Mutation and Repair

Dr. Yuwono
Departemen Mikrobiologi/Klinik FK Unsri/RSMH Palembang
E-mail: judeyon@yahoo.com

MUTATION
Changes to the base

pair sequence of genetic

material (either DNA or
RNA)
Errors in replication
Exposure to uv, ionizing
radiation, chemical
mutagens, or viruses
Occurs deliberately
under cellular control
during processes
(meiosis or
hypermutation)

CLASSIFICATION
Germline mutation
Somatic mutation
Beneficial or
advantageous
Deleterious
Neutral
By effect on Structure
By effect on Function
By aspect of phenotype
affected

Small-Scale Mutation
Substitution: Point mutation

Caused by chemicals or malfunction of DNA replication

Transition: purinepurine,
pyrimidinepyrimidine
Transversion: purinepyrimidine
pyrimidinepurine
PM within protein coding region of a gene:
Silent mutation: same amino acid
Missense mutation: different amino acid
Nonsense mutation: stop codon no amino acid

Small-Scale Mutation
Insertion:

caused by transposable elements or errors

during replication of repeating elements
in the coding region of a gene alter
splicing of mRNA (splice site mutation), or
cause a shift in the reading frame (frame
shift)
can be reverted by excision of the
transposable element

Replication slippage

Small-Scale Mutation
Deletion:

Remove one or more nucleotides from the

DNA
Frameshift mutation
Splice site mutation
Irreversible

Large-Scale Mutation
In chromosomal structure
Amplification (gene duplication)
multiple copies of chromosomal regions
Deletion of large chromosomal regions
loss of the genes within those regions
Others:

Chromosomal translocation
Chromosomal inversion

Loss of heterozygosity:
Loss of one allele, by deletion or recombination

By effect on function
Loss-of-function mutation:

Gene products have less or no function

Null allele Amorphic mutation
Phenotype: most often recessive
Exception: in haploid cell or haploinsufficiency

Gain-of-function mutation:

Change the gene product gains a new and

abnormal function
Phenotype: usually dominant
Neomorphic mutation

By effect on function
Dominant negative mutation:

Antimorphic mutation
Altered gene product acts antagonistically
to the wild-type allele
Altered molecular function often inactive
Phenotype: dominant or semidominant

Lethal mutation:

Lead to a phenotype incapable of effective

reproduction

By aspect of phenotype
affected
Morphological mutation:

Affect the outward appearance of an

individual

Biochemical mutation:

Result in lesions stopping the enzymatic

pathway
Often, morphological mutant are the direct
result of a mutation due to the enzymatic
pathway

Special classes
Conditional mutation:

Has wild-type (or less severe) phenotype

under certain permissive environmental
conditions and a mutant phenotype under
certain restrictive condition
Example: A temperature-sensitive mutation

Causes of Mutation
Spontaneous mutation:

Tautomerism
Depurination
Deamination
Transition
Transversion

Induced mutation:

Caused by mutagen
(chemical and
radiation)

DNA Repair system

Enzymes: DNA polymerase
Each cell has a number of pathways

through which enzymes recognize and

repair mistake in DNA.
DNA can be damaged or mutated in
many ways the process of DNA repair
is an important way in which the body
protects itself from disease

Effect of Mutation
Changes the nucleotide sequence of gene

causes:

errors in amino acid sequence of protein

Alter protein 3D-structure (active site)
Alter protein function (partially or completely nonfunctional protein)

Mutation that alters a protein that plays a critical

role in the body genetic disorder

Only a small percentage of mutations cause
genetic disorders

Effect of Mutation
Mutation in a germ cell: offspring carries

the mutation in all of its cells

hereditary diseases
Mutation in a somatic cell: present in all
descendants of this cell, and certain
mutations can cause the cell to become
malignant cancer

Positive Effect of Mutation

Lead to new versions of proteins that

help an organism and its future

generations better adapt to changes in
their environment
E.g. a specific 32 bp deletion in human
CCR5 (CCR5-32) confers HIV resistance
to homozygotes and delays AIDS onset
in heterozygotes

Clinical Significances
Sickle cell anemia (HbS): the substitution of a hydrophobic

amino acid (V) for an acidic amino acid (E) in the -chain of
hemoglobin
Collagen diseases: Larsen syndrome, scurvy, osteogenesis
imperfecta and Ehlers-Danlos syndrome arising from
abnormal genes or abnormal processing of collagen proteins
Familial hypercholesterolemia: result of genetic defects in the
gene encoding the receptor for low-density lipoprotein (LDL)
Mutation of proto-oncogenes oncogenes: oncoproteins that
contribute to cellular transformation and carcinogenesis
Mutation of c-Ras genes: single amino acid substitutions at
positions 12 or 61 high frequency in colon carcinomas

Terima Kasih