Mechanisms And Effects Of Mutations Flashcards
What kinds of alterations are there in sequence of bases in specific sections of DNA?
- Single nucleotide polymorphism (common)
- Small deletions/ duplications (few bases)
Types of tandem repeats? 2
- Microsatellites 2-3 base pairs
- Minisatellites 10-60 base pairs
Types of variation in genome
- Alteration in sequence of bases in specific sections of DNA
- Tandem repeats
- Larger duplications/ deletions
- Changes in number or structure of chromosomes
Variation in genome can lead to
Altered effects of a protein
Difference in control of genes
Genome variation can lead to (examples)
Normal human variation eye colour
Difference in response to medication
Influence the likelihood of disease (more common)
Directly the result of a genetic disease
Three ways genome variant classified
- Size
- Frequency
- Clinical effects
What is a mutation?
An alteration or change in genetic material
Causes of mutations?
Exposure to mutagenic agents
Spontaneously through errors in DNA replication/ repair
How can polymorphism be non harmful
Sequence variant is in non functional DNA
Sequence variant within gene but doesn’t change aa
Sequence variant changed aa but doesn’t alter protein function
Polymorphism?
Two or more possibilities of a trait on a gene
SNP?
Single nucleotide polymorphism (most common type of variant)
To be called SNP base Change has to have frequency of less than 1%
Example of SNP?
Change of C to a T
One of three patterns CC, CT, TT
How an genome be examined?
Examine bases - sequencing/ microanalysis
Examine large blocks of DNA - FISH/ microanalysis
Chromosomal - light microscopy
Steps of DNA sequencing
- Amplify very small amounts of target DNA (usually by PCR)
- DNA is used as a template to generate a set of fragments that
differ in length from each other by a single base. - The fragments are then separated by size, and the bases at the end are identified, recreating the original sequence of the DNA.
Why sequence DNA?
Determine exact POSITION of mutation
Determine the TYPE of mutation
Next generation sequencing?
Whole molecule sequencing
Much faster and cheaper
Predict health, diagnosis, individualised med
When do mutations occur?
- During cell division
- From intrinsic and extrinsic attacks on DNA
What is reduction division
1 round of replication
2 rounds of division
(Meiosis)
How does meoitic cell division cause human disease
Passed on to offspring
Heritable
How does mitotic division cause disease
Somatic cells affected
Cancer/ non inheritable
Endogenous mechanism
Originate from inside the body
Endogenous mechanisms causing DNA damage
- Depurination - spontaneous breakage of link between purine base and sugar. Loss of A or G.
- Deamintion - C delaminates to U. Substitution of A on new strand.
- Reactive oxygen - attack purine/ pyrimidine rings
- Methylation of cytosines
Methylation of cytosines?
High frequency of deamination of C to T
Common at CpG dinucleotides
Extracellular agents causing DNA damage
- Ultraviolet light - covalent linkage of adjacent Ts to form stable dimers. Stop DNA replication.
- Environmental chemicals
- Ionising radiation - breaks DNA
G2 checkpoint?
Check if DNA replicated correctly before enters mitosis
Prevent passing mutations to daughter cells
Methods of correcting DNA replication errors?
- Proof reading by DNA polymerase
- DNA mismatch repair system (back up)
- DNA double strand break repair
Pathogenic mutations?
Occur in exons and in regulatory sequences in introns
Detection of a pathogenic mutation allows genetic testing for other family members and in some diseases influences clinical management
Types of point mutations
Missense - change in singe base
Nonsense - change of aa to a stop codon. Creates truncated (short) protein.
Frameshift - insertions/ deletions/ duplications
Silent - degenerative. Doesn’t affect amino acid
Splice site - mRNA altered
None sense mediated decay process
Degradation of truncated protein
Splice site mutations
Alters mRNA
Site where introns are spliced from pre mRNA
GU donor sites
AG acceptor sites
Mutations at site causes site to be missed and acceptor site recognised causing removal of exon
Copy number variants
Small arrays of triplet repeats in coding sequences of genes that are prone to expand in number and disrupt gene function
Effects of Larger deletions/ insertions of copy number variants?
- Causes misalignment of chromosomes leading to unequal crossing over of non sister chromatids during meiosis
- deletions more severe
- clinical effects depend on genes involved and gene size
What is spliceosome
The spliceosome precisely removes introns from pre-mRNA to generate mature messages (mRNA), a process referred to as pre-mRNA splicing. The spliceosome is essential for cell function and defective pre-mRNA splicing causes disease
