M. Mansyur Romi Dept. of Anatomy, Embryology & Anthropology GENE MUTATION M. Mansyur Romi Dept. of Anatomy, Embryology & Anthropology

Mutation: any heritable change in the nucleotide sequence of genomic DNA caused by a replication error or by a mutagen. Mutagen  a chemical or physical agent that can cause a mutation in a DNA molecule

Type of mutations Where occur: * Gametic or germinal mutation * Somatic mutation How occur: * Spontaneous mutation * Induced mutation * Directed (adaptive) mutation

Germinal Mutation Somatic Mutation Occurs in a cell that is destined to become an egg or sperm Is transmitted to future generations Somatic Mutation Occurs in a body cell ( liver, bone etc) not ancestral to gametes. Can affect to phenotype of its carrier

Spontaneous Mutation Arise as a natural errors in replication that evade proofreading function of the DNA polymerases that synthesize new polynucleotide  mismatches Result from random thermal motions of atoms and molecules in and near the DNA Small portion and due to foreign chemicals or radiation that get inside cells and near the DNA

1. Error in replication

Mutation rate (  ) The frequency of mutation expressed as the number of mutation per locus per gamete per generation E. coli ~ 1/108 : 1 error in every 108 replication Humans ~ 1/106 – 1/105 : due to a higher complexity of human replication

Induced Mutation Following exposure to an agent, a mutagen, known to produce mutation above the rate at which they occurs spontaneously. Mutagens : Industrial chemicals, pesticides Substances in waste landfills Cigarette smoke components, drugs Radiation from atomic warfare & nuclear power industry, etc

2. Effect of mutagen

Directed (Adaptive) Mutation Arises not as a result of blind variation on the genetical level and consequent selection, but by some sort of purposeful behavior of the cell as a whole The cell is able to mutate favorably under conditions that would select for that new trait Contradicts the darwinian theory of evolution and the central dogma of molecular biology

Size of Material mechanism: Point mutation single nucleotide change not visible under a microscope Broad mutation microscopically visible aberration mechanism: deletion insertion substitution (transversion, transition) etc

Point mutation  common (single site mutation) : replace one nucleotide with another Divided into two categories: Transitions : are purine-to purine or pyrimidine-to-pyrimidine changes : AG, GA, CT, or TC. Transversions : are purine-to-pyrimidine or pyrimidine-to-purine changes: AC, AT, GC, GT, CA, CG, TA or TG

In-frame mutation  maintain reading frame (codon is intact) Out of frame/frame-shift mutation  disrupt reading frame Point mutation: Single nucleotide change  - deletion - insertion - missense - nonsense (create a stop codon) - silent (no amino acid alteration)

Point mutation : Missense Missense Silent

Deletion mutation: In-frame Out of frame

Effects of mutation Change in a morphological trait Nutritional or biochemical variation Change in behavior Changes in gene regulation Lethality

Chemical Mutagenesis Proflavine, causes addition or deletion of single bases during synthesis of new DNA strands. Nitrous acid, replacing amino groups with keto groups. DNA treated with nitrous acid produces errors during subsequent replications. 5-bromouracil, resemble the natural bases that they can be mistakenly incorporated into DNA at the time of replication.

Screening system The Ames test to suggest whether a compound is mutagenic or carcinogenic in animals by determining whether it is mutagenic in bacteria. Sister chromatid exchange after exposing the cells in vitro to the test chemical, researcher look at metaphase for chromosomal defects of various type. Blue mouse test

Radiation Mutagenesis To be mutagenic radiant energy must reach DNA directly or nearby Radiation dose: the amount of radiation absorbed by given amount of substance > units : rontgent, rad, rem, gray Is there a threshold or “ safe dose”?

Radiation Effects Somatic Effect Germinal effect - respect to chronic or low-level ionizing radiation - possible induction of cancer Germinal effect - possible induction of point mutation or chromosomal aberrations - may cause harm to immediate off spring or later descendants - Estimation: 1 rad per generation produces 1 case of genetic disease per 50.000 births in the children of those exposed

Conclusions Mutation is the key processes responsible for the variability in the genome Mutation has various effects on genome function Some cells can modify their repair processes to induce hypermutation and bacteria may be able to carry out programmed mutations

Most mutations can be corrected by DNA repair processes which include: excision procedures by removing damaged nucleotides and mismatch repair systems for correcting replication errors.

Polymorphism: Most polymorphism occurs in intronic sequence  Different nucleotide sequence that occurs in the population as a whole Deletion Insertion Duplication Missense Silent Patient (+) Control (-) Control (+) Mutation Polymorphism Most polymorphism occurs in intronic sequence

Biological system hierarchy supra individual: bio-socio-cultural Ecosystem  environmental health Species  international health Supranational  regional health National  public health Community  community medicine* Family  family medicine Individual organism  personal medicine

Biological system hierarchy infra individual: bio-physico-chemistry Organism Biomedical sciences: Organ system anatomy, physiology, Organ biochemistry, Tissue histology, cell biology, Cellular genetics, Molecular medical chemistry, Submolecular medical physics, etc.