4L. Mutations and polymorphisms Flashcards
Different meanings of mutation and polymorphism
Mutation: process causing inherited change
- Formerly: a variant (allele) of a DNA sequence, which causes disease (formerly)
- Newly: recently occured and it has reference
Polymorphism: genetic (DNA) variability
- Formerly: a variant (allele) of a DNA sequence, which has no effect on phenotype and its frequency is > 1 % in a population (formerly)
- Newly: only if the frequency is known
Better to use terms: sequence or allelic variant
Significance of mutation
Fra nettet: Mutations typically favor a small subset of a population rather than the majority, which often causes evolutionary bottlenecks that change the gene pool of the species in question.
At the same time, some mutations can be a deficit to individuals
Classification of mutations by cause: spontaneous
Spontaneous chemical reactions in bases
1) Tautomerization (OOH or NH2NH, *most common)
2) Depurination (hydrolysis - often cause permanent mutations due to random base matched w/apurinic site)
3) Deamination (in cytosine: -> uracil (repaired), in 5-methylcytosine: -> thymine (not repaired - methylated)
Errors in DNA related processes
- Replication
- Recombination
- Repair
Classification of mutations by cause: induced
By environmental agent - mutagen
1) Physical (radiation)
- Heat, UV, ionizing
2) Chemicals
- Natural toxins (e.g aflatoxin)
- Synthetic substances (lab. subst., pollutants, chemotherapeutics)
3) Biological
- Viruses
Classification of mutations by cause: different DNA repair mechanisms
1) Cell cycle checkpoint machinaries
2) DNA polymerase with proofreading ability
3) Direct repair (no template - mainly prokaryotes)
4) Excision repair (template - in eukaryotes)
5) Single stranded damage repair (SSD)
- Complementer strand as template
a. Nucleotide-excision repair
b. Base-excision repair
c. Mismatch repair
6) Double strand break repair (DSB)
a. Homologous recombination
b. Nonhomologous end-joining
Classification of mutations by cause: role and failure of checkpoint machinary in repair
Cell cycle checkpoint machinaries + what repaired
1) DSB repair (HR, NHEJ)
- Double strand breaks (radio-/chemotherapy)
2) Nucleotide excision repair
- Helix-distorting damage (UV)
3) Mismatch repair
- Mismatches, insertions, deletions (replication errors)
4) Direct reversal
- O6-alkyl-guanine (alkylating agents)
5) Single-strand break repair
- Single strand breaks (ROS)
6) Base excision repair
- Base damage
Classification of mutations by site: in the organism (somatic, generative)
Somatic - Arise in somatic cells
- Passed on to other somatic cells, but not to next generation
- Effect depends on cell and timing
- Results: tumors, complete/sectorial heterochromia (eye color)
Generative - In primordial germ line
- Inherited from one generation to the next one
- Female: Increased risk for nondisjunction with age
- > change in chromosome number - Male: Increased risk for replication errors with age
- > point mutations
Classification of mutations by site: in the gene
1) Promoter mutations -> decreased trancription
2) Exon mutations -> amino acid change or truncated protein (stop)
3) Intron mutations -> errors in splicing
4) Polyadenylation site mutations -> decreased mRNA stability
5) 5’ UTR -> decreased protein synthesis
6) 3’ UTR -> disturbed translation and localization
Classification of mutations by function: loss-of-function
Loss-of-function mutation
- Gene product having less or no function
- Phenotypes associated with such mutations are most often recessive, expressed in homozygote (except: haploinsufficiency)
Classification of mutations by function: gain-of-function
Gain-of-function mutation
- Change the gene product so that it gains a new and abnormal function
- Phenotypes usually dominant, expressed only in heterozygotes
Classification of mutations by function: dominant negative
Dominant negative nutation: haploinsufficiency
- Special loss-of-function mutation with dominant phenotype, so that both homo- and heterozygotes are affected
- One copy of a normal allele is not enough -> mutant phenotype (abnormal gene inhibit normal gene)
- Example: Marphan syndrome, p53
Classification of mutations by function: lethal
Lethal mutations
- Lead to death of organism with the mutation
Classification of mutations by function: back
Back mutation or reversion
- A mutation that restores the original sequence and hence the original phenotype
Classification of mutations by fitness: neutral
Neutral mutation
- During evolution may be harmful or beneficial
Classification of mutations by fitness: beneficial + examples
Beneficial mutation
- Harmful mutation mutated back to wild (back mutation)
- Getting beneficial function
a. CCR5Δ32 - HIV resistency
b. Sickle cell anemia - malaria resistency
c. PCSK9 deletion - no bad cholesterol
d. SLC30A8 - decreased chance diabetes
e. Tetrachromacy - supervision (normal humans: trichromates - 3 types of cones)
