Somatic vs Germ-Line Mutation; Coding vs Non-Coding DNA

Q1 — Sample Band 5–6 response (8 marks), annotated

A somatic mutation is a mutation in a body cell (not a gamete or gamete-producing cell), so it affects the individual but is not inherited by offspring. A germ-line mutation, by contrast, is present in gametes or the gamete-producing lineage and can be passed to the next generation and enter the population gene pool. [1 — defines somatic + contrasts with germ-line]

Figure 1.1 shows that melanoma has by far the highest median somatic mutation burden (~14 mutations/Mb), compared with only ~0.6 mutations/Mb in childhood acute lymphoblastic leukaemia (ALL) — roughly a 20-fold difference between the two extreme cancers in the dataset. Lung cancer in smokers (~8) and colorectal cancer (~3) sit between them. [1 — uses ≥ 2 data points correctly]

The variation reflects exposure to different mutagens. Melanoma arises in skin cells directly exposed to UV radiation, which generates pyrimidine dimers and characteristic C→T transitions — exactly the lesson's UV anchor example, where UV-induced skin-cell mutations contribute to skin cancer in the individual. Lung cancers in smokers carry a tobacco-carcinogen signature; colorectal cancers reflect mostly replication errors and diet; childhood ALL involves cells that have undergone relatively few divisions and minimal mutagen exposure, so the somatic burden is small. [1 — UV anchor + mechanism for variation]

The panel's claim that "high somatic mutation burden in melanoma means melanoma is highly heritable" is wrong on the inheritance dimension. Mutation burden in a melanoma is measured in tumour cells — these are somatic. They are confined to skin and metastases, not present in oocytes or sperm-producing cells, and therefore cannot be passed to children at fertilisation. The patient's children will not inherit the 14 mutations/Mb measured in her tumour. [1 — refutes "heritable" claim using somatic definition]

The claim is also potentially confused with a separate, legitimate point: germ-line susceptibility alleles (e.g. CDKN2A, MC1R variants) can raise relatives' risk of melanoma, but those are inherited risk alleles, not the tumour mutations themselves. So screening relatives for "the same tumour mutations" is the wrong test; screening for inherited risk variants is a different and valid clinical question. [1 — distinguishes tumour mutations from inherited risk alleles]

Applying the lesson's two-dimensional rule explicitly: mutation significance depends on (i) where in the body the mutation occurs (somatic vs germ-line) and (ii) where in the genome it occurs (coding vs non-coding). The melanoma figure speaks only to dimension (ii) at the coding level for somatic cells in the individual. It says nothing about heritability, which is dimension (i). Conflating the two dimensions is exactly the mistake the lesson is designed to prevent. [1 — applies the two-dimensional rule]

Therefore the panel's claim is rejected: high somatic mutation burden does not imply heritability. The defensible conclusion is that melanoma is a high-burden somatic disease driven primarily by UV exposure in the individual, while inheritability of melanoma risk depends on entirely separate germ-line susceptibility variants. [1 — explicit final judgement]

(Effective use of data + accurate biology + precise refutation throughout → 1 final cohesion mark.) [1 — coherence and precision of lesson terminology]

Marking criteria.

• 1 mark — Defines somatic mutation and explicitly contrasts with germ-line on inheritance.
• 1 mark — Uses at least two specific data values from Figure 1.1 to support reasoning.
• 1 mark — Connects melanoma's high burden to UV exposure using the lesson's UV anchor.
• 1 mark — Directly refutes the panel's "heritable" claim using the somatic/germ-line distinction.
• 1 mark — Distinguishes tumour mutations from inherited risk alleles (or equivalently, recognises that germ-line susceptibility variants are a separate question).
• 1 mark — Applies the lesson's two-dimensional rule (inheritance × functional location) explicitly.
• 1 mark — Reaches a justified final judgement that rejects the panel's claim and reframes it correctly.
• 1 mark — Uses precise lesson terminology throughout (somatic, germ-line, coding, gene pool, population relevance, mutagen, UV anchor).

Q2 — Sample Band 5–6 response (8 marks), annotated

Both BRCA1 mutations in Family A and Family B are heritable, meaning they are present in the germ-line and pass to offspring; they differ on the second of Card 4's dimensions — functional location. Family A's mutation is in the coding region (an exon 11 missense substitution), while Family B's mutation is in a non-coding regulatory region (the BRCA1 promoter). Both are therefore germ-line, but only one is coding. [1 — classifies both mutations on the two dimensions]

Figure 2.1 makes the molecular consequences explicit. In Family A, BRCA1 mRNA is essentially normal (~95% of control) because the promoter and transcription machinery are intact, but functional BRCA1 protein activity is reduced to ~35% — the mRNA is made and translated normally, but the resulting protein folds or binds poorly because of the amino-acid substitution. In Family B, mRNA is reduced to ~30% of control because the mutated promoter no longer recruits transcription factors efficiently; the protein that is produced has the normal sequence and presumably normal per-molecule function, but there is simply not enough of it. [1 — explains the mechanism behind each data signature]

The Family B data directly refute the misconception that "non-coding mutations do not matter because they do not code for a protein". The promoter mutation does not change a single amino acid in BRCA1, yet it reduces the cellular pool of functional BRCA1 protein to ~30% of normal — phenotypically very similar to a damaging coding mutation. As Card 3 of the lesson states, non-coding regulatory mutations can change when, where or how strongly a gene is expressed, and that is exactly what Figure 2.1 shows. [1 — refutes the non-coding misconception with data]

Comparing the two families directly across multiple criteria: (i) mRNA level — A normal, B reduced. (ii) Per-molecule protein function — A reduced (defective protein), B normal (the protein that is made works). (iii) Total functional BRCA1 in the cell — both reduced to roughly 30–35% of control, despite the different mechanisms. (iv) Inheritability — both germ-line, both passed to offspring. (v) Population relevance — both relevant: both can spread through families and contribute to inherited cancer risk in the population. [1 — compares on ≥ 3 criteria] [1 — explicit use of the data on each criterion]

Whether one mutation is "worse" depends on how the criterion is framed. If "worse" means "more biologically severe to the individual carrier", both look comparable — both reduce functional BRCA1 to ~30–35% of normal, so the phenotypic risk (e.g. lifetime breast/ovarian cancer risk in BRCA1 carriers) is likely similar. If "worse" means "more diagnostically obvious", the coding mutation in Family A is easier to find — it changes the codon directly and would have been picked up by routine exon sequencing decades earlier, whereas the promoter mutation in Family B would be missed by exon-only screening and requires expression-level data to detect. [1 — environment-dependent judgement, not single-winner]

The defensible overall conclusion is that the two mutations are equivalent in heritability and roughly equivalent in phenotypic severity, but operate through different molecular routes — protein quality (Family A) vs protein quantity (Family B). This is a clean illustration of the lesson's core claim: mutation significance depends on both where in the body (here, both germ-line) and where in the genome (here, coding vs non-coding regulatory) the change sits. [1 — final judgement linked to Card 4's two-dimensional rule]

(Precise lesson terminology applied throughout: germ-line, coding, non-coding, regulatory, promoter, gene expression, transcription, population relevance.) [1 — terminology precision]

Marking criteria.

• 1 mark — Classifies BOTH mutations on the two dimensions: both germ-line; one coding, one non-coding (regulatory).
• 1 mark — Correctly interprets Family A's mRNA/protein signature (normal mRNA, reduced functional protein) and links it to coding-region mechanism.
• 1 mark — Correctly interprets Family B's mRNA/protein signature (reduced mRNA, normal per-molecule function) and links it to a promoter / transcription mechanism.
• 1 mark — Uses the Family B data to refute the non-coding-doesn't-matter misconception explicitly.
• 1 mark — Compares the two mutations on at least three criteria.
• 1 mark — Frames the answer as "depends on the criterion" rather than a single winner.
• 1 mark — Reaches a justified overall conclusion that links back to Card 4's two-dimensional rule (inheritance × functional location).
• 1 mark — Uses precise lesson terminology consistently (germ-line, somatic, coding, non-coding, regulatory, promoter, gene expression, population relevance).