mutations

Question 1

Define mutations.

Answer 1

A permanent change in the DNA of a living organism that is inherited, involving the addition, deletion, insertion or substitution of bases in DNA sequences, which changes the mRNA codon and the amino acid inserted in the polypeptide.

Question 2

What are the types of changes to a gene that can occur?

Answer 2

1. Nucleotide substitutions: the replacement of one nucleotide pair with another
2. Nucleotide insertions or deletions, either in multiples of 3 or NOT in multiples of 3

Question 3

Describe the effect of nucleotide substitutions, in terms of types of mutations.

Answer 3

1. Missense mutation: translation of different amino acid, change in 3D conformation and function of protein
2. Nonsense mutation: changes codon for amino acid into a premature stop codon, premature termination of translation, shorter/truncated polypeptide, resulting in change of 3D conformation and function
3. Silent mutation: changes mRNA codon, but same amino acid is inserted due to degeneracy of genetic code, a.a. sequence unchanged, no change in 3D conformation and function
4. Neutral mutation: changes mRNA codon and a.a. inserted, but no detectable change in function, due to similar chemical and physical properties OR substitution of a.a. that is non essential to protein structure and function

Question 4

Describe the effect of nucleotide deletions and insertions, in terms of types of mutations.

Answer 4

 As the resulting mRNA is read as a series of non-overlapping codons, an insertion or deletion of nucleotides not in multiples of threes will result in a frameshift mutation.
 All the nucleotides downstream of the insertion / deletion site will be improperly grouped
into codons, resulting in extensive missense.
 The frameshift may also cause a new, premature stop codon to be generated (i.e. nonsense mutation) in the reading frame, or result in a read-through of the normal stop codon, resulting in polypeptides of altered lengths. In any case, a frameshift usually results in a non-functional protein.

Question 5

Describe the case study of sickle cell anaemia.

Answer 5

Substitution of a thymine for an adenine at one position in the Hb gene (template strand), which results in a missense mutation. Sixth amino acid residue in polypeptide is changed from a glutamate (hydrophilic) to a
valine (hydrophobic). This substitution creates a hydrophobic spot on the outside of the Hb protein that sticks to the
hydrophobic region of an adjacent Hb protein’s beta chain. The mutant Hb subunits tend to stick to one another when the oxygen concentration is low, particularly when the red blood cells are in capillaries and veins. The aggregated proteins form fibre-like structures within red blood cells. At high oxygen concentration, haemoglobin resumes globular haemoglobin structure.
The fibre-like structures cause the red blood cells to lose their normal morphology and become sickle-shaped. Sickled cells are less able to move through capillaries and can block blood flow, resulting in severe pain and cell death of the surrounding tissue due to shortage in oxygen. The sickled red blood cells are also fragile and easily destroyed, further decreasing the oxygen carrying capacity of blood.

Question 6

Describe spontaneous mutations and how they may be repaired.

Answer 6

Mutations that occur naturally, as a result of errors during DNA replication, recombination or repair.
DNA replicated with fairly high fidelity, but DNA pol occasionally inserts the wrong/too many/too few nucleotides (1/100000). Some are corrected immediately during proofreading (DNA pol recognises mistakes and replaces), or after replication in mismatch repair (incorrectly paired nucleotides cause deformities in the secondary structure that are recognised by enzymes which fix the deformities). Some replication errors fail to be recognised by repair enzymes and can be passed down to next generation.

Question 7

What is DNA slippage and its effects?

Answer 7

Daughter or parental DNA strand slips during DNA replication followed by folding back of the strand. Hence, there is a mispairing between the daughter DNA strand and the parental template strand. This causes parts of the DNA which are folded back to be copied more than once. If this duplicated DNA segment corresponds to a gene, it will result in gene duplication.

Question 8

Describe the effect of physical agents on DNA.

Answer 8

X-rays: production of very reactive free radicals of water, interact with DNA to produce double stranded breaks leading to chromosomal rearrangements and deletions
UV rays: absorbed by bases of DNA, leading to production of a covalent attachment between adjacent pyrimidines in one strand (thymine dimers), base pair substitutions, insertions or deletions. Blocks replication and transcription — lethal if unrepaired

Question 8

Describe the effect of chemical agents on DNA.

Answer 8

Base analogues: molecular structures similar to bases normally found in DNA, may be incorporated into DNA in place of normal bases
Base-modifying agents: modify chemical structure and properties of bases, leads to mispairing and hence base substitution
Intercalating agents: flat molecules with multiple ring structures, intercalate between adjacent bases, leads to insertions or deletions and hence frame shift mutations

Question 9

Describe mutations in chromosome structure.

Answer 9

1. Deletion: breaks in one or more places, can occur near one end (terminal) or from interior (intercalary). Genotypes is altered due to absence of certain gene loci — lethal for both chromosomes, allele on non-deficient homologue is expressed.
2. Duplication: part of chromosome is present more than once, due to unequal crossing over, or through replication error prior to meiosis. Gene redundancy and phenotypic variation
3. Inversion: segment is turned 180, rearranging linear sequence. May produce aberrant gametes, or position effects and altered gene expression
4. Translocation: movement of segment to new location in genome. Can be reciprocal translocation (between non-homologous chromosomes). Produces position effect

Question 10

Describe aneuploidy, its types and how it originates.

Answer 10

Aneuploidy refers to the general condition in which an organism loses or gains one or more chromosomes, but not a complete set. This can be in the form of monosomy or trisomy. This is due to nondisjunction — the failure of chromosomes or chromatids to disjoin and move to opposite poles during division.

Question 11

Describe monosomy in humans.

Answer 11

Only occurs of the X chromosome in the 45, X Turner Syndrome. Female external genitalia and internal ducts but ovaries are rudimentary. Short stature, skin flaps on the back of the neck and underdeveloped breasts. Intelligence is normal. Does not occur in any of the other autosomes.

Question 12

Describe trisomy in humans,

Answer 12

1. 47, XXY Klinefelter syndrome
2. Down syndrome, only human autosomal trisomy where a significant number of individuals survive longer than a year past birth — extra chromosome 21

Question 13

Describe polyploidy and how it originates.

Answer 13

Instances where more than two multiples of the haploid chromosome set are found. Originates when :
1. Addition of one or more extra sets of chromosomes, identical to the normal haploid component of the same species resulting in autopolyploidy.
2. Combination of chromosome sets from different species may occur as a consequence of interspecific matings resulting in allopolyploidy

Question 13

Describe types of autopolyploidy.

Answer 13

Autotriploids: Failure of all chromosomes to segregate during meiotic divisions (first/second division) can produce diploid gamete, which is fertilised by a haploid gamete. Or under experimental conditions with tetrapolyploids (teraploids produce 2n gametes).
Autotetraploids: more likely to be found in nature due to even number of chromosomes. Used for crops that are of greater value due to larger sizes or more vigorous growth.

Question 14

Describe allopolyploidy.

Answer 14

Hybridisation of two closely related species. When haploid ovum with sets AA is fertilised by haploid sperm with sets BB, hybrid is AB, which may be sterile due to inability to produce gametes — some or all of the chromosomes are not homologous and are unable to synapse in meiosis. If the AB genetic combination undergoes natural or induced chromosome doubling, a fertile AABB tetraploid is produced (aka allotetraploid/amphidiploid).

Question 15

Define genetic screening.

Answer 15

Genetic screening is the analysis of a person’s DNA to check for presence of one or more alleles that are associated with disease.

Question 16

What is genetic testing?

Answer 16

When a person from a family with a genetic disease begins to develop symptoms, he or she may be tested for the disease. People who are free of the symptoms may also be tested like this — this is known as genetic screening.

Question 17

What is maternal genetic screening/prenatal genetic screening? What factors contribute to high-risk pregnancies?

Answer 17

Maternal genetic screening, also known as prenatal genetic screening, are tests that provide information about the health of a foetus – an unborn child.
Factors include:
 Pregnancy over the age of 35
 Family or personal history of genetic conditions
 History of miscarriage or stillbirth
 Lifestyle factors (e.g. exposure to cigarette smoke, radiation)

Question 18

Describe the different types of prenatal genetic screening test

Answer 18

Carrier screening: Blood tests conducted on both biological mother and father of the foetus to determine if they carry a recessive allele that codes for a particular disease. If both parents are carriers / heterozygotes, risk of the foetus presenting with serious symptoms of the disease is increased. More tests may be advised to confirm the genetic condition of the foetus.
Cell-free foetal DNA screening using NIPT: After 10 weeks, there is sufficient foetal DNA circulating in the pregnant woman’s bloodstream to screen the foetus for abnormal chromosome number or common mutations.
Serum protein level screening: Increased levels of certain proteins in blood may indicate abnormalities in the foetus, like PAPP- A, free beta-hCG, AFP, estriol and inhibin-A. The serum tests are carried out at specific junctures throughout a pregnancy.