.4

16
 Spontaneous Mutation

De novo or new mutations

Not caused by exposure to known mutagen
Result from errors in DNA replication
DNA bases have slight chemical instability
Exist in alternating forms called tautomers
Figure 12.4
As replication fork encounters unstable
tautomers, mispairing can occur

17
Figure 12.5

Figure 12.4

18
 Spontaneous Mutation Rate
Rate differs between genes
- Larger genes usually have higher
mutation rates
Each human gene has about 1/100,000
chance of mutating
Each individual has multiple new mutations
Figure 12.4
Mitochondrial genes mutate at a higher rate
than nuclear genes because they cannot
repair their DNA
19
Mutation Rates

20
 Determining Mutation Rate

Estimates of spontaneous mutation rate

can be derived from observation of new,
dominant traits

For autosomal genes,

Figure 12.4
mutation rate = # of new cases/2X
where X = # of individuals examined

21
Table 12.4
22
 Mutational Hot Spots

In some genes, mutations are more likely

to occur in regions called hot spots
Short repetitive sequences
- Pairing of repeats may interfere with
replication or repair enzymes
Figure 12.4
Palindromes
- Often associated with insertions or
deletions
23
DNA symmetry
increases the
likelihood of
mutation
Figure 12.4

Figure 12.6

24
Repeated genes
are prone to
mutation by
mispairing
during meiosis
Figure 12.4

Figure 12.7

25
 Induced Mutations
Caused by mutagens, many are also
carcinogens and cause cancer
Examples:
- Alkylating agents: remove a base
- Acridine dyes: add or remove base
- X rays: break chromosomes
- UV radiation: creates thymine dimers
Figure 12.4

Site-directed mutagenesis: Changes a gene in a

desired way
26
 Ames Test
An in vitro test of the mutagenicity of a substance

One version uses Salmonella bacteria with

mutation in gene for histidine
- Bacteria are exposed to test substance
- Growth on media without histidine is recorded
- Bacteria only grow if mutations haveFigure
occurred
12.4
- Substance can be mixed with mammalian liver
tissue prior to testing to mimic toxin processing
in humans
27
 Exposure to Mutagens
Some mutagen exposure is unintentional
- Workplace
- Industrial accidents
- Chernobyl
- Medical treatments
- Weapons Figure 12.4

- Natural sources
- Cosmic rays, sunlight, earth’s crust
28
Figure 12.8
29
 Types of Mutations
Mutations can be classified in several
ways

- By whether they remove, alter, or add

a function
Figure 12.4
- By exactly how they structurally alter
DNA
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 Point Mutations
A change of a single nucleotide
Transition = Purine replaces purine or
pyrimidine replaces pyrimidine
A to G or G to A or
C to T or T to C
Transversion = Purine replaces pyrimidine
Figure 12.4
or pyrimidine replaces purine
A or G to T or C
T or C to A or G 31
Consequences of Point Mutations

Missense mutation = Replaces one amino

acid with another
Nonsense mutation = Changes a codon
for an amino acid into a stop codon
- Creates truncated proteins that are
often non-functional Figure 12.4
A stop codon that is changed to a coding
codon lengthens the protein

32
 Splice Site Mutations
Alters a site where an intron is normally
removed from mRNA

Can affect the phenotype if:

1) Intron is translated or exon skipped
- Example: CF mutation Figure 12.4
2) Exon is skipped
- Example: Familial dysautonomia (FD)
33
 Deletions and Insertions
The genetic code is read in triplets
Nucleotides changes not in multiples of 3
lead to disruptions of the reading frame
Cause a frameshift mutation and alter
amino acids after mutation
Nucleotide changes in multiples ofFigure
3 will12.4
NOT cause a frame-shift
- But they can still alter the phenotype
34
 Deletions and Insertions
A deletion removes genetic material
- Male infertility: Tiny deletions in the Y
An insertion adds genetic material
- Gaucher disease: Insertion of one base
A tandem duplication is an insertion of
identical sequences side by sideFigure 12.4
- Charcot-Marie-Tooth disease: Tandem
duplication of 1.5 million bases
35
Note: Different types of mutations can cause the
same single-gene disorder
- Example: Familial hypercholesterolemia

Figure 12.4
Figure 12.9

36
 Pseudogenes
A DNA sequence similar to a gene but
which is not translated
May not even be transcribed into RNA
May have evolved from original gene by
duplication and acquired mutation
Crossing over between a pseudogene
Figure 12.4
and functional gene can disrupt gene
expression
37
 Expanding Repeats
Insertion of triplet repeats leads to extra amino
acids
- The longer proteins shut down the cells
Some genes are particularly prone to expansion
of repeats
Number of repeats correlates with earlier onset
and more severe phenotype Figure 12.4
Anticipation is the expansion of the triplet repeat
with an increase in severity of phenotype with
subsequent generations
38
 Myotonic Dystrophy:
A Triplet Repeat Disease

Figure 12.10
Figure 12.10 39
Copy Number Variants (CNV)

Are sequences that vary in number from

person to person
Range in size from a few bases to millions
Account for about 25% of our genome
CNVs may have no effect on the
phenotype or they can disrupt aFigure
gene’s12.4
function and harm health

40
 Copy Number Variants (CNV)

Indeed, CNVs correlated to cholesterol level

might be used to give medical advice

Figure 12.4

Figure 12.11

41
 Importance of Position

The degree that a mutation alters phenotype

depends on:
- Where in the gene the change occurs
- How it affects conformation or expression
of encoded protein
Examples – Hemoglobin and prionsFigure 12.4
- Certain mutations exert effects while
other do not
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 Globin Mutations
Table 12.5

43
 Prion Disorders

A prion disease can be inherited or acquired

The prion protein exists in both normal and

infectious conformations
- The normal form has a central core made
up of helices Figure 12.4

- In a disease-causing form, the helices

open into a sheet
44
 Prion Disorders

The amino acid in 129th position is key to

developing prion disease
Individuals homozygous with valine (VV) or
methionine (MM) develop disease
Heterozygotes have normal function
Position 178 is also important dueFigure
to the12.4
folding of the protein

45
 Not All Mutations
Impact Protein Function
Silent mutations are mutations that do not
alter the encoded amino acid
Example:
- A mutation from CAA to CAG alters the
DNA, but the protein sequence remains
Figure 12.4
unchanged
- CAA and CAG both code for glutamine
- These are called synonymous codons
46
 Not All Mutations
Impact Protein Function
A missense mutation alters the encoded
amino acid to another amino acid
- Creates a nonsynonymous codon
Some nonsynonymous mutations are
conservative; Encode a chemically similar
Figure 12.4
amino acid and may not alter function
The impact of a missense mutation is not
predictable from protein sequence alone
47
A conditional mutation produces a phenotype
under particular conditions or environments
Glucose 6-phosphate dehydrogenase enzyme
responds to oxidants, chemicals that strip
electrons from other molecules
High levels of oxidants occur when eating fava
beans or taking certain antimalarial drugs

Conditions Individuals with G6PD Figure 12.4

mutations
Low oxidants No phenotype
High oxidants RBCs burst; Hemolytic anemia
48
 G6PD Deficiency Hemolytic
Anemia

Figure 12.12
49
 DNA Repair
Errors in DNA replication or damage to DNA
create mutations
- May result in cancer
Fortunately, most errors and damage are
repaired
Type of repair depends upon the type of 12.4
Figure
damage or error
Organisms vary in their ability to repair DNA
50
 Types of DNA Repair

In many modern species, three types of

DNA repair peruse the genetic material

1) Photoreactivation repair
2) Excision repair
Figure 12.4
3) Mismatch repair

51
 Photoreactivation Repair

Enzymes called photolyases use light

energy to break the extra bonds in a
pyrimidine dimer

Enables UV-damaged fungi to recover

from exposure to sunlight Figure 12.4

Humans do not have this type of repair

52
 Excision Repair
Pyrimidine dimers and surrounding bases
are removed and replaced
Humans have two types of excision repair
Nucleotide excision repair
- Replaces up to 30 bases
- Corrects mutations caused by different insults
Figure 12.4
Base excision repair
- Replaces 1-5 bases
- Specific to oxidative damage
53
Excision
Repair

Figure 12.13

Figure 12.13 54
Mismatch Repair
Enzymes detect
nucleotides that do
not base pair in
newly replicated DNA Figure 12.14

The incorrect base is

excised and replaced
Figure 12.4
Proofreading is the
detection of
mismatches
55
 Figure 12.15

Figure 12.15 56
 Failure of DNA Repair
If both copies of a repair gene are mutant,
a disorder can result
The protein p53 monitors repair of DNA
If damage is too severe, the p53 protein
promotes programmed cell death or
apoptosis
Figure 12.4
Mutations may occur in genes encoding
DNA repair proteins
Lead to overall increase in mutations
57
 Repair Disorders:
Trichothiodystrophy
At least five genes are involved

Symptoms reflect accumulating oxidative

damage
Figure 12.4
Faulty nucleotide excision repair or base
excision repair or both
58
 Repair Disorders:
Inherited Colon Cancer
Hereditary nonpolyposis colon cancer

Affects 1/200 individuals

Defect in mismatch repair Figure 12.4

HNPCC gene is on chromosome 2

59
 Repair Disorders:
Xeroderma Pigmentosum
Autosomal recessive;
Seven genes involved
Malfunction of excision
repair Figure 12.16

Thymine dimers remain Figure 12.4

and block replication
Must avoid sunlight
Only 250 cases worldwide
60
 Repair Disorders:
Ataxia Telangiectasis
Autosomal recessive disorder
Defect in cell cycle checkpoint kinase
Cells continue through cell cycle without
pausing to inspect DNA
Individuals with AT have 50X the Figure
risk of12.4
developing over general population
Heterozygotes have a two- to sixfold
increase in cancer risk
61