4. Genetic variations Flashcards
Significance of genetic variability
Provides raw material for evolution and allows the adaptation of the species to unexpected changes of environment
Genetic variability is increased by (6)
- Sexual reproduction
- Meiosis (generation of gametes)
- Homologous recombination (crossing over)
- Independent assortment of homologous chromosomes
- Fertilisation
- Mutations (new variations produced)
Which allele is the most frequents in a population?
The normal/wild allelic variant
A mutant is an allelic variant of a DNA sequence which…
Causes disease (has recently occurred and it has reference)
Polymorphism
Is an allelic variant of a DNA sequence, which has no effect on phenotype and its frequency is >1% in a population
Spontaneous mutations can be caused by
- Spontaneous chemical reactions in bases (tautomerization, deputisation, deamination)
- Errors in DNA related processes (relocation, recombination, repair)
Frequent tautomer of adenine
Amino form
Rare tautomer of adenine
Imino form
Tautomerization of an adenine residue can result in..
Transition of A-T to a G-C base pair
Rare tautomer of cytosine and adenine
Imino form
Rare tautomer of thymine and guanine
Enol form
Process of depurination
- A base eg. G is lost (depurination)
- Apurinic site cannot provide a template for a complementary base on the newly synthesized strand
- Nucleotide with incorrect base (usually A) -> Into new strand
- Next round of replication. Wrong nucleotide used as template
- =Permanent mutation
Deamination
Removal of NH2 to produce different nucleotide
- Cytosine -> Uracil (repaired)
- Cytosine -> Thymine (not repaired)
Examples of induced mutation
By environmental agent =mutagen
- Physical: Radiation (heat, UV, ionization)
- Chemicals (natural toxins, synthetic substances)
- Biological: Viruses
Checkpoints in cell cycle
- Restriction point (right before S)
- G2 (right before M)
- M (spindle)
Participants of checkpoint machinery
- Sensor and transducer (protein kinases)
- Effector
- Senses and stops cell cycle in case of DNA damage
Transducers of G1 checkpoint
ATM and BRCA1
Mutation of ATM causes
Ataxia telangiectasia
- Neurodegenerative, inherited (AR) disease
- Characterized by radio sensitivity and different tumors
BRCA mutation found in
Breast, ovarian and other types of cancer
Effector of G1 checkpoint
p53
Responsible for correction of DNA errors
DNA polymerase with proofreading ability
Direct repair of DNA
The change is reversed, no template is needed, mainly in prokaryotes
Excision repair of DNA
Template is needed, in eukaryotes
What kind of repair mechanisms exists in mitochondria?
None, only repair mechanisms for nuclear DNA
Nucleotide-excision repair is defective in
- Xeroderma pigmentosum
+ Cockayne syndrome, Trichothiodystrophy
3 ways to repair single strand damage (SSD)
- Nucleotide-excision repair
- Base-excision repair
- Mismatch repair
Mismatch repair is defective in
Hereditary non-polyposis colon cancer
Repair of double strand breaks (DSB)
- Homologous recombination
- Non-homologous end-joining
Template in homologous recombination
- Sister chromatid (after S phase)
- Homologous chromosome
=safety
Template in non-homologous end-joining
No template, may result in loss of nucleotides = deleterious
Mutations might be somatic or generative. Difference between the two
- Somatic: Passed on to other somatic cells but not to next generation
- Generative: In primordial germ line, inherited from one generation to the next one
Increased risk for nondisjunction with age, might lead to
Change of chromosome number
Increased risk for replication errors with age, might lead to
Point mutations
What happens to the association between homologous chrs. in oogenesis with age?
Association gradually weakens (cohesion molecules detach from sister chromatids) -> eventually chiasma also dissociates
6 places where mutations can happen in the gene
- Promotor region -> dec. transcription
- Exon -> AA change or truncated protein (stop)
- Intron -> Errors in splicing
- Polyadenylation site -> Dec. mRNA stability
- 5`UTR -> Dec. protein synthesis
- 3´UTR -> Disturbed translation and localisation
Splicing mutations
When there is a mutant splice donor (or acceptor) e.g. donor GU is changes for CU. Next sequence is recognised as donor sequence -> mutant RNA
By function, mutations may be (5)
- Back mutation/reversion
- Lethal mutations
- Suppressor mutation
- Gain-of-function mutations
- Loss-of-function mutation
Haploinsufficiency is a special type of …. mutation
Loss-of-function
Size of mutations
- Large scale: Genome mutations (chr. nr. change)
- Medium scale: Chr. mutations (chr. structure change)
- Small scale: Not visible
Frameshift mutation
If number of nucleotide is not a multiple of three
In-frame mutation
If number of nucleotide is a multiple of three
Tandem repeats
- Satellite DNA
- Minisatellite (10-60bp)
- Microsatellite (2- some bp)
Interspersed repeats
SINEs (short interspersed elements
LINEs (long interspersed elements)
Trinucleotide repeats (micro satellite) can be found in what regions?
Both in coding and non-coding regions
Cause of 40% of Hemophilia A
Inversion mutation due to recombination between L1 repetitive sequences within and outside the F8 gene
Sickle cell anaemia is the result of what kind of mutation
Missense mutation
Point mutations
- Silent
- Missense
- Nonsense
Silent mutation
Change in nucleotide sequence that does not change the AA specified by the codon
Missense mutation
A single nucleotide change resulting in a codon that codes for a different amino acid
Nonsense mutation
Change in nucleotide sequence that results in an early stop codon
Duchenne muscular dystrophy cause
Frameshift mutation leading to non-functional dystrophin
Becker muscular dystrophy cause
In frame mutation leading to a partially functional dystrophin
