Mutations & cancer Flashcards
Defn. Gene mutation
is a mutation that involves a change in the nucleotide sequence of a DNA molecule at a particular gene locus
Defn. Chromosomal abberation/ mutation
is a mutation that involves a change in the structure or number of chromosomes
Types of gene mutation
- Substitution
- Addition
- Deletion
Gene mutation: Substitution
Substitution is the replacement of one or more nucleotide pairs with another pair of nucleotides
Gene mutation: Addition
Addition is the insertion of one or more nucleotide pairs into a DNA sequence
Gene mutation: Deletion
Deletion is a mutation in which one or more nucleotide pairs are removed from a DNA sequence
Frameshift mutation
- Additions or deletions often have a disastrous effect on the resulting protein
- mRNA is read as a series of triplet nucleotide during translation, addition or deletion of nucleotide pair may alter the reading frame (triplet grouping) of the genetic message
- Frameshift mutations occur whenever the number of nucleotides inserted or deleted is not a multiple of three
- All the nucleotides that are downstream of the addition or deletion will be improperly grouped into codons. which results in extensive change in the sequence of amino acids
- The change in codons may also result in premature termination
- Unless the frameshift is very near the end of the gene, it will produce a protein that is almost certain to be non-functional
Numerical aberration (aneuploidy)
is the condition during which an organism possesses an extra chromosome (2n+1) or lacks a chromosome (2n-1)
Non-disjunction is an error during meiosis when:
- a pair of homologous chromosomes fail to separate during Anaphase I of meiosis
- or sister chromatids fail to separate during Anaphase II of meiosis
Aberrant gametes:
1. A gamete receives two of the same type of chromosome/ extra chromosome
1. A gamete with no copy of a particular type of chromosome/ lacks a chromosome
2. If aberrant gamete fuses with a normal gamete during fertilisation, the zygote will have an extra chromosome or a missing chromosome
3. Non-disjunction during anaphase I of meiosis results in all aberrant gametes (50% have n+1 chromosomes and 50% have n-1 chromosomes)
3. Non-disjunction at anaphase II of meiosis results in half normal gametes and half aberrant gametes
Change in no. of sets of chromosomes present in the cell (Polyploidy)
- condition where an organism acquires more than two complete sets of chromosomes
- eg. triploids, tetraploids
- triploidy may arise by the fertilisation of an abnormal diploid egg produced by non-disjunction of all its chromosomes with a normal sperm
- tetraploidy could result in the failure of 2n zygote to divide after replicating its genetic material. Subsequent normal mitotic divisions would then produce a 4n embryo
Down’s syndrome
is an aneuploid condition in humans.
It is the result of an extra chromosome 21, such that each somatic cell has a total of 47 chromosomes. Down’s syndrome is often called trisomy 21 as there are three chromosomes 21
Structural aberration
- Deletion of a chromosomal fragment
- Duplication of a chromosomal fragment
- Inversion of a chromosomal fragment
- Translocation of a chromosomal fragment
Structural aberration: Deletion
Deletion occurs when a chromosomal fragment is lost. Certain genes will be missing from the affected chromosome
Structural aberration: Duplication
occurs when a detached chromosomal fragment from a sister chromatid become attached as an extra fragment to a non-sister chromatid of a homologous chromosome / the other sister chromatid during meiosis
Structural aberration: Inversion
occurs with a fragment of a chromosome breaks off and reattaches to the original chromosome in a reverse orientation
Structural aberration: Translocation
occurs when chromosomal fragment breaks and joins with a non-homologous chromosome
Effects of gene mutations
- Silent mutation
- Missense mutation
- Nonsense mutation
SIlent mutation
Mutations that have no effect on amino acid sequence. no observable effect on phenotype of organism.
Some substitution mutations are silent due to the redundancy/ degeneracy of the genetic code
Missense mutation
change amino acid but have little effect on the protein because new amino acid may have properties similar to those of the amino acid it replaces
Substitution usually results in missense mutations
Nonsense mutation
- A point mutation can also change a codon for an amino acid into a stop codon.
- This causes translation to be terminated prematurely.
- This nonsense mutation results in the polypeptide formed being shorter than the polypeptide encoded by the normal gene.
- Nearly all nonsense mutations lead to non-functional proteins
Sickle-cell anaemia
- Autosomal recessive disorder
- The genetic basis of sickle-cell anaemia is due to mutation of a single base pair in the gene coding for one of the polypeptides of haemoglobin
- The substitution of a single nucleotide, from CTT to CAT in the DNA’s template strand of chromosome 11 leads to a change in the codon of mRNA
- Original amino acid coded for is glutamate is changed to valine at the sixth position
- Glutamate is hydrophillic while valine is hydrophobic
- The mutated haemoglobin tends to polymerise into long rigid chains when not bound to oxygen due to hydrophobic interactions between the hydrophobic regions on different Hb molecules
- The long fibres distort the membrane if the RBC, giving it its distinct sickle shape
- This results in the decreased oxygen-carrying ability of the RBC
- in individuals who are homozygous for the mutant allele, altered Hb results in the sickling of RBC and produces the multiple symptoms associated with the sicle
Causative factors
increases the chance of cancerous growth
- Physical factors
- Ionising radiation
- Ultra-violet light - Chemical factors (carcinogens)
- Biological
- Viruses
- Fungus - Genetic factor
- mutated genes such as either oncogenes or tumour suppressor genes found in gametes of parents - Loss of immunity
Proto-oncogenes
- Proto-oncogenes encode proteins that stimulate normal cell division
- The gain-of-function mutation of proto-oncogenes to oncogenes leads to increase in the amount of proto-oncogene’s protein product or permanently activated proteins
- this will result in uncontrolled cell division, possibly leading to cancer
- Gain-of-function mutation result in a dominant allele as the effect of the normal allele is masked by the mutated allele. Only 1 allele of a gene need to be mutated to have an effect
- Eg. Ras gene codes for Ras protein, which is a G protein that relays a signal from growth factor receptor on cell surface membrane to a cascade of protein kinases which result in normal cell division
Tumour suppressor genes
- Tumour suppressor genes encode proteins that inhibit cell division or promote apoptosis (controlled cell death)
- The loss-of-function mutation of tumour suppressor genes to mutated tumour suppressor genes leads to no protein product or decrease in amount of protein product or permanently deactivated proteins
- This will result in uncontrolled cell division, possibly leading to cancer
- Loss-of-function mutation result in a recessive allele as the normal dominant allele encodes functional protein. 2 alleles of a gene need to be mutated to have an effect
- Eg. p53 gene codes for p53 protein, which is a transcription factor that promotes synthesis of protein that triggers cell cycle arrest or promote apoptosis when DNA damage is detected
Checkpoints during the mitotic cell cycle
- G1 checkpoint ensures that the cell size is adequate and there are sufficient nutrients available and growth factors present for cell to undergo mitosis
-> if the cell doesn’t pass the G1 checkpoint, the cell will exit the cycle, switching into a non-dividing state called the G0 phase - G2 checkpoint ensures that the cell size is adequate and semi-conservative DNA replication has been completed successfully
- Metaphase checkpoint ensures that all chromosomes are attached to spindle fibres/ microtubules at the metaphase plate before proceeding to anaphase
