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.

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?

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.

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.

Mutations are said to be the primary source of genetic variability. Explain the relationship between mutations, the evolution of species and biodiversity.

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.

During bacterial DNA replication, DNA polymerase mistakenly incorporates a guanine (G) deoxyribonucleotide opposite a thymine (T) on the template, giving rise to a G-T mismatch in one of the newly synthesized strands that is not detected by immediate proofreading activity.

1. a) Deduce what percentage of descendant double-stranded DNA molecules will carry a permanent mutation fixed in both strands after two successive rounds of replication starting from that initial molecule.
2. b) Justify how the resulting base pairs are distributed in each of the four final DNA molecules, assuming that the initial pair was A-T and no subsequent repair system acts.
3. c) The mismatch repair system is only effective if it acts before the newly synthesized strand is methylated. Justify what consequence it would have on genome stability if this system repaired the methylated template strand instead of the newly formed daughter strand.