Mechanisms of genetic variation

DNA, the hereditary material of life

 Mutations
Mutation - any change in the DNA sequence, or in chromosome
number, form or structure.

Everyone acquires some changes to their DNA during their lifetime

Original sequence

Mutant sequence
 Types of mutations

For protein coding regions in the DNA, DNA

alterations may cause:
1. Substitution mutations
2. Frameshift mutations

For non protein coding sequences, DNA

alterations may produce changes in patterns
of gene expression.
 Substitution mutations
mutation that exchanges one base for another
The genetic code
 3 types of substitution mutation
Original DNA codon: 3-ACG-5
mRNA codon: 5-UGU-3
1. Missense: codon change produces a different amino acid

2. Silent: codon change produces the same amino acid

3. Nonsense: codon results in a "stop" codon

 Types of mutations
Insertion - mutation in which extra base pairs are inserted into a
new place in the DNA.

Deletion - mutations in which a section of DNA is lost or deleted

 Effect of insertion and deletion
mutations: frameshifts

Insertions and deletions can alter a gene so that its message is

no longer correctly divided.
frameshifts
Frameshift mutations generate incorrect or truncated proteins
Effect of frameshift mutations on
protein sequence
A

B
 Sources of mutations

Replication errors
Chemical agents
Physical agents
UV
Biological agents
viruses
The DNA double helix acts as a template
for its own duplication
 Chemical mutagens
Base analogs
can be incorporated into DNA and form transient
tautomers
Can lead to transition mutations

Base modifiers
Chemically modify DNA bases

DNA intercalators
slip in between adjacent base pairs in dsDNA
lead to the insertion or deletion of one or more base pairs
Results in frameshift mutations
Mechanism of mutation
induced by 5-bromouracil, a
base analog
 Mutagen metabolism
Aflatoxin, produced by molds that grow on
peanuts, is activated by cytochrome p450 to
form a highly reactive mutagenic compound
 Base modification

Treatment of DNA with nitrous acid results in the

conversion of adenine into hypoxanthine.
Hypoxanthine pairs with cytosine, inducing a transition
from A-T to G-C.
Base modifying agents
 Intercalating agents

Acridine dyes induce frameshift mutations by intercalating into

the DNA, leading to the incorporation of an additional base on
the opposite strand.
 UV light produces pyrimidine dimers

Ultraviolet light induces cross-links between adjacent pyrimidines

Pyrimidine dimer cannot fit into a double helix
Replication, gene expression blocked until the lesion is removed
Viruses: biological mutagens
Upon entry into host cell, viral
genome has two possible fates:

1. Lysogeny
Genetic material is integrated
into the host chromosome

2. Lysis
Genetic material not
incorporated into host
chromosome
Directs host cell to make virus
proteins
Results in cell lysis
Integration of viral
genome into host
genome

May result in gene

alteration
 Human papilloma viruses (HPV)

Extremely common sexually transmitted infections

In >90% of cases, the infections are harmless and go away

without treatment

HPV a risk factor for cervical cancer because of its ability to

interfere with normal gene expression

HPV vaccine targets certain sexually transmitted strains of

HPV
Gardasil
Cervarix
How certain papillomaviruses are thought to give rise
to cervical cancer
 DNA repair mechanisms

All cells possess mechanisms to repair

damaged DNA
4 types of repair pathways:
1. direct repair
2. base-excision repair
3. nucleotide-excision repair
4. mismatch repair
Table 5-2. Inherited Syndromes with Defects in DNA Repair

NAME PHENOTYPE ENZYME OR PROCESS

AFFECTED
MSH2, 3, 6, MLH1, colon cancer mismatch repair
PMS2
Xeroderma skin cancer, cellular UV nucleotide excision-repair
pigmentosum (XP) sensitivity, neurological
groups AG abnormalities
XP variant cellular UV sensitivity translesion synthesis by
DNA polymerase
Ataxiatelangiectasia leukemia, lymphoma, cellular ATM protein, a protein
(AT) -ray sensitivity, genome kinase activated by double-
instability strand breaks
BRCA-2 breast and ovarian cancer repair by homologous
recombination
Werner syndrome premature aging, cancer at accessory 3-exonuclease
several sites, genome and DNA helicase
instability
Bloom syndrome cancer at several sites, accessory DNA helicase for
stunted growth, genome replication
instability
Fanconi anemia congenital abnormalities, DNA interstrand cross-link
groups AG leukemia, genome instability repair
46 BR patient hypersensitivity to DNA- DNA ligase I
damaging agents, genome
instability
 Antioxidants
Aging and chronic diseases, e.g., heart
disease and cancer, believed to result from
damage caused by free radicals

Free radicals activity combated by

antioxidants
molecules or atoms with an extra electron
extra electrons stabilize, neturalize free radicals
 Antioxidant defense system

Includes vitamins E and

C, and the carotenoids
(pigments present in
colored vegetables and
some colored fruits)

Higher intakes of these

nutrients are associated
with lower rates of
cancer and
cardiovascular disease
 Mutation effects depend on affected
cell type
1. Somatic mutations - occur in non-reproductive cells and
won't be passed on to offspring.
e.g., the golden color on half of this Red Delicious apple was caused
by a somatic mutation. Its seeds will not carry the mutation.

2. Germline mutations - occur in reproductive cells like eggs

and sperm

The only mutations that matter to evolution are those that can
be passed on to offspring,
i.e., germline mutations.
 Types of mutations
DNA expression mutation

Protein itself is not changed

Effect is on where and how much of a protein is made

1. can result in proteins being made at the wrong time or in

the wrong cell type
2. can also result in too much or too little of the protein
being made.
Mutations in control genes

Mutation in a gene "conductor" can cause a cascade of effects in the

behavior of genes under its control.
Mutations in control genes can substantially change the way the
organism is built.
 Effects of mutations in control genes

Hox, a control gene, designates where the head goes and

which regions of the body grow appendages.
Scientists have studied flies carrying Hox mutations that
sprout legs on their foreheads instead of antennae!
 A single mutation is not enough to
cause cancer
Cancer incidence rises
steeply as a function of
age.
If a single mutation is
required to trigger
cancer and this
mutation had an equal
chance of occurring at
any time, the
incidence would be
independent of age.
A tumor develops through
repeated rounds of
mutation and proliferation
Cancers result from somatic mutation

damage to DNA a fundamental event in

carcinogenesis
Clear correlation for three classes of agents:
1. chemical carcinogens
2. ionizing radiations such as x-rays
3. viruses
 Cancer and gene mutations
Three classes of genes are frequently mutated in
cancer:
1. Proto-oncogenes
2. Tumor suppressor genes
3. DNA repair genes

Genes involved in metabolism also modulate

cancer risk
 Proto - oncogenes
Stimulate normal cell development
When mutated, converted into oncogenes
Abnormal protein activity promotes abnormal cell growth,
proliferation
e.g., K-ras, c-myc
 Tumor suppressor genes
Negative effect on regulation of the cell cycle, cell
division and differentiation
May also induce apoptosis
e.g., p53
Mutational events in
colorectal cancer
development
OMIM-175100
 Mutations are random, not directed

Mutations can be beneficial, neutral, or harmful for the

organism, BUT do not "try" to supply what the organism
"needs."
Factors in the environment may influence the rate of
mutation but do not influence the direction of mutation.
e.g., exposure to harmful chemicals may increase the mutation rate,
but will NOT cause more mutations that make the organism resistant to
those chemicals.

THEREFORE, mutations are random whether a particular

mutation happens or not is unrelated to how useful that
mutation would be.
Sickle cell anemia: a case study of the
effects of mutation

Sickle cell anemia: a genetic disease with severe

symptoms, including pain and anemia

The disease is caused by a mutated version of the

gene that helps make hemoglobin a protein that
carries oxygen in red blood cells (RBCs).

Gene is homozygous recessive

 Sickle cell anemia: a case study
There are effects at the DNA level

There are effects at the protein level

The mutation in the DNA slightly

changes the shape of the hemoglobin
molecule, allowing it to clump together.
 Sickle cell anemia: a case study

There are effects at the cellular level

When RBCs carrying mutant hemoglobin are
deprived of oxygen, they become "sickle-shaped" .
This shape can sometimes interrupt blood flow.

There are negative effects at the whole organism

level
Under conditions such as high elevation and Normal red blood cells
intense exercise, a carrier of the sickle cell allele
may occasionally show symptoms such as pain and
fatigue.

There are positive effects at the whole organism

level
Carriers of the sickle cell allele are resistant
to malaria, because the parasites that cause this
disease are killed inside sickle-shaped blood cells.
sickle cells