Polymorphisms and Mutations Flashcards
What is a mutation?
- change in genetic sequences
- can be a big change or a ingle base pair change
There are different mutation types and different causes- What can these mutations lead to?
- dramatic impacts to phenotypes
- subtle changes
- or no change
- can be positive such as resistance or negative
How frequent do mutations occur?
- trillions of cells in mammals body to changes is high
Cells are exposed to mutagenic forces every hour - these can cause endogenous and exogenous changes.
What are examples of these mutants?
- UV damage = break DNA
- oxidative damage
- chemical mutagens
- Infections = retroviruses
- spontaneous DNA decay
- errors during DNA replication e.g. cancer in cells that have to replicate quickly
DNA replication in mammal is very good at not making mistakes - what is the occurrence rate?
- only occurs on average 1 in 10 billion
How many base pairs are in the cow genome?
- 3 billion base pairs
In RNA viruses, the replication error of the RNA genome is far more common - what is the occurrence rate?
- 1 in 10,000
What is advantageous about errors in RNA virus replication of RNA?
- this can be an advantage if they change antigens and invade adaptive immune response as they may not be as easily recognised or have antibodies against them
There are two key aspects in reduction of mutations during DNA replication in eukaryotes - What are these?
- proof-reading DNA polymerases
- mismatch repair mechanism in DNA replication
DNA polymerases are not just one protein - what is their structure?
- Quaternary structure with sub-units
In mammal DNA how may DNA polymerases are there and what roles do they play?
- there are multiple DNA polymerases
- Play different roles in DNA replication
What are the different roles of DNA polymerases?
- Some play a greater role in initiation of replication (Pol alpha)
- some more important in leading strand (pol epsilon) replication
- some lagging strand replication (pol beta)
What is Polymerase gamma important in?
- important in mitochondrial DNA replication
What does exonuclease activity allow for?
- the ability to identify a mistake and cut this out
- DNA polymerase has an exonuclease subunit that gives proof reading ability and allows it to cut out mistakes
Even with proof reading exonuclease activity, DNA polymerases make an error - what is the occurrence of this?
- every 1 in 100,000 bases
- in a cow genome that is 30,000 mistakes per cell replication
How can DNA polymerase errors be partly resolved?
- by mis-match repair mechanisms
How do mis-match repair mechanisms work?
- need to identify mis-matched pairs
- insertion or deletion loops
- needs to fix these mistakes
What are insertion or deletion loops?
- extra base e.g., addition of an extra A
- or deletion in a newly synthesised strand
What molecules identify mis-match?
- range of enzymes named Mut
- MutL
- MutS
What do endonucleases do in the mismatch repair mechanism?
- cut out wrong base
What does polymerase beta do in the mis-match repair mechanism?
- heal over gap where exonucleases have cut
What does DNA ligase do in the mis-match repair mechanism?
- sticks DNA back together
Even with proof reading enzymes and mis-match repair mechanisms, what will still occur?
- mutations
What are mutations the basis of?
- they are the basis of evolution
- therefore breeds, species, genetic diseases
What do all polymorphisms begin with?
- All polymorphisms began with a mutation
- a change in the base, specific allele
What is the general rule for polymorphism occurrence?
- polymorphisms are present in >1% of the population
Mutations can be changes where and to what?
- can be changes within the coding region of the gene (exons)
- or changes in introns, promotor, regulatory regions
What is one key reason for Texel sheep musculature?
- point mutation in 3’ UTR (untranslated - pass stop codon in gene) of myostatin = impacts MiRNA post-transcription control
Why can mutations be advantageous?
- give a selective advantage and passed in to offspring
What do selectively neutral mutations lead to?
- no effect and are kept
- also known as silent mutations
What does deleterious do?
- decreases reproductive success either by increasing individuals susceptibility or predisposition to certain disease, disorder or impacting breeding outcomes
Mutations do not have a permanent classification - mutations can give advantages in different ..?
- time
- location
- tissue
- disease dependant
= generally an average
Mutations can be categories by what?
- small-scale mutations
Gives examples of small-scale mutations:
- base substitutions
- insertions
- deletions
What are base substitutions?
- single nucleotide polymorphisms (SNP)
- single base pair change
INDEL (insertion or deletion) is often in what?
- often in breeding
Small-scale mutations are often where?
- can be in coding regions
- promotors
- intronic regions
- regulatory regions
- non-gene related DNA
In the coding region (exons) these single nucleotide polymorphisms (point mutations) can be what and what do each impact?
- synonymous/non-synonymous
- missense/non-sense
- conservative or non-conservative
- lead to impacts in the phenotype
What is a synonymous mutation?
- not leading to a change in the amino acids
What is a non synonymous mutation?
- a change in the amino acid
What is missense?
- missense is when the codon changes to another amino acid codon
What is non-sense?
- non-sense is when it introduces a premature stop codon
What happens due to non-sense mutations leading to a premature stop codon?
- there is a truncated (smaller protein) missing amino acids encoded after the new stop codon
What can detect some nonsense mutations and where can it detect this?
- eukaryotic cells can detect this at the site of translation
What can eukaryotic cells detecting nonsense mutations lead to?
- can lead to nonsense mediated decay = no product so not protein gets produced
How does nonsense mediated decay work?
- proteins with the ribosome detect exon junction complexes (proteins)
- these are present upstream (- 20bp) of exon/exon boundaries
- added during RNA splicing
- if after the stop mRNA will be destroyed
For missense mutations, we can define the change depending on the relationship between what?
- the relationship between the original AA encoded and the new AA
What are the parameters for missense mutation definition?
- size
- charge
- functional impact
What is a conservative mutation?
- an amino acid replacement in a protein that changes a given amino acid to a different amino acid with similar properties
What is a non-conservative mutation?
- when the amino acid substitution involves two amino acids with very different chemical properties
In coding regions, insertion and deletions in multiples of 1 or 2 bp will lead to what?
- will lead to frame-shift mutations
What do frame-shift mutations lead to?
- all codons downstream of the insertion or deletion will not encode correctly
What happens if there are insertions of three?
- there are tolerated more often
There can be larger insertions and deletions what are examples of this?
- exons or whole genes being moved/duplicated
- gene copy differences between species common
What can gene duplication within species lead to?
- can lead to copy number variation
What is copy number variation?
- difference between individuals in copy numbers of specific genes
- more common than previously through
Mutations can also be large-scale mutations - what are examples of these?
- gene/region duplications
- chromosomal deletions
- chromosomal inversions
- chromosomal insertions
- chromosomal translocations
What can large-scale mutations play a big role in?
- speciation
What is aneuploidy?
- having missing or extra chromosomes
What are the common clinical features of a X monosomy?
- usually normal external genitalia
- abnormal oestrus or no clinical signs of oestrus
- small or hypoplastic ovaries
What does an X monosomy mutation cause and in what species?
- causes sterility in horses, cats and dogs, cattle and pigs
What are the clinical features of a xxx trisomy?
- normal eternal genitalia
- usually lack of clinical signs
- sone time irregular oestrus
What does a mutation in XXX trisomy cause and in what species?
- infertility in dogs and horses
What are the clinical signs of a mutation in XXY trisomy?
- small and hypoplastic testes
- abnormal spermatogenesis
- oligospermia or azoospermia
What does a XXY mutation cause and in what species?
- sterility in cats and cattle dog and horse and pig
What are the clinical signs of a XYY trisomy?
- usually normal phenotype
- small testes
What does a XYY trisomy cause and in what species?
- infertility in cattle
