1. Causes and Effects of mutation

2. Gametic and somatic mutations
Gametic – affect testis of males or ovaries of females
can be inherited
Somatic – affect autosomes only
occur beyond zygote formation
are not heritable
affect the individual during their lifetime e.g. Chimaeras
mixture of cell types, some with the mutation and others without
can cause cancer, if gene regulation is disrupted

3. What causes mutation? Environmental Factors
Radiation (short wavelength EMWs, subatomic particles )
Ionising radiation e.g. x-rays, γ-rays
Non-ionising radiation e.g. UV light
Chemicals such as benzene, formaldehyde, carbon tetrachloride, mustard gas, alkylating agents, base analogs, nitrous acid

4. Ionising radiation - x-rays, γ rays
Cause deletions, insertions, inversions or translocations as a result of oxidative damage to DNA
Oxidative Damage
Occurs when IR interacts with water, causing an electron to be ejected from water
Irradiated water molecules become unstable and split into hydrogen ions and hydroxyl radicals
Hydrogen ions react with oxygen, forming hydroperoxyl (HO2)radicals
Both radicals are strong oxidizing agents
They cause the breakdown of the poly-sugar phosphate DNA backbone
Medical treatment associated with development of cancers (e.g. leukaemia, thyroid cancer and skin cancer)

5. Non-Ionising radiation - UV radiation
Wavelength 1000 – 4000 Å, particularly longer-wave UVA
UV light is absorbed by nucleic acids
Causes excitation of purines and pyrimidines
The excited molecules form dimers – formation of covalent bonds between adjacent purines/pyrimidines
Dimerization of thymine disrupts its base pairing with adenine
Thymine pairs with guanine instead
An AT pair is converted to a GC pair
Result: Substitution mutation

6. Chemical Mutagens
Alkylating agents: molecules which replace amino or keto groups in nucleotides with an alkyl group, such as CH3 or Ch3CH2
Base analogs: mutagenic molecules which can be substituted for purines or pyrimidines during nucleic acid synthesis, resulting in anomalous arrangements
Nitrous acid: changes the hydrogen bonding patterns of amine groups on A and C, leading to the formation of diazo groups
Aspergillus fungus release toxins that induce liver cancer

7. Functional groups- basics

8. Other Mutagens
Environmental poisons – Organic solvents such as formaldehyde, tobacco, coal tars, benzene, asbestos, some dyes
Alcohol– High alcohol intake increases the risk of some cancers
Diet high in lipids, especially fats and those containing burned or highly preserved meat

9. Errors in Cell Division
1. DNA replication

10. 2. Nondisjunction during Meiosis

11. 3. Maternal Age Human females are born with all the eggs they’ll need
The gametes are as old as an individual female is
Genetic errors in female gametes increase over time
Older females have a greater risk of chromosome abnormalities
Paternal age does not increase the risk of chromosome abnormalities as males produce new gametes throughout their lifetime

12. The effect of mutations
Not all are harmful
Survival advantage
Most common among bacteria and viruses but also seen in insects
If no selective pressure may remain in population
Survival – most common among viruses and bacteria – MRSA, also occur in multicellular organisms.
Sometimes neutral and no immediate effect. If there is no selective pressure against it, a mutation may be carried in the population and be of benefit (or harm) later on.

13. Harmful mutations...1 Cystic fibrosis - three nucleotides are lost
Sickle cell anaemia - 1 base change, typically in the beta chain
Abnormal haemoglobin
Albinism – caused by mutation in gene - enzyme pathway of melanin production
CF – loss of 3 nucleotides
Sickle cell anaemia – 1 base change
Albinism – not common in the wild because of predation

14. Harmful Mutations...2 Haemoglobin
Haemoglobin is a tetramer
2  chains, 2 -chains
The nucleotide sequences have been worked out
Several inherited diseases of abnormal haemoglobin occur on the -chain, which contains 146 amino acids
The genes for these polypeptides are found on different chromosomes
The -chain gene is found on chromosome-11
The -chain gene is found on chromosome-16

15. Harmful mutations…3 Sickle cell anaemia
Caused by a point mutation in the β-globin chain of haemoglobin
The hydrophilic amino acid glutamic acid is replaced with the hydrophobic amino acid valine at the sixth position
This point mutation is a substitution

16. Start: Third Term
Point Mutations

17. Point Mutations…1
Structural abnormalities which involve changes in a very small segment of DNA molecule
Nucleotide or nucleotide pair
Result in deletions, insertions or substitutions
Deletion; loss of a single nucleotide or nucleotide pair in a codon or a gene
Insertion (addition); addition of one or more extra nucleotides to a gene or histone
Substitution; replacing a nucleotide with a different one in a specific codon

18. Point Mutations…2 1. Deletion 2. Insertion 3. Substitution
One or more base pairs is lost from a sequence:
Example:
CGATGG –– CATGG
GCTACC GTACC
2. Insertion
One or more base pairs is added to a sequence
CGATGG –– CGAATGG
GCTACC GCTTACC
3. Substitution
One base-pair is replaced by another
G to C or A to G
C G T C

19. Point Mutation
Comparison: Insertion/Deletion
A point mutation can result in a frame-shift or in-frame mutation.

20. Possible Results of a Mutation…1
The five possible results of a mutation are:
1. Silent mutation:
When a base pair is substituted the change still codes for the same amino acid in the sequence
Example:
TCT and TCC both code for the amino acid Serine
2. Substitution:
When a base pair is substituted and the new codon codes for a different amino acid
TCT codes for Serine and CCT codes for Proline

21. Possible Results of a Mutation…2
3. Premature Stop:
When a substitution results in the formation of a STOP codon before all of the codons have been read and translated by the ribosome
Example:
GTGGTCCGAAACACC –– GTGGTCTGAAACACC
Val-Val-Pro-Asn-Thr Val-Val-STOP
4. Codon Deletion or Insertion:
A whole new amino acid is added, or one is missing from the mutant protein
GTGGTCCGAAACACC –– GTGGTCTGCCGAAACACC
Val-Val-Pro-Asn-Thr Val-Val-Cys-Pro-Asn-Thr

22. Possible Results of a Mutation…3
5. Frame Shift:
When a deletion or insertion results in a different base pair being the beginning of the next codon, changing the whole sequence of amino acids
Example:
GTGGTCCGAAACACCT –– GTGGTCGAAACACCT
Val-Val-Pro-Asn-Thr Val-Val-Glu-Thr-Pro

23. Types of Point Mutations – Effects on Protein
Missense mutations are point mutations that result in a single amino acid change within the protein
Nonsense mutations are point mutations that create a premature "translation stop signal" (or "stop" codon), causing the protein to be shortened
Silent mutations are point mutations that do not cause amino acid changes within the protein

24. Distinguishing Frameshift from Inframe Mutations
Frameshift mutation
Genetic information is altered
DNA sequence no longer divisible by three
Genetic information is read out of phase (incorrect order)
Triplet nature of gene expression (codon) disrupts reading the frame
Incorrect information = mutant (inactive, or abnormal) protein
Result; altered phenotype and/or premature death
Inframe mutation
Insertion or deletion which is evenly divisible by three

25. Effects of Substitution (Missense mutation) - SCA
Effects at DNA level

26. Effects at the protein level

27. Effects on structure of RBCs

29. Summary - SCA

30. Revisit from here, after completing
MUTATION 2

31. Effects on the organism’s fitness
Negative effects:
At high altitude and intense exercise, a carrier of the sickle cell allele experiences pain and fatigue
Positive effects:
Carriers are resistant to malaria, because the parasites that cause this disease are killed inside sickle-shaped red blood cells

32. Beneficial mutations
Bacteria – Antibiotic resistance through mutation – Transfer between bacterial species – Superbugs such as MRSA have arisen this way MRSA stands for methicillin-resistant Staphylococcus aureus – The term is used to describe a number of strains of the bacteria, Staphylococcus aureus – That are resistant to a number of antibiotics, including methicillin RNA viruses - such as HIV – Mutates it’s protein coat so that the host human is unable to make antibodies quick enough against it

33. Neutral mutations Neither harmful or beneficial to the organism
May be important in an evolutionary sense
Silent mutations
Virtually impossible to detect
No observable effect

34. Summary…1 A mutation can be A replicable change in nucleotide sequenceOr
DNA damage which is a non-replicable alteration in DNA structure
Mutations come in a variety of (often overlapping) categories including
Point mutations
Silent mutations
Missense mutations
Nonsense mutations
Insertions
Deletions
Frameshift mutations

35. Summary…2
A mutation may also involve changes in the number of chromosomes
Ploidy; aneuploidy, diploidy
Have deleterious effects
Down’s syndrome; Kleinfeler’s syndrome; Turner’s syndrome

36. Summary…3 Mutations Mutant types Are generally deleterious
Have negative effects on affected individuals
Mutant types
Are not able to compete favourably with normal individuals
Appear less frequently in a population
Kept at low frequency by natural selection