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