008 mutation Flashcards
1
Q
what is a mutation?
A
- any change in the genetic information contained in an organisms genes or chromosomes
2
Q
give some examples of mutations
A
- translocation
- insertion
- deletion
- duplication
- substitution
- addition
- transposition
3
Q
what is translocation of chromosomes?
A
- when a section of chromosome is swapped with another chromosome
- no gain or loss of genetic info
- many leukaemias are associated with these
4
Q
what is insertion in terms of chromosomes?
A
- section of a chromosome inserted into another chromosome
- problems arise at segretion
5
Q
what is deletion in terms of chromosomes?
A
- removal of a whole section of chromosome, usually at the ends
- results in abnormal gene loading
- common in lots of diseases e.g. Prader-Wili and Angelman syndrome
6
Q
what is duplication in terms of chromosomes?
A
- sections of chromosomes duplicated
- leading to abnormal gene loading and dosage effects (overexpression of genes)
- the larger the region duplicated the worse the problem
7
Q
what are DNA substitutions?
A
- changing a nucleotide base for another
- transitions and transversions
8
Q
what are transitions in DNA?
A
- when nucleotide bases are substituted but still chemically similar, so purine for a purine ( e.g. A to G) or pyrimidine for a pyrimidine (e.g. C to T)
9
Q
what are transversions in DNA?
A
- when nucleotide bases are substituted and are not chemically similar, so purine to pyrimidine or pyrimidine to purine ( e.g. A to C)
10
Q
what are DNA deletions?
A
- deletions of bases, genes or a whole section of a chromosome
- random deletion
- polymerase slippage (during replication polymerase slips and accidentally cuts out or adds a bit of DNA)
- uneven crossing over
11
Q
what are DNA additions?
A
- adding a single base, gene or section of DNA
- viral insertion (especially retroviruses), can upregulate gene expression by recruiting transcription factors if near a gene
- polymerase slippage ( during replication polymerase slips and accidently cuts or adds a bit of DNA)
- uneven crossing over
12
Q
what are DNA transpositions?
A
- transposons
- parts of the genome are cut out and moved to somewhere else
13
Q
what is the universal genetic code?
A
- there are multiple codons that code for the same amino acids
- so decreases the chance that a mutation will cause a problem
14
Q
describe the mutagen of the formation of rare tautomeric form of bases
A
- tautomeric forms of bases pair differently from their normal form
- they are transition ( still same group e.g. purine to purine e.g. A to G)
- a change in their chemical structure causes the tautomeric base to bind to a different paired base
- e.g. a rare imino form of cytosine masks as a thymine so A binds instead of G
15
Q
describe the effect of mutagen alkylating agents like ethyl methane sulfonate
A
- alkylating agens can introdue alkyl groups (e.g. -CH3, - CH3,CH2…) into nucleotides at various positions
- can also trigger misrepair of DNA
- causes transitions (swap but same group)
- e.g. Guanine masks as adenine ( G –> A) or Thymine masks as a cytosine (T –> C) so thus their pair also changes
16
Q
give examples of 2 mutagens that cause deamination of DNA bases
A
- nitrous acid (HNO2)
- heat
17
Q
what effect does mutagen nitrous acid have on DNA?
A
- deaminated nucleotides, replacing NH2 with O groups
- cytosine –> uracil/thymine
- adenine –> hypoxanthine (guanine)
18
Q
what effect does mutagen heat have on DNA in terms of NH2 group?
A
- deaminates nucleotides (NH2 replaced with O groups)
- cytosine –> thymine
- guanine –> cytosine
19
Q
what effect does mutagen UV light have on DNA?
A
- causes dimerisation of adjacent pyrimidines, particularly thymine residues
- these distort the structure of DNA and prevent normal base pairing
- the bases often need to be removed and replaced but could be incorrectly replaced
20
Q
what effect does mutagen ionizing radiation (e.g. X-rays, gamma rays) have on DNA?
A
- cause the formation of intracellular free radicals, as it knocks electrons off water
- these radicals damage individual bases and single or double strand breaks
- broken ends can join onto other chromosomes causing various abnormal chromosomal rearrangements
23
Q
what effect does mutagen of bulky adducts like aflatoxin B have on DNA?
A
- large chemical groups that form covalent associations with DNA, particularly bases
- these bases are often removed to leave apurinic sites which need to be replaced but could be replaced with the wrong base
24
Q
describe the effects of mutagen Aflotoxin B on DNA
A
- found in food in the developing world
- produced by the fungus Aspergillus flavus oryzae which grows on grain, peanuts… when stored in damp conditions
- cytochrome p450 converts it into its reactive form in the liver
- then it intercalates, bins and removes guanine bases from DNA
- strongly associated with hepatocellular carcinoma
25
Q
what is a point mutation?
A
- single substitution of bases
26
Q
what is a silent mutation?
A
- when a base is substituted by another base that will still produce the same amino acid due to the universal code
- usually has no effect
27
Q
what is a missense mutation?
A
- when a base is substitued by another base which changes the amino acid it is coded for which can change the structure/function of the protein
28
Q
what is a frameshift mutation?
A
- adding or removing a base or bases which causes every codon/amino acid to read incorrectly from that point onwards causing a completely different/non-functional protein to be formed
29
Q
what is a nonsense mutation?
A
- when a base is substituted to form a stop codon so the gene is no longer read after that so the protein is not fully formed
30
Q
describe splice site mutations
A
- when a mutation occurs in splicing processing sequences (splice donor or splice acceptor sequences) causes changes in the number of exons and introns included in mature mRNA
- e.g. accidentally including introns or removing exons
31
Q
describe the effect mutagen intercalators have on DNA
A
- intercalators e.g. ethidium bromide (used to stain DNA), acridine orange (used in fish tanks) are flat molecules that fit into one of the grooves of DNA molecule between bases
- they can interfere with DNA replication and repair and cause slipped-strand mispairing
- causes insertions and deletions
32
Q
what does a splice donor mutation cause?
A
- does not remove intron for mature mRNA
33
Q
what does a splice acceptor mutation cause?
A
- removes exons from DNA
34
Q
describe the mechanism and effect of DNA polymerase slippage/slipped strand mispairing
A
- when DNA polymerase slips during DNA replication causing it to expand or contract
- an important source of variation in repeat regions
- can occur in homopolymer tracts (e.g. ccccccc…)
- most probable cause of repeat number variation in microsatellites
35
Q
give some examples of trinucleotide expansion mutation diseases (likely due to DNA polymerase slippage)
A
- fragile X syndrome (CGG excess repeat on X chromosome)
- spinocerebellar ataxia
- Huntington’s disease (CAG excess repeats on chromosome 4)
36
Q
what is the main mechanism for short tandem repeat number variation?
A
- DNA polymerase slippage
37
Q
what is the main mechanism for insertions/deletions of DNA?
A
- unequal crossing over
- incorrect alignment of homologous chromosomes
- crossing over results in an insertion in 1 molecule and deletion in the other
- could also cause expanded trinucleotide repeats
38
Q
what is the mechanism for recurrent deletion?
A
- when there are 2 sequences that are similar, 1 may form a loop and then line up during recombination leading to misalignment and recombination
44
Q
what is mosaicism?
A
- a mutation occuring after fertilisation, but pre-embryo stage then some daughter cells will have the mutation and some will not
- causing a mosaic of cells with some with mutations and some without
- the earlier the mutation the more cells of multiple types to be effected
- if a mutation occurs later e.g. blastocyst then the mutation will be more localised to a specific cell type
45
Q
what is the mode of inheritance of hereditary hemorrhagic telangiectasia?
A
- dominance haploinsufficiency
- mutations in endoglin gene on chromosome 9
- codes for endoglin - a growth hormone receptor (TGF- beta receptor) which is expressed in the endothelial cells lining blood vessels
- insufficient endoglin due to this mutation causes disease: causes multiple arteriovenous malformations and reduced number of capillaries
46
Q
what is dominance haploinsufficiency?
A
- a single copy of the wild-type allele at a locus in a heterozygous combination with a variant allele is insufficient to produce the wild-type phenotype
- Haploinsufficiency may arise from a new or inherited loss-of-function mutation in the variant allele, such that it yields little or no gene product (often a protein)
- Although the other, standard allele still produces the standard amount of product, the total product is insufficient to produce the standard phenotype.
- This heterozygous genotype may result in a non- or sub-standard, deleterious, and (or) disease phenotype.
47
Q
what is the dominant negative effect?
A
- when the product of the mutant allele interferes with the action of the normal allele
- usually because the protein needs to form a multimer to be active
- 1 defective component inserted into the multimer can destroy the activity of the whole complex
- e.g. osteogenesis imperfecta (due to mutated allele in collagen type 1 gene)
48
Q
describe the dominant negative effect of osteogenesis imperfecta
A
- mutated allele in collagen type 1 gene
- collagen fibrils are built of arrays of triple helical procollagen units
- the type 1 procollagen is made of 2 chains encoded by COL1A1 and COL1A2 genes
- mutant chains disrupt the whole fibril
- null mutants (mutations that cause no expression) are less severe
49
Q
describe how dominant mutations can cause gain of function and give an example
A
- most mutations have no effect or loss of function but some rarely do cause gain of an undesirable function
- e.g. alpa-1-antitrypsin deficiency, normal role is to inhibit elastase in the lung, most mutations in alpha-1-antitrypsin reduce this function
- but a rare single nucleotide mutation can change its specificity from elastin to thrombin
- this results in serum thrombin being mopped up = haemophilia
50
Q
describe how retinoblastoma is an example of dominance at the level of the organism, but recessivity at the level of the cell
A
- 2 mutant alleles of tumour suppressor genes in a cell will result in unregulated cell growth (tumour)
- but if an individual inherits only 1 mutant allele then most cells will be protected against unregulated growth by the normal allele (recessive)
- however, a small number of cells will pick up somatic mutations in the normal allele leading to unregulated growth
- thus an individual inheriting only 1 mutant allele will develop tumours (dominant) at level of organism
- retinoblastoma (RBI gene)
