Download Cause and effect of mutation

Causes and Effects of
mutation
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
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
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)
Non-Ionising radiation - UV radiation
—Wavelength 1000 – 4000 Å, particularly longerwave 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
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
Functional groups- basics
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
Errors in Cell Division
1. DNA replication
2. Nondisjunction during Meiosis
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
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
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
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
Harmful mutations…3
Sickle cell anaemia
• Caused by a point mutation in the βglobin 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
Start: Third Term
Point Mutations
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
Point Mutations…2
1. Deletion
– 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
Example:
– CGATGG –– CGAATGG
– GCTACC GCTTACC
3. Substitution
– One base-pair is replaced by another
Example:
– G to C or A to G
– CG T C
Point Mutation
Comparison: Insertion/Deletion
A point mutation can result in a frame-shift or in-frame mutation.
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
Example:
• TCT codes for Serine and CCT codes for Proline
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
Example:
• GTGGTCCGAAACACC –– GTGGTCTGCCGAAACACC
• Val-Val-Pro-Asn-Thr Val-Val-Cys-Pro-Asn-Thr
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
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
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
Effects of Substitution
(Missense mutation) - SCA
• Effects at DNA level
Effects at the protein level
Effects on structure of RBCs
Summary - SCA
Revisit from here,
after completing
MUTATION 2
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
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
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
Summary…1
• A mutation can be
• A replicable change in nucleotide sequence
Or
• 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
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
Summary…3
• Mutations
– 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