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Febr.19. 2016
Genetic variability
- is increased by – mutation
– sexual reproduction
fertilisation
- significance
DNA
Mutation
(causing any
change)
Appearance of
new variant
by mutation Survival of rare allele
• by the cause
• by the site
• by the function
• by the fitness
• by the size
By the cause mutations may be
• Spontaneous
• Induced
Spontaneous mutation
T-A
(Purine-Purine)
results
Depurination (hydrolysis)
Deamination
DNA methylation
(regulation of DNA functions,
see epigenetics)
Induced mutation
– chemicals
• Natural toxins
• Synthetic substances
– Laboratory substances
– Pollutants
– Chemoterapeutics
Natural substances
Psoralen
Acrylamide Polyacrylamide
Pollutants
DNA adduct
Mutation
Biological warfare agent
Mustard gase
M
G1
G2 Go
G2
Restriction
point
- Growth factors
- anchorange
Checkpoints: S
Restriction point
G2 Interphase
M (spindle)
Function and activity of
checkpoint machinery
G1 G2 M
sensor
protein kinases
transducer
effector
s t o p of c e l l c y c l e
repair
Ataxia telangiectasia
(ATM=sensor)
UTR UTR
3 4
1/ Promoter mutations decreased transcription
2/ Exon mutations amino acid change or truncated protein (stop) see
later
3/ Intron mutations errors in splicing
4/ Polyadenylation site mutations decreased mRNA stability
5 5 UTR disturbed ribosome binding
Mutations of other regulatory sequences (enhancers, silencers) also may
influence transcription.
Most frequent
Function and mutations
Back mutation or reversion is a point mutation that restores the
original sequence and hence the original phenotype.
Lethal mutations are mutations that lead to the death of the
organisms which carry the mutations.
Gain-of-function mutations - change the gene product such that it
gains a new and abnormal function. These mutations usually have
dominant phenotypes.
Loss-of-function mutations - gene product having less or no function.
Phenotypes associated with such mutations are most often recessive.
Exception is when the reduced dosage of a normal
gene product is not enough for a normal phenotye
(this is called haploinsufficiency).
Dominant negative mutations - the altered gene product acts
antagonistically to the wild-type allele.
These mutations are characterised by a dominant
phenotype. In humans, dominant negative
mutations have been implicated in cancer (e.g.
mutations in genes p53, ATM).
Fitness and mutations
• Large
Genome mutation = change of chromosome number
Cytogenetics
• Medium
Chromosome mutations = change of chromosome structure
• Small
gene mutations = ranging from a change of single nucleotide to a whole
gene (not visible)
Affecting the lenght of DNA
Deletion (single base or shorter-longer sequences)
– Tandem repeats
• Satellite DNA
– pericentromeric heterochromatin
• Minisatellite (VNTR)
– 10-60 bp
– Telomere
• Microsatellite (STR=short tandem repeats)
– 2- some bp
– good markers of kinship
– Repeat number expansion diseases
– Interspersed repeats
• SINEs (Short Interspersed Elements),
• LINEs (Long …) e. g. L1
38
Microsatellite
(STR = short tandem repeats)
• 1-4 bp
• Trinucleotide (triplet) repeats are very frequent
– only few of them cause disease
Trinucleotide repeats may be either in coding(C) or
noncoding (NC) region
NC
NC
(huntingtin)
(Huntingtin)
C
C coding
NC noncoding
Polyglutamine Polyalanine
disorders disorders
• CAG repeats
• Neurodegenerative disorders
• Different proteins
• Variable length
• Expansion
• Replicational slippage
Replication slippage
Huntingtin
MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQQQPPPP
PPPPPPPQLPQPPPQAQPLLPQPQPPPPPPPPPPGPAVAEEPLHRPK
KELSATKKDRVNHCLTICENIVAQSVRNSPEFQKLLGIAHELFLLCSDD...
• 350 kD protein
• ubiquitously expressed
• function unknown Huntington
• correlation between
repeat size and age of
onset and the severity of
disease (Huntington healthy
chorea)
Polyglutamine Polyalanine
disorders disorders
• Expansion • Stable
Disorder Gene
• Holoprosencephaly ZIC2
Deletion or insertion of a single nucleotide (InDel)
mRNA
protein
Mutant protein
Medium InDel mutations
• Deletion
– Pl. Hypodontia
(Deletion of Pax 9)
• Insertion
– (retro)transposons
• Eg. L1 hemophilia A
L1 is a LINE: Long Interspersed Elements
L1 insertion and recombination in Hemophilia A
51
Single nucleotide substitution
Nucleotide substitutions in coding region
Pyr ↔ Pyr
Transition Pu ↔ Pu
Transversion Pyr ↔ Pu
– Phenotype polymorphism
– Protein polymorphism (Immunoglobulins, ABO blood groups)
– Genetic (DNA) polymorphism
Rate of genetic polymorphism
In
human genome there are many, that is
why can be used for personal identification
Minisatellite (VNTR)
Telomere
ATGGTAAGCCTGAGCTGACTTAGCGT
ATGGTAAACCTGAGTTGACTTAGCGT
SNP SNP
Disease resistant population Disease susceptible population
Association ≠ correlation
1 kb - 5 megab
About 1500 CNV
12% of genome
2900 gene
is based on mutations and polymorphisms
Giude to point mutations