Biology • Year 12 • Module 6 • Lesson 5
Somatic vs Germ-Line Mutation; Coding vs Non-Coding DNA
Apply the two-dimensional mutation rule to real cancer somatic-mutation data, a real regulatory-vs-coding case study, and a classification scenario.
1. Interpret somatic-mutation burden across cancers
The table below shows the median number of somatic (non-inherited) mutations per tumour for four cancer types, drawn from large whole-exome sequencing studies. Use it to reason about why somatic mutation matters for the individual but not directly for the population. 7 marks
| Cancer type | Median somatic mutations / tumour (coding regions) | Main known mutagen / driver |
|---|---|---|
| Melanoma (skin) | ~ 14 mutations / Mb | UV light |
| Lung (smokers) | ~ 8 mutations / Mb | Tobacco carcinogens |
| Colorectal | ~ 3 mutations / Mb | Replication errors + diet |
| Childhood leukaemia (ALL) | ~ 0.6 mutations / Mb | Few; mostly replication errors |
Median mutation rates summarised from Alexandrov et al. (2013) Nature 500:415–421 (typical values).
1.1 Identify the cancer with the highest somatic mutation burden, and the main mutagen responsible. Explain in one sentence why this is consistent with the lesson's UV–skin-cancer anchor example. 2 marks
1.2 All four cancers in the table involve large numbers of somatic mutations. Explain, using lesson terms, why none of these somatic mutations contribute directly to population genetic change, no matter how many a patient accumulates. 3 marks
1.3 A patient with melanoma worries that her children may inherit the mutations driving her tumour. Respond to her concern in 2–3 sentences using the somatic vs germ-line distinction. 2 marks
2. Regulatory-region vs coding-region mutations — two case studies
The lesson's Card 3 insists that non-coding regulatory mutations can still matter — sometimes more than coding mutations. Use the two real examples below to apply that idea. 8 marks
Case A — TERT promoter mutation in melanoma (somatic). The TERT gene codes for the telomerase enzyme. A single base change in the promoter of TERT (outside the coding sequence) creates a new transcription-factor binding site, switching telomerase back on in adult skin cells where it should normally be off. Re-activated telomerase prevents telomere shortening, allowing damaged skin cells to keep dividing. This promoter mutation is present in ~70% of cutaneous melanomas but the TERT protein coding sequence itself is unchanged.
Case B — Lactase persistence (germ-line). The lactase enzyme (LCT gene) breaks down lactose in milk. In most mammals, lactase production is switched off after weaning. In some human populations, a single base change about 14 kilobases upstream of LCT (in an enhancer region of the neighbouring MCM6 gene — non-coding regulatory DNA) keeps lactase expression switched on into adulthood. The lactase protein sequence itself is identical to non-persistent individuals. The variant is heritable and has spread through specific populations under strong selection.
2.1 For each case, classify the mutation on both dimensions from Card 4: (i) somatic vs germ-line, (ii) coding vs non-coding. 4 marks (1 per classification)
2.2 Explain, using lesson terms, why these two examples together refute the misconception that "a mutation in non-coding DNA does not matter because it does not code for a protein." 3 marks
2.3 Which of the two non-coding mutations is population-relevant, and why? 1 mark
3. Sequence reasoning — coding vs regulatory change
Two patients each carry a single-base change in the same gene region. The reference (healthy) sequences and the patient sequences are shown below in monospace. 7 marks
Patient X — change inside the protein-coding exon (reading frame starts at codon 1):
Reference (codons): ATG GAA GCC TGG AAA ...
Met Glu Ala Trp Lys
Patient X (codons): ATG GAA GCC TGA AAA ...
Met Glu Ala STOP --
Patient Y — change inside the promoter region, 80 bp upstream of the same gene:
Reference (promoter): ...TATAAA...TTGACA... (TATA box + binding site intact)
Patient Y (promoter): ...TATAAA...TTAACA... (binding site disrupted)
Effect: transcription factor no longer binds efficiently
→ reduced transcription
→ ~25% of normal mRNA produced
→ protein coding sequence UNCHANGED
3.1 Classify Patient X's mutation (coding or non-coding) and describe its molecular consequence in one sentence. 2 marks
3.2 Classify Patient Y's mutation (coding or non-coding) and describe its molecular consequence in one sentence. 2 marks
3.3 A student says "Patient Y's mutation is harmless because the protein is normal." Evaluate this claim. 3 marks
4. Classify the scenarios on both dimensions
For each scenario, classify the mutation on (i) somatic vs germ-line, and (ii) coding vs non-coding (where stated), and tick whether it is population-relevant. 8 marks (2 per row)
| Scenario | Somatic / Germ-line | Coding / Non-coding | Population-relevant? (Y/N + 1-line reason) |
|---|---|---|---|
| 4.1 A UV photon causes a thymine-dimer mutation inside the p53 coding exon of a basal skin cell. | |||
| 4.2 A mutation occurs in the BRCA1 coding exon in a developing spermatocyte and is passed to a child. | |||
| 4.3 A mutation occurs in a gene's enhancer region in an oocyte, reducing expression of that gene in offspring tissues. | |||
| 4.4 A liver cell acquires a mutation in the TERT promoter, reactivating telomerase and contributing to hepatocellular carcinoma in the patient. |
Q1.1 — Highest burden + UV anchor (2 marks)
Melanoma has the highest burden (~14 mutations/Mb) and the main mutagen is UV light [1]. This matches the lesson anchor: UV-induced skin-cell mutations contribute to skin cancer in the individual; the high mutation rate reflects skin's direct UV exposure and is consistent with melanoma being a UV-driven somatic cancer [1].
Q1.2 — Why none contribute to population change (3 marks)
All of these mutations occur in body cells (skin, lung, colon, leukocyte precursors) — they are somatic mutations [1]. Somatic mutations are not present in gametes, so they cannot be passed to offspring at fertilisation [1]. Because they cannot enter the gene pool, they cannot contribute to long-term population genetic change no matter how many accumulate — the mutations end with the individual [1].
Q1.3 — Patient reassurance (2 marks)
The somatic mutations in the patient's melanoma are confined to her skin cells (and metastases) — they are not present in her oocytes [1]. Because only germ-line mutations are inherited, these tumour mutations cannot be passed to her children; she may still carry separate inherited risk alleles (e.g. familial CDKN2A or MC1R variants), but those are a different question to "tumour mutations being inherited" [1].
Q2.1 — Classification of both cases (4 marks)
Case A (TERT promoter melanoma): (i) somatic — occurs in adult skin cells, not the germ-line [1]; (ii) non-coding — the mutation is in the promoter, not the coding sequence [1]. Case B (lactase persistence): (i) germ-line — inherited and present in every cell, including gametes [1]; (ii) non-coding — the mutation is in an upstream regulatory enhancer, not the coding sequence; the LCT protein itself is identical [1].
Q2.2 — Why these cases refute the misconception (3 marks)
In Case A, a non-coding promoter mutation switches telomerase back on in skin cells and contributes directly to melanoma — a clear, severe phenotype with no change to the TERT protein sequence [1]. In Case B, a non-coding enhancer mutation changes when the lactase gene is expressed (continued expression into adulthood instead of being switched off after weaning) — again a clear phenotype with no change to the protein sequence [1]. Both cases show that mutations in non-coding regulatory DNA can change phenotype by altering gene expression, so the claim that non-coding DNA does not matter because it does not code for a protein is wrong [1].
Q2.3 — Which is population-relevant (1 mark)
Case B (lactase persistence) is population-relevant because it is a germ-line mutation: it is inherited, has spread through specific populations under selection, and is part of the human gene pool. Case A is somatic and ends with the individual [1].
Q3.1 — Patient X (2 marks)
Patient X has a coding mutation [1]. The fourth codon has changed from TGG (Trp) to TGA, a premature STOP codon — this is a nonsense mutation producing a truncated, non-functional protein [1].
Q3.2 — Patient Y (2 marks)
Patient Y has a non-coding mutation — the change is in the promoter, 80 bp upstream of the gene, outside the coding sequence [1]. The change disrupts a transcription-factor binding site, reducing transcription so that only ~25% of normal mRNA is produced; protein structure is unchanged but the amount of protein available is much lower [1].
Q3.3 — Evaluate "harmless because protein is normal" (3 marks)
The claim is wrong [1]. Although Patient Y's protein sequence is unchanged, the promoter mutation reduces transcription to ~25% of normal, so cells produce only a quarter of the normal protein amount — phenotype depends on whether enough functional protein is made, not only on its sequence [1]. This is exactly the Card 3 principle: non-coding mutations can change phenotype by altering the timing, location or amount of gene expression [1].
Q4 — Classification grid (8 marks; 2 per row)
4.1 Somatic; coding; No — confined to a skin cell, not in gametes, so not inherited.
4.2 Germ-line; coding; Yes — present in a gamete-producing cell, passed to a child, can enter the gene pool.
4.3 Germ-line; non-coding (regulatory); Yes — heritable, alters expression patterns in offspring, can enter the gene pool even though it does not change protein sequence.
4.4 Somatic; non-coding (regulatory / promoter); No — significant for the individual (drives cancer) but confined to liver cells, not the germ-line, so not population-relevant.
1 mark for each correct dimension pair; 1 mark for the population-relevant call with justification.