Mutations

What is a mutation? Explain the difference between a gene (or point) mutation and a chromosome mutation, giving an example of each.

In the diagram, sequence A is a normal mRNA fragment and sequences B and C have undergone a mutation. State which type of mutation (substitution, insertion or deletion) has occurred in each of them and reason which one causes a frameshift and why.

What is a structural chromosome mutation? Give two examples of structural alterations of chromosomes (deletion, duplication, inversion or translocation) and explain briefly what one of them consists of.

A mutation changes the codon GAA to GAG, and both codons code for the same amino acid (glutamic acid). What is this type of mutation called, and why does it not alter the resulting protein?

A deletion of a single nucleotide occurs in a gene within the coding region. Explain what happens to the reading frame from that point onwards, why all the subsequent amino acids can change and reason whether a deletion of this type located at the beginning of the gene or at the end will be more damaging.

In the CFTR gene, the most common mutation causing cystic fibrosis (ΔF508) consists of the loss of three nucleotides: CTT. The sequence of the coding strand of DNA between codons 506 and 509 is:

5'-... ATC ATC TTT GGT ...-3' (Ile506 - Ile507 - Phe508 - Gly509).

After the deletion of the three central nucleotides CTT (the last base of ATC 507 and the first two of TTT 508), the resulting sequence is: 5'-... ATC ATT GGT ...-3'.

1. a) Knowing that both ATC and ATT code for isoleucine, justify why this mutation does not alter the downstream reading frame and what is the only alteration suffered by the primary structure of the CFTR protein.
2. b) In another patient, a single-nucleotide deletion is detected in that same region (the loss of the 'C' in triplet 507). Explain what consequences this mutation will have on the reading frame, on the downstream amino acid sequence, and on the probability of the protein being truncated.
3. c) There are drugs in development ('correctors') that manage to get the CFTR protein to the cell membrane if it retains its full length, even if it lacks one amino acid. Predict, with reasoning, which of the two patients could benefit from this therapy and why it will be completely ineffective in the other.

Name two mutagenic agents, one physical and one chemical, and briefly explain how they damage DNA.

Mutations can be spontaneous or induced. Explain the difference between them and give an example of a cause of each type.

Cells possess DNA repair systems that correct many of the lesions that escape DNA polymerase. Explain what happens when a lesion is not repaired and reason why people with xeroderma pigmentosum, who have a defective system for repairing the thymine dimers caused by ultraviolet light, show such a high risk of skin cancer.

Explain the difference, in terms of their consequences and their transmission to offspring, between a mutation occurring in a somatic cell and one occurring in a germ cell.

Down syndrome is due to the presence of an extra copy of chromosome 21 (trisomy 21). Explain what type of mutation it is, how it can originate through non-disjunction during meiosis and reason why mutations of this type affect many traits simultaneously.

Are all mutations harmful? Reason your answer and give an example of a mutation that has turned out to be beneficial for a species.

In a region where malaria is endemic, the frequency of the mutant allele $Hb^S$ (responsible for sickle cell anemia in homozygosity) remains stable at around 0,12 due to the selective advantage it confers on heterozygotes against infection by Plasmodium.

1. a) Following an intensive health campaign, malaria is completely eradicated in that region. Reasonably predict how the frequency of the $Hb^S$ allele will evolve over the following generations.
2. b) Justify why the $Hb^S$ allele will not immediately disappear from the population despite being lethal or severely deleterious in homozygosity.
3. c) A person states: "Now that malaria has disappeared, the $Hb^S$ mutation has ceased to exist in the population." Refute this statement by clearly distinguishing between the origin of a mutation and its adaptive value depending on the environment.

To study the origin of antibiotic resistance, an experiment inspired by the Luria-Delbrück fluctuation test was designed: 20 independent tubes were inoculated with an identical and very low number of ampicillin-sensitive bacteria, allowing them to grow to saturation. Simultaneously, a large flask with a volume equivalent to that of the 20 tubes combined was cultured. Equal aliquots were then plated on ampicillin-containing plates:

• Samples from the large flask yielded a very similar number of resistant colonies to one another (mean of 24 colonies, with very low variance).

• Samples from the 20 independent tubes showed enormous fluctuation: most tubes yielded 0 or 1 resistant colony, while a few yielded more than 300 colonies.

1. a) Interpret these results: do they demonstrate that resistance is induced by exposure to the antibiotic or that it is due to pre-existing spontaneous mutations? Justify your answer by explaining the cause of the high variance among the independent tubes.
2. b) Predict what result would have been observed on the plates from the 20 tubes if the presence of the antibiotic were the direct stimulus triggering the mutation in a small, constant fraction of bacteria.