Mutations & cancer

Question 1

Defn. Gene mutation

Answer 1

is a mutation that involves a change in the nucleotide sequence of a DNA molecule at a particular gene locus

Question 2

Defn. Chromosomal abberation/ mutation

Answer 2

is a mutation that involves a change in the structure or number of chromosomes

Question 3

Types of gene mutation

Answer 3

1. Substitution
2. Addition
3. Deletion

Question 4

Gene mutation: Substitution

Answer 4

Substitution is the replacement of one or more nucleotide pairs with another pair of nucleotides

Question 5

Gene mutation: Addition

Answer 5

Addition is the insertion of one or more nucleotide pairs into a DNA sequence

Question 6

Gene mutation: Deletion

Answer 6

Deletion is a mutation in which one or more nucleotide pairs are removed from a DNA sequence

Question 7

Frameshift mutation

Answer 7

1. Additions or deletions often have a disastrous effect on the resulting protein
2. 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
3. Frameshift mutations occur whenever the number of nucleotides inserted or deleted is not a multiple of three
4. 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
5. The change in codons may also result in premature termination
6. Unless the frameshift is very near the end of the gene, it will produce a protein that is almost certain to be non-functional

Question 8

Numerical aberration (aneuploidy)

Answer 8

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

Question 9

Change in no. of sets of chromosomes present in the cell (Polyploidy)

Answer 9

• 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

Question 10

Down’s syndrome

Answer 10

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

Question 11

Structural aberration

Answer 11

1. Deletion of a chromosomal fragment
2. Duplication of a chromosomal fragment
3. Inversion of a chromosomal fragment
4. Translocation of a chromosomal fragment

Question 12

Structural aberration: Deletion

Answer 12

Deletion occurs when a chromosomal fragment is lost. Certain genes will be missing from the affected chromosome

Question 13

Structural aberration: Duplication

Answer 13

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

Question 14

Structural aberration: Inversion

Answer 14

occurs with a fragment of a chromosome breaks off and reattaches to the original chromosome in a reverse orientation

Question 15

Structural aberration: Translocation

Answer 15

occurs when chromosomal fragment breaks and joins with a non-homologous chromosome

Question 16

Effects of gene mutations

Answer 16

1. Silent mutation
2. Missense mutation
3. Nonsense mutation

Question 17

SIlent mutation

Answer 17

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

Question 18

Missense mutation

Answer 18

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

Question 19

Nonsense mutation

Answer 19

• 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

Question 20

Sickle-cell anaemia

Answer 20

1. Autosomal recessive disorder
2. 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
3. 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
4. Original amino acid coded for is glutamate is changed to valine at the sixth position
5. Glutamate is hydrophillic while valine is hydrophobic
6. 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
7. The long fibres distort the membrane if the RBC, giving it its distinct sickle shape
8. This results in the decreased oxygen-carrying ability of the RBC
9. 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

Question 21

Causative factors

increases the chance of cancerous growth

Answer 21

1. Physical factors
   - Ionising radiation
   - Ultra-violet light
2. Chemical factors (carcinogens)
3. Biological
   - Viruses
   - Fungus
4. Genetic factor
   - mutated genes such as either oncogenes or tumour suppressor genes found in gametes of parents
5. Loss of immunity

Question 22

Proto-oncogenes

Answer 22

1. Proto-oncogenes encode proteins that stimulate normal cell division
2. 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
3. this will result in uncontrolled cell division, possibly leading to cancer
4. 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
5. 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

Question 23

Tumour suppressor genes

Answer 23

1. Tumour suppressor genes encode proteins that inhibit cell division or promote apoptosis (controlled cell death)
2. 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
3. This will result in uncontrolled cell division, possibly leading to cancer
4. 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
5. 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

Question 24

Checkpoints during the mitotic cell cycle

Answer 24

1. 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
2. G2 checkpoint ensures that the cell size is adequate and semi-conservative DNA replication has been completed successfully
3. Metaphase checkpoint ensures that all chromosomes are attached to spindle fibres/ microtubules at the metaphase plate before proceeding to anaphase

Question 25

Defn. Cancer

Answer 25

Combination of 2 properties, cells have the ability to
- proliferate in an uncontrolled fashion
- spread throughout the body

Question 26

Mutation of proto-oncogenes

Answer 26

• When a proto-oncogene mutates into an oncogene, it becomes over-expressed/ permanently activated (gain-of-function mutation)
• As long as one copy of the proto-oncogene is mutated, it can result in cancer
• Majority of oncogenes develop from acquired mutations

Question 27

Mutation of tumour suppressor genes

Answer 27

• Cells possess tumour suppressor genes which encode proteins that prevent uncontrolled cell division
• any mutation that causes the under-expression / inactivation of a tumour suppressor protein may contribute to the onset of cancer, as it stimulates growth through the absence of suppression
• Proto-oncogenes undergo gain-of-function mutation to become oncogenes while tumour suppressor genes undergo a loss-of-function mutation to become mutated tumour suppressor genes
• cancer only develops when both copies of the tumour suppressor gene are mutated
• mutations of TSG can be inherited and acquired

Question 28

Cancer development: accumulation of mutations

Answer 28

• Cancer is a multi-step process.
• Several mutations must occur for a cell to become fully cancerous. Cancer results from an accumulation of mutations in a single cell
• A person may inherit a form of one or more genes that makes him/her more likely to develop a specific type of cancer
• These usually result in the appearance of at least one active oncogene and the mutation or loss of several tumour-suppressor genes
• Mutant TS alleles are usually recessive
  -in most cases, mutations must knock out both alleles in a cell’s genome to block tumour suppression
• alleles of oncogenes are usually dominant
• in malignant tumours, the gene for telomerase is activated. production of telomerase in cancer cells removes a natural limit on the number of times the cells can divide
• these mutations result in uncontrolled proliferation of cells forming tumour

Question 29

Tumour angiogenesis

Answer 29

is required before tumours can grow beyond a few millimeters in diameter

Question 30

Metastasis

Answer 30

Cancer cells enter the circulatory system, and metastasize to distant sites