Mutations:Mutations:a source of variationa source of variation

Mutations are the source of Mutations are the source of variationvariation

A mutation is a heritable change in genetic material.A mutation is a heritable change in genetic material. Different forms of the same gene resulting from Different forms of the same gene resulting from

mutations are known as alleles.mutations are known as alleles. Alleles are the forms of a gene located at the site or Alleles are the forms of a gene located at the site or

locus on the chromosome.locus on the chromosome. Alleles are the basis of heritable variation. Alleles are the basis of heritable variation. Over the course of evolution, many mutations have Over the course of evolution, many mutations have

occurred giving rise to considerable genetic allelic occurred giving rise to considerable genetic allelic variation within species, and the process of meiosis variation within species, and the process of meiosis ensures random distribution of particular parental alleles ensures random distribution of particular parental alleles to offspring.to offspring.

Point MutationsPoint Mutations

Mutations in genes involving the alteration Mutations in genes involving the alteration of a single base in DNA are referred to as of a single base in DNA are referred to as point mutationspoint mutations. .

These include:These include: substitution mutationssubstitution mutations, which occur as a , which occur as a

result of a substitution of one nucleotide for result of a substitution of one nucleotide for another, or another, or

frameshift mutationsframeshift mutations, resulting from the , resulting from the addition or deletion of a single nucleotide.addition or deletion of a single nucleotide.

Substitution MutationsSubstitution Mutations

There are three types of substitution mutations:There are three types of substitution mutations: Missense mutationsMissense mutations

involve a substitution that results in the replacement of the involve a substitution that results in the replacement of the original amino acid with a different amino acid.original amino acid with a different amino acid.

Silent mutationSilent mutation involve substitution that does not affect the amino acid coded involve substitution that does not affect the amino acid coded

for. An example would be a change from CAC to CAT, both for. An example would be a change from CAC to CAT, both codons are for the amino acid histidine.codons are for the amino acid histidine.

Nonsense mutationNonsense mutation involve a nucleotide substitution that results in the replacement involve a nucleotide substitution that results in the replacement

of the original amino acid with a stop codon.of the original amino acid with a stop codon.

Examples of substitution mutationsExamples of substitution mutations

Original Sequence

Silent Mutation

Missense Mutation

Nonsense Mutation

Frameshift MutationsFrameshift Mutations If a single base pair is inserted in or deleted from the DNA, the If a single base pair is inserted in or deleted from the DNA, the

reading frame (codon sequence) of the mRNA is altered and the reading frame (codon sequence) of the mRNA is altered and the wrong amino acids may be incorporated for the remainder of the wrong amino acids may be incorporated for the remainder of the sequence. sequence.

Original SequenceOriginal Sequence

THE FAT CAT SATTHE FAT CAT SAT

InsertionInsertion

ATH EFA TCA TSA TATH EFA TCA TSA T

DeletionDeletion

THE FAC ATS ATTHE FAC ATS AT

Block MutationsBlock Mutations Block mutations are different types of Block mutations are different types of

chromosome mutations that can only occur chromosome mutations that can only occur during meiosis. during meiosis.

They are called They are called block mutationsblock mutations as they involve as they involve the rearrangement of whole blocks of genes the rearrangement of whole blocks of genes rather than individual bases within a gene. rather than individual bases within a gene.

Block mutations include:Block mutations include: deletionsdeletions inversionsinversions duplicationsduplications translocationstranslocations

DeletionsDeletions A break may occur at two points in the A break may occur at two points in the

chromosome, and the middle piece falls chromosome, and the middle piece falls out. out.

The two ends then rejoin to form a The two ends then rejoin to form a chromosome missing some genes. chromosome missing some genes. Alternatively the end of a chromosome Alternatively the end of a chromosome may break off.may break off.

InversionsInversions The middle piece of the chromosome falls out The middle piece of the chromosome falls out

and rotates through 180 degrees and then and rotates through 180 degrees and then rejoins. rejoins.

There is no loss of genetic material but the There is no loss of genetic material but the genes will be in a reverse order for this segment genes will be in a reverse order for this segment of the chromosome.of the chromosome.

TranslocationsTranslocations Involves the movement of a group of genes between Involves the movement of a group of genes between

different (non homologous) chromosomes. different (non homologous) chromosomes. A piece of one chromosome breaks off and joins onto A piece of one chromosome breaks off and joins onto

another chromosome. another chromosome. This will cause major problems when the chromosomes This will cause major problems when the chromosomes

are passed to gametes as some will receive extra genes, are passed to gametes as some will receive extra genes, while others will miss out.while others will miss out.

DuplicationsDuplications A segment is lost from one chromosome and A segment is lost from one chromosome and

added to another. added to another. The chromosome with the missing segment The chromosome with the missing segment

removed is deficient in genes.removed is deficient in genes. Some gametes will receive double the genes will Some gametes will receive double the genes will

others will have no gene for the affected others will have no gene for the affected segment.segment.

Somatic and Germ Line MutationsSomatic and Germ Line Mutations

Germ line mutationsGerm line mutations occur in germ line cells and occur in germ line cells and will will be inheritedbe inherited by offspring formed by fertilization of these by offspring formed by fertilization of these germ cells. germ cells.

Examples include PKU and albinism.Examples include PKU and albinism.

Somatic mutationsSomatic mutations only affect the individuals in which only affect the individuals in which they arise; they they arise; they cannot be inheritedcannot be inherited by future by future generations. generations.

Example – person with one blue eye and one blue and brown Example – person with one blue eye and one blue and brown eye. The size of the sport reflects the number of cell divisions eye. The size of the sport reflects the number of cell divisions that occurred after the somatic mutations. that occurred after the somatic mutations.

Somatic mutations may be important in cancer as many Somatic mutations may be important in cancer as many cancers are due to a genetic change in a single cell cancers are due to a genetic change in a single cell resulting in uncontrolled growth and division.resulting in uncontrolled growth and division.

Detecting MutationsDetecting Mutations Mutations are usually because of the effect they have on the individual Mutations are usually because of the effect they have on the individual

carrying them. carrying them. A large range of molecular techniques allows mutations in genes to be A large range of molecular techniques allows mutations in genes to be

analysed. analysed. DNA sequencing can provide a complete DNA sequence for the gene under DNA sequencing can provide a complete DNA sequence for the gene under

investigation. Alternatively, if the gene is large, rapid PCR-based investigation. Alternatively, if the gene is large, rapid PCR-based procedures have been developed.procedures have been developed.

Example: Finding the common A → T missense mutation associated with Example: Finding the common A → T missense mutation associated with sickle cell anaemia:sickle cell anaemia:

The relevant region of the The relevant region of the -globin gene is amplified by PCR and then digested -globin gene is amplified by PCR and then digested with the restriction enzyme MstII. with the restriction enzyme MstII.

The restriction enzyme sequence is present in the normal sequence but not in The restriction enzyme sequence is present in the normal sequence but not in the sickle cell sequence, therefore gel electrophoresis will show different sized the sickle cell sequence, therefore gel electrophoresis will show different sized bands depending on the alleles carried by the person being tested.bands depending on the alleles carried by the person being tested.

(a) A portion of the β-globin gene is shown. The MstII site is present in the normal allele, but missing in the sickle-cell allele. The positionof the PCR primers used is shown.

(b) A diagram of an electrophoretic gel showing the DNA fragments produced when the DNA of anindividual carrying two copies of the normal allele (Track 1) or an individual carrying two copies of the sickle-cell allele is PCR-amplifiedand exposed to the restriction enzyme MstII. The DNA size standards in Track 3 allow thesize of the bands in Tracks 1 and 2 to be estimated with accuracy.

Finding the common A → T missense mutation Finding the common A → T missense mutation associated with sickle cell anaemiaassociated with sickle cell anaemia

How do mutations arise?How do mutations arise?

Mutations may either be spontaneous or Mutations may either be spontaneous or induced.induced. Spontaneous mutations arise naturally as Spontaneous mutations arise naturally as

random changes in the base sequence of random changes in the base sequence of DNA.DNA.

Induced mutations occur following deliberate Induced mutations occur following deliberate or accidental exposure to radiation or other or accidental exposure to radiation or other agents.agents.

Spontaneous MutationsSpontaneous Mutations Arise naturally as random changes in the base sequence of DNA.Arise naturally as random changes in the base sequence of DNA. Occur at an average rate of approximately one in a millionOccur at an average rate of approximately one in a million Are the result of rare, undetected and unrepaired errors of DNA Are the result of rare, undetected and unrepaired errors of DNA

synthesis.synthesis. Types of Spontaneous mutations include:Types of Spontaneous mutations include:

TautomerismTautomerism - A base is changed by the repositioning of a hydrogen - A base is changed by the repositioning of a hydrogen atom.atom.

DepurinationDepurination - Loss of a purine base (A or G). - Loss of a purine base (A or G). DeaminationDeamination - Changes a normal base to an atypical base; C → U, - Changes a normal base to an atypical base; C → U,

(which can be corrected by DNA repair mechanisms), or spontaneous (which can be corrected by DNA repair mechanisms), or spontaneous deamination of 5-methycytosine (irreparable), or A → HX deamination of 5-methycytosine (irreparable), or A → HX (hypoxanthine).(hypoxanthine).

TransitionTransition - A purine changes to another purine, or a pyrimidine to a - A purine changes to another purine, or a pyrimidine to a pyrimidine.pyrimidine.

TransversionTransversion - A purine becomes a pyrimidine, or vice versa. - A purine becomes a pyrimidine, or vice versa...

Tautomeric Shifts and DeaminationTautomeric Shifts and Deamination

Induced MutationsInduced Mutations Mutations that occur following deliberate or accidental exposure to radiation Mutations that occur following deliberate or accidental exposure to radiation

or other agents are called induced mutations.or other agents are called induced mutations. The agents that induce mutations are called The agents that induce mutations are called mutagensmutagens.. Induced mutations can occur more frequently than spontaneous mutationsInduced mutations can occur more frequently than spontaneous mutations Exposure to naturally occurring mutagens during the course of evolutionary Exposure to naturally occurring mutagens during the course of evolutionary

history has contributed to the spontaneous mutation rate, however, in recent history has contributed to the spontaneous mutation rate, however, in recent history, the number of chemicals added to the environment as a result of history, the number of chemicals added to the environment as a result of agricultural and industrial practices and warfare has increased.agricultural and industrial practices and warfare has increased.

Chemicals that cause mutations are called mutagens. Chemicals that Chemicals that cause mutations are called mutagens. Chemicals that cause an increase in cell division without direct changes to genetic material cause an increase in cell division without direct changes to genetic material are caused carcinogens. A chemical can be both a mutagen and a are caused carcinogens. A chemical can be both a mutagen and a carcinogen.carcinogen.

Mutagens have a cumulative effect on an individual – i.e. repeated small Mutagens have a cumulative effect on an individual – i.e. repeated small doses over a long period of time may be just as harmful as a single, larger doses over a long period of time may be just as harmful as a single, larger dose.dose.

Types of MutagensTypes of Mutagens RadiationRadiation

Ionising radiation e.g. nuclear fallout, UV light, X rays, gamma rays. Ionising radiation e.g. nuclear fallout, UV light, X rays, gamma rays. Overexposure to UV rays (sunlight) can result in mutagenesis and skin cancer. Overexposure to UV rays (sunlight) can result in mutagenesis and skin cancer. X rays have higher energy than UV radiation and can break DNA and even X rays have higher energy than UV radiation and can break DNA and even

cause chromosome breakage, resulting in cell death or mutational change. cause chromosome breakage, resulting in cell death or mutational change. Radiation from radioactive elements can have similar effects.Radiation from radioactive elements can have similar effects.

Viruses and microorganismsViruses and microorganisms Viruses such as hepatitis B, HIV, and Epstein-Barr virus can upset genes and Viruses such as hepatitis B, HIV, and Epstein-Barr virus can upset genes and

potentially trigger cancer when they integrate into the genome.potentially trigger cancer when they integrate into the genome.

Alcohol and dietary componentsAlcohol and dietary components Diets high in fat, especially those containing burned and/or fatty highly preserved Diets high in fat, especially those containing burned and/or fatty highly preserved

meat, slow the passage of food through the gut giving time for mutagenic irritants meat, slow the passage of food through the gut giving time for mutagenic irritants to form in the bowel.to form in the bowel.

Environmental poisons and irritantsEnvironmental poisons and irritants Many chemicals are mutagenic. Many chemicals are mutagenic. Synthetic and natural examples include organic solvents such as benzene, Synthetic and natural examples include organic solvents such as benzene,

asbestos, formaldehyde, tobacco tar, vinyl chlorides, coal tars, some dyes and asbestos, formaldehyde, tobacco tar, vinyl chlorides, coal tars, some dyes and nitrites.nitrites.

DNA Repair SystemsDNA Repair Systems DNA repairDNA repair is the process by which a cell identifies and corrects is the process by which a cell identifies and corrects

damage to DNA. damage to DNA. In human cells, both normal metabolic activities and environmental In human cells, both normal metabolic activities and environmental

factors such as UV light can cause DNA damage, resulting in as factors such as UV light can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day. many as 1 million individual molecular lesions per cell per day.

Many of these lesions cause structural damage to the DNA Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. gene that the affected DNA encodes.

Other lesions induce potentially harmful mutations in the cell's Other lesions induce potentially harmful mutations in the cell's genome, which will affect the survival of its daughter cells after it genome, which will affect the survival of its daughter cells after it undergoes mitosis. undergoes mitosis.

Consequently, the DNA repair process must be constantly active so Consequently, the DNA repair process must be constantly active so it can respond rapidly to any damage in the DNA structure. it can respond rapidly to any damage in the DNA structure.

DNA Repair SystemsDNA Repair Systems DNA repair is mediated by enzymes. DNA repair is mediated by enzymes. In many cases DNA repair occurs during replication by randomly In many cases DNA repair occurs during replication by randomly

incorporating bases into the gap. If the base incorporated is not the incorporating bases into the gap. If the base incorporated is not the same as the ‘missing base’, this results in a missense mutation in same as the ‘missing base’, this results in a missense mutation in the synthesized strand. the synthesized strand.

The rate of DNA repair is dependent on many factors, including the The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. cell type, the age of the cell, and the extracellular environment.

A cell that has accumulated a large amount of DNA damage, or one A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred by its DNA, can that no longer effectively repairs damage incurred by its DNA, can enter one of three possible states:enter one of three possible states:

an irreversible state of dormancy, known as senescence an irreversible state of dormancy, known as senescence cell suicide, also known as apoptosis cell suicide, also known as apoptosis unregulated cell division, which can lead to the formation of a tumor unregulated cell division, which can lead to the formation of a tumor

DNA RepairDNA Repair