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Semester 1- MTM > Mechanisms and Effects of Mutations > Flashcards

Mechanisms and Effects of Mutations Flashcards

1
Q

what variation in the genome exists?

A
  • Alterations in the sequence of DNA bases in a specific section
  • repetitive elements
  • larger deletions/duplications of a DNA segment
  • changes in number or structure of chromosomes
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2
Q

what 2 alterations of sequences of DNA bases can occur?

A

single nucleotide polymorphisms (SNPs) – very common
small deletions or duplications of a few bases

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3
Q

what are the two types of repetitive elements?

A

minisatellites (tandem repeat of 2-6 bp) – less than 100 bp in total

micro satellites (tandem repeats of 10-60 bp) – span several kb

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4
Q

what can larger deletions/duplications of a DNA lead to?

A

may result in single or multiple gene deletion/duplication
(copy number variation)

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5
Q

what does change in number and structure of chromosomes do?

A

causes variation within genome
can lead to problems

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6
Q

how does variation in the genome affect health?

A

it all depends on the type of variation and where it occurs.
Some changes will result in little effect or no effect whilst others can cause medical conditions.

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7
Q

what are the 4 outcomes that genome variation can lead to?

A
  • normal human variation e.g. eye colour
  • differences in response to medications (i.e. effect of antidepressants)
  • influence likelihood of disease (i.e. diabetes)
  • directly result in a genetic condition (i.e. sickle cell diseases)
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8
Q

what 3 things do you consider when classifying genome variation?

A

Size:
Large (chromosomal rearrangement)
Small (single base change)

Frequency:
Common (single nucleotide polymorphism)
Rare (mutation within a gene in one family)

Clinical Effects:
non-pathogenic (does not disrupt gene function – no change in phenotype)
pathogenic (disrupt gene function – expected to have clinical effect.)

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9
Q

what is a mutation?

A

a random and rare change to an organism DNA base sequence

Usually harmful
Can alter gene function and phenotype
Occur due to exposure to mutagenic agents but more arise spontaneously through errors in DNA replication/repair
More likely to be recognised if effects are detrimental

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10
Q

what is polymorphism?

A

difference in DNA) which are non-harmful
sequence variant is located in non-functional DNA
sequence variant is within gene but does not change the amino acid (degenerate code)
sequence variant changes an amino acid but not the function of the protein

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11
Q

what is single nucleotide polymorphism (SNP) ?

A

the change in a single DNA base at a particular locus within the DNA sequence

They are usually not harmful as they are so common - if they were harmful they would have been selected against in evolution

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12
Q

give an example of how an SNP may occur in a genome?

A

To be called a SNP a base change has to have a frequency of greater than 1% in the population.

e.g. a DNA sequence at a particular locus in some people will be AATC and in others it will be AAGC.
Because we have two alleles for each gene a person can have one of three patterns for this SNP – AATC x 2, AAGC x2 or AATC & AAGC

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13
Q

what methods can you use to examine the genome?

A

Bases- sequencing & microarray analysis
large blocks of DNA- microarray analysis & fluorescence in situ hybridisation (FISH)
chromosomal- light microscopy

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14
Q

what is Sanger sequencing?

A

dideoxy/ chain termination method
developed by Fred Sanger 1977

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15
Q

describe the chain termination method

A

1) Amplify small amounts of target DNA (usually by PCR)
2) DNA is then used as template to generate a set of fragments that differ in length from each other by a single base
3) Fragments are then separated by size and bases at the end are identified -achieved using fluorescently-labelled ddNTP terminators (dideoxynucleoside triphosphates) in automated sequencing

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16
Q

why sequence DNA?

A
  • sequencing allows us to determine the exact position of a mutation within a gene
  • determine the mutation type (e.g. single base change)
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17
Q

what has been developed for next generation sequencing?

A

Whole genomes can be sequenced for cheaper and much faster
e.g 100,000 genome project- NHS patients having genome sequenced

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18
Q

when can mutations occur?

A

during cell division
from intrinsic and extrinsic attacks on DNA:
- due to endogenous mechanisms
- due to extracellular agents

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19
Q

what would happen if there is an error in DNA replication before meiosis?

A

Error in DNA replication before cell division will be passed on to all egg/sperm will be passed on to next generation, so all cells will be affected in the offspring

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20
Q

what would happen if there is an error in DNA replication before mitosis?

A

Error in DNA replication before cell division, passed on to somatic cells, so you get somatic changes e.g. cancer . Non-inheritable

21
Q

what endogenous mechanisms in the body causes DNA damage?

A

Depurination
Deamination
Reactive oxygen (from oxidative metabolism)
methylation of cytosines

22
Q

how does depurination cause DNA damage?

A

the spontaneous fission (breakage) of the link between a purine base and a sugar. Causes a loss of adenine or guanine from helix
Results in deletion of base or incorrect nucleotide in new strand

23
Q

how does deamination case DNA damage?

A

cytosine deaminates to uracil
causes substitution of an adenine in the new strand of DNA during semi-conservative replication

24
Q

how does reactive oxygen cause DNA damage?

A

(from oxidative metabolism)
attack purine/pyrimidine rings

25
Q

how does methylation of cytosines cause DNA damage?

A

methylation of cytosines to 5-methyl-cytosine can result in the spontaneous deamination of that cytosine base to a thymine base
Therefore, there is a high frequency of C => T transitions in genome especially at CpG dinucleotides (cytosine followed by guanine in DNA sequence)
They are 30-40% of all point mutation
The frequent effect is the production of a non-sense mutation CGA –> TGA (arginine –> stop codon)

26
Q

what extracellular agents in the body cause DNA damage?

A

UV light
Environmental chemicals
ionising radiation

27
Q

how does UV light cause DNA damage?

A

results in the covalent attachment of adjacent thymine bases on the DNA strand to form a stable dimer - disrupts 3D structure and can stall replication machinery.
The bases that are damaged by sunlight (and by chemicals) are exercised and the strand resynthesised)

28
Q

how does environmental chemicals cause DNA damage?

A

interpolate into DNA, cause DNA breaks, or chromosome aneuploidy (abnormal no. of chromosomes)

29
Q

how does ionising radiation cause DNA damage?

A

causes breaks in DNA

30
Q

what happens after a mutagenic hit to the DNA?

A

DNA repair systems
cell division is stopped

if that’s unsuccessful then replication occurs and the mutation is passed on to daughter cells

31
Q

what checkpoint in the cell cycle helps prevent DNA damage?

A

the G2 checkpoint in interphase which check if all the DNA is replicated correctly and if all DNA damage is repaired before the cell enters mitosis. This is to prevent mutations being passed on to daughter cells.

32
Q

what are the 3 ways in which correcting DNA replication occurs?

A

proof reading by DNA polymerase
DNA mismatch repair system
DNA double strand break repair

33
Q

how does DNA polymerase proof read DNA?

A

checking of base after addition to see whether it is correct; immediate excision if incorrect

34
Q

how does DNA mismatch repair systems correct DNA?

A

(used as backup)
mismatch usually repaired by excision repair mechanisms
Replication copy errors leave mismatched nucleotides
This will result in a permanent mutation if the error DNA is replicated again
A protein complex recognises the mismatch, excises mismatched new strand & uses the old strand as a template to resynthesise a new strand

35
Q

what happens if there is a mutation within the mismatch repair system?

A

Mutations within the mismatch repair genes themselves (genes that code for the protein complex) means people mismatch repair mechanism does not work
this leads to the accumulation of somatic mutations - predisposed to cancers

36
Q

how does DNA double strand repair correct DNA damage?

A

can’t use the template strand as both strands are broken
So instead:
The other homologous chromosome is used to synthesise the missing DNA.
Might not be a complete match however e.g. different allele

Or another method is simply joining the broken ends. The ends are cleaved by nucleases so they are even and they are then joined together by ligase enzymes. This is error prone because you get a loss of genetic material due to deletion at the repair site.
(Mutations in genes involved in DNA repair by homologous recombination can redispose to cancer.)

37
Q

where do pathogenic mutations occur?

A

pathogenic mutations occur in the Exons (coding regions) however can happen in introns (in regulatory sequences)

38
Q

what are the types of mutations?

A

silent
missense
nonsense
splice- site
frameshift

39
Q

what are silent mutations?

A

Base pair change that doesn’t alter Amino Acid sequence (degenerate code) (commonly SNPs).
Most common type as effect is neutral so not subject to natural selection.
However, they can create a cryptic splice site (potential site of interaction for spliceosome).

40
Q

what part of the codon determines the AA?

A

usually only the first two bases in a codon will determine the amino acid, the last one is usually redundant. E.g. UAX where x = UAGC will usually code for same amino acid.

41
Q

what are missense mutations?

A

A mutation changes the codon for another AA
Can be a harmful mutation if the AA is very different in e.g. size, charge or chemical properties.
Or it can be a polymorphism with a neutral effect if the exchanged AAs are similar in nature

42
Q

what are nonsense mutations?

A

Change from an AA to a stop codon (UAA UGA UAG)
It causes truncation of protein due premature end of translation
The allele with the mutation is unlikely to retain normal activity.
The aberrant transcript is usually degraded by nonsense-mediated decay process.

43
Q

what are splice- site mutations?

A

Take place at the site where introns are spliced from pre-mRNA
Can lead to altered mRNA.
Normal splicing depends upon GU & AG donors & acceptor sites at 5’ & 3’ ends of intron.
If there is a mutation at these sites e.g. AG –> AC the site is missed and so next acceptor site is recognised and so an exon is removed as a result.
This results in substantial changes in both the size and the content of a protein.

44
Q

what are frameshift mutations?

A

Insertion or deletion of base pairs (not multiple of three)
Produces stop codon downstream
AA sequence post-mutation site is altered
This results in a shortened, altered protein being expressed or degraded by nonsense-mediated decay.

45
Q

what determines the varying effect of mutations on health?

A

Mutations have varying effect on health depending on where they occur and whether they alter the function of essential proteins.

46
Q

what determines the varying effect of mutations on health?

A

Mutations have varying effect on health depending on where they occur and whether they alter the function of essential proteins.

47
Q

what are copy number variants?

A

A small array of triplet repeats in the coding sequences of genes are prone to expand in number & disrupt gene function. If they expand above the upper normal limit they cause they cause diseases

48
Q

what diseases does copy number variants result in?

A

myotonic dystrophy
Huntington disease
fragile- X mental retardation

49
Q

how does copy number variants occur?

A

Repeat sequences in DNA cause misalignment of chromosomes and therefore unequal crossing over of non-sister chromatids during meiosis.
This causes duplication and deletion of chromosome segments
This may affect a gene, several genes or section of a chromosome
Clinical effects dependent on genes involved and gene size
Deletions are usually more severe than insertions

Semester 1- MTM (15 decks)

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