Post on 11-Jan-2016
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Mutation and Repair
Dr. YuwonoDepartemen Mikrobiologi/Klinik FK Unsri/RSMH PalembangE-mail: judeyon@yahoo.com
MUTATION
CLASSIFICATION Germline mutation Somatic mutation Beneficial or
advantageous Deleterious Neutral By effect on Structure By effect on Function By aspect of phenotype
affected
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)
Small-Scale Mutation
Substitution: Point mutationCaused 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 non-
functional 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