MUTATIONS

2

Mutations

• A mutation is a spontaneous change in the genetic material. • Generally they occur when DNA is copied or when cells

divide. • Can only be passed to the next generation if they happen in

the germ cells – those that produce the gametes

• If they happen in somatic or body cells, they cannot be passed on.

• An accumulation of mutations may contribute to: – ageing – cancer

3

• Mutations can happen randomly.• Mutation rate increased by certain environmental

factors: – ionising radiation

• α, β, and γ-radiation

– UV radiation– chemicals:

• benzene • phenols • furans • tobacco tar (a mixture of many noxious chemicals) • all of these are mutagens

4

Gene mutation: • changes in the DNA • result in a different

allele or gene• e.g. sickle cell

anaemia and cystic fibrosis

Chromosome mutation:• cause changes to the

structure or number of chromosomes

• e.g. Down’s syndrome

There are two basic types of mutation:

5

Gene Mutations

• These are changes in base sequence in the DNA.

• If it is a change in a single base, such a mutation is known as a point mutation.

• There are three basic ways in which a base can be changed:– base substitution – base addition – base deletion

6

Base Substitution

• Quite simply one base is substituted for another.• Example:

– the DNA triplet AAA might be changed to AAG • Q. What would be the effect of such a change?

– AAA codes for phenylalanine – AAG codes for phenylalanine

• This substitution causes no change in the amino acid coded for – it is a silent mutation

7

• Substituting a single base often has no effect on the amino acid coded for: – this is because the DNA code is degenerate – i.e. the same amino acid may have several codes – example: CAA, CAG, CAT and CAC all code for valine

• In such cases any mutation is a silent mutation – it has no effect on the phenotype

• Alternatively, a point mutation may have a significant effect: – substitution results in a different amino acid being coded for (as

happens in sickle cell disease)– a code that gives a totally different instruction (e.g. Stop)

8

Q. What would be the effect of a base substitution changing the DNA triplet ACA to

ACT or ACC?• ACA codes for cysteine• ACT codes for the stop instruction• ACC codes for tryptophan

9

Base Addition and Deletion

Addition• An extra base is inserted into the DNA sequence.• Upsets the coding for every amino acid after the

insertion.

Deletion• A base is removed from the DNA sequence. • Upsets the coding for every amino acid from the

deletion onwards.

10

• Base additions and deletions always have larger effects than substitutions:– they cause a ‘frame shift’ in the code

• Instead of a single amino acid being affected, every one after the change could be affected.

• That said, even a single changed amino acid can have profound consequences. – (See sickle cell anaemia and cystic fibrosis.)

11

Chromosome Mutations

• Chromosome mutations are gross changes to the structure of chromosomes.

• Non-disjunction is responsible for some chromosome mutations, i.e. failure of chromosomes to separate during cell division.

• Example:– Down’s syndrome

• chromosome 21 fails to separate during meiosis • an egg cell receives two copies of this chromosome • fertilisation results in a zygote with three copies of the 21st

chromosome • trisomy 21, causes Down’s syndrome

12

• Other examples are: – Klinefelter’s syndrome (XXY)– XYY syndrome – Turner’s syndrome (XO)

13

If it’s during meiosis: • a diploid gamete is

produced• fertilisation of which

produces a triploid cell

If it’s during mitosis in the zygote:• a tetraploid results

Sometimes whole sets of chromosomes fail to separate during cell division.

Such polyploid plants are relatively common. If such polyploidy happens in animals, the embryo

fails to develop properly and aborts.

14

• Polyploid plants are relatively common.• They are important in the evolution of:

– modern wheat (Triticum aestivum)– a salt marsh grass (Spartina townsendii)

Spartina townsendii, a common grass of salt marshes.

Wheat (Triticum asestivum) in a field untreated with selective herbicides.

15

Examples of Gene Mutations

• There are several examples of gene mutation that you may already be familiar with:– sickle cell anaemia– phenyl ketonuria– cystic fibrosis– industrial melanism in insects

• Details of these will be examined on the following slides.

16

Sickle Cell Anaemia

• Sickle cell anaemia is an inherited blood disorder.• It affects a significant number of people of Afro-

Caribbean and African descent. – Haemoglobin is a globular protein made from four

polypeptide chains, each of which has an iron containing haem group.

– There are two α and two β polypeptides. • A mutation causes a change in amino acid 6 of the β

polypeptide chain.– In the homozygous state this causes sickle cell anaemia.

17

• A possible code for the first seven amino acids of normal haemoglobin in the transcribing strand of DNA is:

CAT-GTA-AAT-TGA-GGA-CTT-CTC- - -

• However, a base substitution results in a changed sequence:

CAT-GTA-AAT-TGA-GGA-CAT-CTC- - -

18

Q. Which amino acids are coded for by both of these sequences?

CAT-GTA-AAT-TGA-GGA-CTT-CTC- - -

↓ Val – His – Leu – Thr – Pro – Glu – Glu - -

CAT-GTA-AAT-TGA-GGA-CAT-CTC- - -

↓ Val – His – Leu – Thr – Pro – Val – Glu - -

19

Val – His – Leu – Thr – Pro – Glu – Glu - -

Val – His – Leu – Thr – Pro – Val – Glu - -

Q. Which is the changed amino acid and what is it replaced with?

• Sixth amino acid is changed: – from glutamate to valine

• The replacement of acidic glutamate with non-polar valine results in the haemoglobin becoming insoluble under low oxygen concentrations.

20

Q. In small groups discuss why such an apparently minor change might have such a big effect.

• Things you may want to consider: effect on overall protein structure; effect on haemoglobin solubility, especially at low O2 concentration; effect on red blood cell shape; whether the allele is present in homozygous or heterozygous state…

• Summarise the main points.

21

Effect on protein (Hb) structure

The sixth amino acid of the β polypeptide (glutamic acid or glutamate) is replaced by valine.

Effect on haemoglobin solubility

The haemoglobin molecule is made insoluble under low O2 conditions and forms fibres in the cytoplasm.

Effect on red blood cell shape

The red blood cell can be pulled into a sickle or crescent moon shape by the fibres.

Effect on oxygen carriage

Sickled red cells cannot carry O2. Furthermore, they can get trapped in capillaries and reduce O2 supply further.

Whether homozygous or heterozygous

The effect is more severe in the homozygous state, i.e. two copies of the allele. Suffer from sickle cell anaemia.

22

Phenylketonuria (PKU)

• Phenylketonuria is a genetic disease caused by an abnormal base sequence that codes for the enzyme phenylalanine hydroxylase.

• Consequently: – the enzyme is not made – phenylalanine is not metabolised and its concentration

builds up – damages nerve cells • The amino acid phenylalanine is found in many

foodstuffs and is usually metabolised to tyrosine. – Tyrosine can be further metabolised into melanin and

thyroxine.

23

Phenylalanine hydroxylase

phenylalanine tyrosine

melanin an important pigment

thyroxinea key hormone controlling metabolism

24

Q. What are the potential consequences of PKU if it is not identified and treated?

Build up of phenylalanine• Damage to nerve cells and severe mental retardation. Lack of tyrosine• Other metabolites not made:

– lack of melanin – lack of thyroxine and retarded growth

Q. How is PKU identified?• Screened for at birth• Heel prick blood test done within 2–3 days of birth

25

Q. How is PKU treated?• Special diet with phenylalanine levels reduced so that

normal brain cell development occurs.Q. Why do low-calorie drinks containing aspartame

carry the message ‘warning this drink contains a source of phenylalanine’?

• The sweetener is metabolised by the liver into phenylalanine.

• If drunk by those with PKU...

This type of warning is for PKU sufferers.

26

Cystic Fibrosis

• Cystic fibrosis is an inherited genetic condition. • It is an autosomal recessive (carried on chromosome

number 7) and so must be present in the homozygous state to be expressed.

• People with cystic fibrosis are unable to make a chloride transfer protein that is normally present in the cell surface membranes.

• Consequently, a thick mucus is produced: – can accumulate in the lungs, causing respiratory infection– can block secretion of pancreatic enzymes

27

Q. Suggest why failure to transfer chloride ions results in a thick mucus.

• Chloride ions are osmotically active: – when secreted into the mucus they lower its

water potential – water is drawn into the mucus, thinning it – if less chloride is secreted, water is not drawn into

the mucus which remains thick and viscous

28

Industrial Melanism

• Before the Industrial Revolution, trees and rocks were covered with lichens. Many insects had colour patterns that camouflaged them against the background.

• Burning coal produced pollution (SO2 and smoke) which killed the lichens and blackened the trees and rocks.

• Variants with a darker colour (melanics) were favoured...

• The case of the peppered moth (Biston betularia) is well documented.

29

• The normal, pre-industrial form had a speckled appearance and was camouflaged, protecting it from predatory birds during the day.

• Speckled or peppered appearance is recessive. • A dominant mutation that codes for dark colour occurs

fairly frequently, but individuals with this mutation were at a selective disadvantage and so did not survive.

• After the industrial revolution, selection pressure changed and the melanic form had a selective advantage. The rest is history.

30

Q. What selection pressure operated against the melanic variants before the Industrial Revolution?

• Predation: – birds could see the melanics against the lichen covered trees and

rocks

Q. How did selection pressure change with the industrial revolution?

• Lichens disappeared (sensitive to SO2) and the trees and rocks were blackened with soot.

• Peppered variants were visible.Q. Suggest what effect clean air legislation has had upon the

frequency of melanic insects such as the peppered moth in Britain.

• Melanic frequency reduced.• No soot blackening of trees and lichens recover.

31Melanic and peppered forms of Biston betularia on a birch tree. Image licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

Melanic or carbonaria form is visible against the pale background

Speckled or typica form is well camouflaged against the pale background