Session 14 ILOs - DNA and Chromosomal mutations

Question 1

Define mutation and mutagenesis

Answer 1

Mutation: a heritable alteration in a gene or chromosome

Mutagenesis: the process by which mutations are generated

Question 2

Explain and describe the consequences of single nucleotide (and other small) mutations

Answer 2

Single nucleotide mutations - where a single nucleotide base is altered/changed

2 types:

1. Transition - change for same type of base (e.g. purine for purine)
2. Transversion - change for different type of base (e.g. purine for pyrimidine)

Consequences:

• Can change gene product (e.g. change in amino acid = missense mutation)
• Can change the amount of gene product (mutations affecting the regulatory sequences)
• Can change the polypeptide length (e.g. frameshift mutation or in STOP codon)
• Does not have an effect (e.g. silent mutation)

Question 3

Define and describe the consequences of missense, nonsense, frameshift, silent/neutral, synonymous and non-synonymous mutations, as well as mutations of the stop codon and regulatory sequences

Answer 3

1. Missense
   - Point mutation where a single nucleotide change results in a codon that codes for a different amino acid
2. Nonsense
   - Point mutation in a codon which changes it to a stop codon which causes a protein to terminate or end its translation earlier than expected
3. Frameshift
   - Caused by a deletion or insertion in a DNA sequence that shifts the way the sequence is read (not divisible by 3)
4. Silent/neutral
   - Point mutation where the change in base does not change the amino acid sequence (due to degenerate nature of DNA)
5. Synonymous and non-synonymous mutations
   Synonymous mutation - nucleotide substitution that does NOT change the amino acid in the protein
   Non-synonymous mutation - nucleotide substitution that changes the amino acid in the protein
6. Mutations of the stop codon and regulatory sequences
   - Mutations of the stop codon can occur which increases the length of the polypeptide
   - Mutations of the regulatory sequences can alter the amount of gene product

Question 4

Explain how fork slippage and transposable elements cause mutations

Answer 4

Fork slippage can cause mutations because it can lead to trinucleotide expansions and trinucleotide repeat disorders EXAMPLE Huntington’s disease (polyglutamine repeats in huntingtin protein)

Transposable elements are specific repetitive DNA sequences that move around randomly and can cause mutations by nucleotide sequence changes

Question 5

Describe in general terms the potential consequences of mutations at the gene level

Answer 5

A gene mutation is a permanent alteration in the DNA sequence that makes up a gene, such that the sequence differs from what is found in most people.

Mutations range in size; they can affect anywhere from a single base pair to a large segment of a chromosome that includes multiple genes

Question 6

Define and describe the numerical and structural abnormalities

Answer 6

Numerical abnormalities: when there is a different number of chromosomes in the cells of the body from what is usually found

• Polyploidy (gain of haploid set of chromosomes)
• Aneuploidy (loss or gain of whole chromosomes)
• Mosaicism (presence of 2 or more cell lines in an individual)

Structural abnormalities: when part of an individual chromosome is missing, extra, switched to another chromosome, or turned upside down

• Deletions (incl. microdeletions)
• Inversions
• Substitutions or insertions
• Translocations (reciprocal or Robertsonian)
• Isochromosomes (double p or double q)
• Ring chromosomes
• Marker chromosomes

Question 7

Define trisomy and monosomy, and know examples of syndromes associated with these

Answer 7

Trisomy: a type of aneuploidy in which there are three instances of a particular chromosome, instead of the normal two.
EXAMPLES: Trisomy 21 (Down syndrome) or Trisomy 13 (Patau syndrome)

Monosomy: a form of aneuploidy with the presence of only one chromosome from a pair
EXAMPLE: Turner Syndrome (usually with one X chromosome only and the other is missing)

Question 8

Describe reciprocal and Robertsonian translocations and their potential consequences in both somatic and germ line cells

Answer 8

Reciprocal translocations: 2 different chromosomes exchange segments with each other
Consequences: meiotic consequences - usually harmless and may be found through prenatal diagnosis. However, carriers of balanced reciprocal translocations have increased risks of creating gametes with unbalanced chromosome translocations, leading to infertility, miscarriages or children with abnormalities

Robertsonian translocations: an entire chromosome attaches to another chromosome, at the centromere
Consequences: meiotic consequences and risk of aneuploidy - a person with a Robertsonian translocation has an increased risk of miscarriage for each pregnancy and an increased risk of the baby being born with a disability (females are at higher risk)

Question 9

Describe and appreciate cytogenetic testing

Answer 9

Cytogenetic testing involves chromosomal analysis of blood or bone marrow to look for specific gene mutations

Examples:

• Cytogenetic analysis e.g. karyotyping
• Fluorescent in situ hybridisation (FISH)
• Microarray hybridisation
• DNA sequencing