Chapter 2C

Mutation
Objectives:

• understand how errors in DNA replication can give rise

to mutations (substitution, insertion and deletion of
bases)

• know that some mutations will give rise to cancer or

genetic disorders, but that many mutations will have no
observable effect
 Definition of Mutation

Mutation
=
Permanent change in the DNA sequence

Affects one or more than one base pair

•Mutations may result in an altered polypeptide; as

the DNA base sequence of a gene determines the
sequence of amino acids that make up a
polypeptide, mutations in a gene can
sometimes lead to a change in the polypeptide
that the gene codes for.

•Mutations occur spontaneously during DNA

replication
 Chromosome mutations

Chromosome mutations
=
Mutations that alter the

Number Order

of genes on the chromosomes

 Diploid becomes tetraploid  Crossing over during meiosis
eg plant treated w/ colchicine eg rearrangement of gene sequence

 Non-disjunction during meiosis  Homologous recombination

eg Down’s syndrome eg spontaneous or artificial
Three chromosomes 21
 Non-homologous recombination
eg spontaneous or artificial
 Gene mutations

Gene mutations
=
Mutations that alter the

Sequence of genes

The order of the bases inside the genes

eg during DNA replication when proof-reading fails

due to chemicals Agents causing mutations
due to UV =
due to radiations (X-rays) Mutagens
due to expression of some genes (oncogenes)
 Types of Mutations

Mutations

Are inherited only if they occur during

the formation of / in the cells producing
gametes

Do not always have consequences

 Types of Mutations

Three kinds of mutation

Point mutation Insertion Deletion

=
Substitution

One/more than one base pair is

Swapped for removed

another one
added
 Types of Mutations

Normal strand
ATG TTA CCG CAG
Point mutation = Substitution ATG TTT CCG CAG
substituted
 Types of Mutations

Normal strand
ATG TTA CCG CAG
Point mutation = Substitution ATG TTT CCG CAG
substituted
Normal strand
Insertion
ATG TTA CCG CAG
ATG TTG ACC GCA G
added
ATG TTG GCT AGT ACC GCA G
Insertion of nucleotides

•A mutation that occurs when a nucleotide is randomly inserted into the

DNA sequence is known as an insertion mutation

•An insertion mutation changes the amino acid that would have been
coded for by the original base triplet, as it creates a new,
different triplet of bases
• Remember that every group of three bases in a DNA sequence codes
for an amino acid

•An insertion mutation also has a knock-on effect on other base

triplets by changing the triplets further on in the DNA sequence
• This means that insertion mutations cause what is known as
a frameshift mutation; they don't only change the triplet where the
insertion has occurred, but every triplet downstream of the insertion

•This may dramatically change the amino acid sequence

produced from this gene and therefore the ability of the polypeptide to
function
 Types of Mutations

Normal strand
ATG TTA CCG CAG
Point mutation = Substitution ATG TTT CCG CAG
substituted
Normal strand
Insertion
ATG TTA CCG CAG
ATG TTG ACC GCA G
added
ATG TTG GCT AGT ACC GCA G
Normal strand

ATG TTA CCG CAG

ATG TTC CGC AG deleted
Deletion Normal strand

ATG TTA CCG CAG

ATG TTA G
Deletion of nucleotides

•A mutation that occurs when a nucleotide is randomly

deleted from the DNA sequence

•Like an insertion mutation, a deletion mutation changes the triplet

in which the deletion has occurred, and also changes every
group of three bases further on in the DNA sequence
• This is known as a frameshift mutation

•This may dramatically change the amino acid sequence

produced from this gene and therefore the ability of the
polypeptide to function
 Types of substitution Mutations

Normal mRNA

5' 3'
Normal Protein
Stop
NH2 end COOH end

Genetic code is degenerate

No effect on the protein sequence

Silent mutation C becomes U

GGC = Gly
GGU = Gly too

Stop

One amino acid changes

Missense mutation G becomesA

GGC = Gly
AGC = Ser
Stop

One codon becomes a stop codon, protein is shorter

Nonsense mutation A becomes U

AAG = Lys
UAG = Stop codon

Stop
•A substitution mutation will only change the amino acid for the
triplet in which the mutation occurs, and will have no impact on
triplets located elsewhere in the gene.

•Substitution mutations include

• Silent mutations
• The mutation does not alter the amino acid sequence of
the polypeptide; this is due to the degenerate nature of the
genetic code

• Missense mutations
• The mutation alters a single amino acid in the polypeptide
chain, e.g. sickle cell anaemia is caused by a single substitution
mutation changing a single amino acid in the haemoglobin
protein

• Nonsense mutations
• The mutation creates a premature stop codon, causing the
polypeptide chain produced to be incomplete and therefore
affecting the final protein structure and function, e.g. cystic
fibrosis can be caused by a nonsense mutation
• Note that a stop codon provides a signal for the cell
Effects of Mutations

•Most mutations do not alter the polypeptide or only alter it

slightly so that its appearance or function is not changed
• This is possible because the genetic code is degenerate; the
base sequence can be changed without necessarily altering
the amino acid

•However, a small number of mutations code for a significantly

altered polypeptide
• A mutation changes the DNA base sequence
• One or many amino acids in the primary structure of a protein
is altered
• Different bonds form in the secondary and tertiary structures
of the protein
• The final 3D structure of the protein is altered
 Types of Mutations

Genetic code is degenerate

•Very rarely this can give rise to a protein that provides an organism
with an advantage, e.g. resistance to an antibiotic, or the ability to
digest a new type of food

• Mutations that provide an advantage can drive the process of

evolution by causing natural selection to occur

• Individuals with an advantage are more likely to survive and

reproduce

• The advantageous mutation is more likely to be passed on

• The mutation becomes more common in the population

 Sickle-cell anemia

Anemia = Decrease in
Red Blood Cells’ number
OR Hemoglobin content

A sickle
Sickle-cell anemia
 Sickle-cell anemia

A SINGLE amino acid in Beta Hemoglobin is “wrong”

Missense mutation

6th amino acid

 Hemoglobin mutations

Properties of Effect on
DNA mRNA Amino Acid Disease
AA protein

Original
CTC GAG Glutamic Acid Hydrophilic Normal None
codon 6

Mutation 1 CTT GAA Glutamic Acid Hydrophilic Neutral None

Mutation 2 GTC CAG Glutamine Hydrophilic Neutral None

Loses water Sickle Cell

Mutation 3 CAC GUG Valine Hydrophobic
solubility Anemia
The abnormal hemoglobin crystalizes in low
concentration of oxygen as a result the red blood
cells of a sufferer collapse into a sickle shape.
Sickle cells may clump together and block the
flow of blood.
Person suffering from it gets tired quickly even
for a mild work due to less oxygen carried to the
cells by the abnormal hemoglobin. As a result,
there will be less aerobic respiration, producing
less energy.
Sickle-cell anemia

Blocked artery
All cells downstream die
 2: Pattern of inheritance
Objectives:

• understand what is meant by the terms gene, allele,

genotype, phenotype, recessive, dominant, codominance,
homozygote and heterozygote.

• understand patterns of inheritance, including the

interpretation of genetic pedigree diagrams, in the context of
monohybrid inheritance

• understand sex linkage on the X chromosome, including red-

green color blindness in humans
Chromosomes
 When a cell divides, chromatin fibers are very highly
folded, and become visible in the light microscope as
chromosomes.

 During interphase (between divisions), chromatin is more

extended, a form used for expression genetic information.
• DNA is organized into informational units called genes

• Chromosomes contain hundreds to thousands of genes

Homologous Chromosomes

• Pair of chromosomes (maternal

and paternal) that are similar in
shape and size.

• Homologous pairs carry genes

controlling the same inherited
traits.

• Each locus (position of a gene) is

in the same position on
homologues
There are 22 matching pairs of
chromosomes (homologous
chromosomes) called autosomes.

The 23rd pair are non-matching

chromosomes and are called the
sex chromosomes. They determine an
individual’s sex. Females have two X
chromosomes, and males have an X and
a Y chromosome. Y chromosomes has
missing portions and therefore smaller
than the X chromosome.

How are the Chromosomes Numbered?

Each chromosome has been assigned a
number based on its size.
Genes & alleles

•A chromosome is a long DNA molecule which contains many genes.

•A gene is a length of DNA that codes for a single polypeptide

• The position of a gene on a chromosome is its locus (plural
loci)

•Each gene can exist in two or more different forms called alleles

• Different alleles of a gene have slightly different nucleotide

sequences but they still occupy the same locus on the
chromosome

• Different alleles arise by the process of mutation

• E.g. each allele might produce a different coat colour in mammals

• One allele might code for a black coat while the alternative
allele might code for a chestnut coat

•When writing about genes it is conventional to use a single letter to

represent a gene, while different alleles may be indicated by using
upper and lower case letters, e.g. A and a
Homologous pair of chromosomes
Homozygous & heterozygous

•Every individual has two copies of

each allele; one on each
chromosome in a homologous
pair

• The chromosomes may

not contain the same
alleles of each gene

•When an individual has two

identical alleles at a locus they
are said to be homozygous, or
a homozygote
• Homo = the same

•When an individual has two

different alleles at a locus they
are said to be heterozygous, or
a heterozygote
• Hetero = different
•Alleles are dominant; they are always expressed in the phenotype no
matter which other allele is present

• This means they are expressed in both heterozygous and

homozygous individuals, e.g.
• A horse with the genotype AA would be said to
be homozygous dominant and would have a black coat
phenotype

• A horse with the genotype Aa would be said to

be heterozygous and would still have a black coat
phenotype, as the allele for black coat color is dominant over
the lower case allele

• It is possible to refer to a heterozygous individual as

a carrier of the recessive allele; the allele doesn't show in
the phenotype but could still be passed on to offspring

•Others are recessive; they are only expressed in the phenotype if no

dominant allele is present

• This means that it is only expressed when present in a

homozygous individual, e.g.
• A horse with the genotype aa would be said to
General symbols used in pedigree Analysis.
1.

X-linked recessive Autosomal recessive

Autosomal Dominant X-linked dominant

Refer to Mathematic support for
students for practice question
3: Sex-Linkage
• A karyotype is simply a picture of a
person’s chromosomes. In order to get
this picture, the chromosomes are
isolated, stained, and examined under
the microscope.
• Most often, this is done using the
chromosomes in the white blood cells. A
picture of the chromosomes is taken
through the microscope.
• Then, the picture of the chromosomes is
cut up and rearranged by the
chromosome’s size.
• The chromosomes are lined up from
largest to smallest. A trained
cytogeneticist can look for missing or
extra pieces of chromosome.
•Sex-linked genes are located on the sex chromosome

•This means the sex of an individual affects which alleles they pass
on to their offspring through their gametes

•If the gene is on the X chromosome, males (XY-

heterogametic), will only have one copy of the gene,
whereas females (XX- homogametic) will have two

• The X chromosome has many more genes on it than the Y

chromosome, so sex-linkage that involves the Y chromosome
is very rare

•Sex linkage is notated using a capital letter to represent the

chromosome X or Y and a superscript letter to represent the allele
•There are three genotypes for females, e.g. for a genetic
trait caused by a recessive allele
• XAXA = unaffected
• XAXa = carrier
• XaXa = affected

•Males have only two genotypes, e.g.

• XAY = unaffected
• XaY = affected

•It is not possible for males to be carriers of X-linked traits, nor

for them to pass such traits on to their sons; males only
pass Y chromosomes on to their sons
Question:
4: Cystic Fibrosis
Genes can affect the phenotype of an organism

• A gene codes for a single polypeptide

• The polypeptide can affect the phenotype, e.g. it could form

part of an enzyme or a membrane transport protein

Genetic disorders are often caused by a mutation in a gene that

results in a differently-functioning or non-functioning protein
that alters the phenotype of the individual
Cystic fibrosis

•Cystic fibrosis is a genetic disorder of cell membranes caused by

a recessive allele of the CFTR (Cystic Fibrosis Transmembrane
Conductance Regulator) gene located on chromosome 7

• This gene codes for the production of chloride ion channels required
for secretion of sweat, mucus and digestive juices
• A mutation in the CFTR gene leads to production of non-functional
chloride channels
• This reduces the movement of water by osmosis into the
secretions
• The result is that the body produces large amounts of thick, sticky
mucus in the air passages, the digestive tract and the reproductive
system

•Because cystic fibrosis is determined by a recessive allele, this means

• People who are heterozygous won’t be affected by the disorder but
are carriers
• People must be homozygous recessive in order to have the
disorder
• If both parents are carriers the chance of them producing a child
with cystic fibrosis is 1 in 4, or 25 %
• If only one of the parents is a carrier with the other parent being
Cystic fibrosis is a genetic disorder caused by a
recessive allele
 Cystic fibrosis

Effects of main mutations in CFTR gene

The respiratory system

•Mucus in the respiratory system is a necessary part of keeping the

lungs healthy
• It prevents infection by trapping microorganisms
• This mucus is moved out of the respiratory tract by cilia

•In people with cystic fibrosis, due to the faulty chloride ion channels,
the cilia are unable to move as the mucus is so thick and sticky

•This means microorganisms are not efficiently removed from the lungs
and lung infections occur more frequently

•Mucus builds up in the lungs and can block airways which limits gas
exchange

• The surface area for gas exchange is reduced which can

cause breathing difficulties

•Physiotherapy can support people with cystic fibrosis to loosen the

mucus in the airways and improve gas exchange
The digestive system

•Thick mucus in the digestive system can cause issues because

• The tube to the pancreas can become blocked, preventing

digestive enzymes from entering the small intestine

• Digestion of some food may be reduced and therefore key

nutrients may not be made available for absorption

• The mucus can cause cysts to grow in the pancreas

which inhibit the production of enzymes, further reducing
digestion of key nutrients

• The lining of the intestines is also coated in thick

mucus, inhibiting the absorption of nutrients into the
blood
The reproductive system

•Mucus is normally secreted in the reproductive system to prevent

infection and regulate the progress of sperm through the reproductive
tract after sexual intercourse

•The mucus in people with cystic fibrosis can cause issues in both men
and women

• In men the tubes of the testes can become blocked, preventing

sperm from reaching the penis

• In women thickened cervical mucus can prevent sperm reaching

the oviduct to fertilize an egg
5: Genetic
Screening
Some circumstances, e.g. in a pregnancy where there is a family
history of a genetic disorder, may require individuals to determine if
they have a particular allele present in their genome

This can be determined by genetic screening

•There are three main uses of genetic screening

• Identifying individuals who carry an allele at a gene locus
for a particular disorder
• The screening of embryos prior to implantation during fertility
treatment; this is Preimplantation Genetic Diagnosis (PGD)
• Testing a fetus before birth; this is prenatal testing
Identification of carriers

•Carrier testing is offered to individuals with a history of genetic

disorders in their family

•It can show whether people who have no symptoms carry the allele for
particular disorders, such as cystic fibrosis
• Cell samples can be extracted from, e.g. blood or saliva, before
being tested for the presence of specific alleles

•Couples can be tested prior to having children to determine the

probability of future children inheriting the disorder

•Some of the benefits of carrying out genetic screening at this stage

include
• Families can make informed decisions before having children
• Women can decide whether to have prenatal testing during
pregnancy
Preimplantation Genetic Diagnosis (PGD)

•IVF, or in vitro fertilisation is a type of fertility treatment during

which fertilisation is carried out in the lab; embryos produced in this
way can be implanted into the uterus where they develop into a foetus

•Sometimes a couple might choose to have a child by IVF if they know that
they are at increased risk of certain genetic disorders, as it allows
them to screen any embryos produced using PGD

•PGD involves analysis of the DNA of an embryo prior to implanting it

into the uterus
• The sample of DNA to be analysed can be obtained by taking cell
samples from embryos produced during IVF

•Benefits of PGD include

• Evidence suggests that the process does not harm the embryo in
any way
• Reduces the chances of having a baby with a genetic disorder
• It avoids abortion as it is carried out before implantation of the
embryo
• It is worth noting that some people believe that an embryo is as
worthy of human status as a foetus or a baby, so the
discarding of affected embryos after PGD is not ethically
Prenatal testing
•Prenatal testing is offered to pregnant women with a family history of
genetic disorders

•It involves testing the foetus for genetic diseases during the course of a
pregnancy

•The DNA can be obtained by chorionic villus

sampling or amniocentesis in the uterus
•Chorionic villus sampling
• This involves removing and testing a small sample of cells from
the placenta using a fine needle
• The cells contain foetal DNA which can be analysed for genetic
disorders, allowing parents to make informed decisions about the
pregnancy and foetus
• Advantages of this process include
• It is carried out at around 11-14 weeks of pregnancy, so any
problems can be picked up early on
• A relatively large tissue sample can be collected,
providing plenty of cells to analyse
• Results are available rapidly
• Potential implications of chorionic villus sampling that should be
considered include
• The process has a 1-2 % risk of miscarriage
•Amniocentesis

• This involves removing and testing a small sample of cells from

amniotic fluid using a fine needle
• The amniotic fluid is the fluid that surrounds the foetus within
the uterus

• The fluid contains foetal cells which contain DNA to be analysed

• Potential implications of amniocentesis that should be considered

include
• It is carried out at around 15-20 weeks of pregnancy; this is
relatively late in the pregnancy, making decisions about
abortion more difficult for some parents
• The procedure has a 1 % risk of miscarriage
• It takes 2-3 weeks for results to be available

•Benefits of prenatal testing include

• The tests allow parents to make informed decisions about the
progress of a pregnancy
• Results can help parents prepare for the future care of the child,
including medical treatment
Implications of Prenatal Genetic Screening

•Prenatal genetic screening involves analysis of the DNA of a

foetus taken from the uterus during pregnancy
• Examples of prenatal screening methods include chorionic villus
sampling and amniocentesis
•Both forms of prenatal screening come with associated risks and
potential ethical dilemmas, so it is important that parents considering this
type of screening have thought about the implications
• Positive implications
• Prenatal screening can provide advance notice of the birth of a
child with a genetic disorder, giving time for parents to
be educated and to make decisions about medical
treatments
• The risk of harm to the foetus during prenatal screening are
low; around 1-2 % for both methods
• Some parents may feel able to make the decision to end a
pregnancy on discovering that a foetus has a life-limiting or
potentially fatal diagnosis
• Some parents may choose to continue with a pregnancy after
receiving a fatal diagnosis, but they have time to process the
results and grieve before the birth of a child who may not
survive for long outside the uterus
•Negative implications
• Both methods of prenatal screening bring a small risk of
miscarriage
• Amniocentesis provides results relatively late in pregnancy,
making decisions about termination of a pregnancy very difficult for
some parents
• Prenatal screening is not 100 % accurate
• False positive results may lead to the termination of a healthy
pregnancy
• False negative results may give false expectations for the health
of a foetus
• Parents may experience pressure from society or their medical
team to abort a foetus with a genetic disorder
• Some parents may believe that a foetus has human status even
very early on during a pregnancy, meaning that they would not
consider abortion to be an option even after early testing