Biology • Year 12 • Module 6 • Lesson 4
Chromosomal Mutation — Case Studies
Apply the four chromosomal mutation categories to three real human examples: Down syndrome (trisomy 21), cri-du-chat syndrome (5p deletion) and the Philadelphia chromosome (BCR–ABL1 translocation in CML).
1. Case study — Down syndrome (trisomy 21)
Down syndrome is the most common chromosome number disorder in humans. Affected individuals carry three copies of chromosome 21 instead of two — a condition called trisomy 21. Trisomy usually arises from non-disjunction during meiosis I or II in one parent, in which both copies of chromosome 21 segregate into the same gamete. A "karyotype" image below represents the chromosomes of a person with Down syndrome — note the chromosome-21 group has three bars instead of the usual two. 8 marks
Stylised karyotype — chromosome 21 group (the rest of the karyotype is not shown)
Typical (chr 21): 2 copies
Down syndrome (chr 21): 3 copies
1.1 Identify whether trisomy 21 is best classified as a structural chromosomal mutation (deletion / duplication / inversion / translocation) or as a chromosome number change. Justify your answer. 2 marks
1.2 Explain why an extra whole chromosome (rather than a small point mutation) is associated with such broad developmental effects, using the lesson's scale logic. 3 marks
1.3 Using the term gene dosage, explain why having three copies of chromosome 21 (rather than two) can alter how much of certain gene products are made. 3 marks
2. Case study — cri-du-chat syndrome (5p deletion)
Cri-du-chat syndrome (literally "cry of the cat") is caused by a deletion of part of the short arm of chromosome 5 (often written as 5p−). The deleted region varies in size, but always removes multiple genes. Affected children show developmental delay, a distinctive high-pitched cat-like cry in infancy (caused by abnormal larynx development), and characteristic facial features. The stylised diagram below shows a normal chromosome 5 and a 5p− chromosome 5. 7 marks
Stylised comparison — chromosome 5
Typical chr 5
(full 5p — short arm intact)
5p− chr 5
(short-arm segment deleted)
2.1 Classify cri-du-chat syndrome using the lesson's four structural categories. Justify your choice. 2 marks
2.2 The deleted region contains several genes. Explain why losing a multi-gene segment is likely to produce more wide-ranging effects than a single missense point mutation in just one of those same genes. 3 marks
2.3 The size of the deleted segment varies between affected individuals. Predict, and justify, whether children with larger deletions are likely to show more or fewer symptoms than those with smaller deletions. 2 marks
3. Case study — Philadelphia chromosome and chronic myeloid leukaemia (CML)
The Philadelphia chromosome is a small abnormal chromosome found in chronic myeloid leukaemia (CML). It arises from a reciprocal translocation between chromosome 9 and chromosome 22, written as t(9;22). The translocation joins part of the BCR gene (chromosome 22) with most of the ABL1 gene (chromosome 9), producing a fusion gene called BCR–ABL1. The fusion protein is a constantly active tyrosine kinase that drives uncontrolled white-blood-cell division. The stylised diagram below shows the rearrangement. 8 marks
Stylised reciprocal translocation — t(9;22)
Before
chr 9 (with ABL1, red tip)
chr 22 (with BCR, amber tip)
After t(9;22)
"derivative" chr 9
Philadelphia chr (BCR–ABL1 fusion)
3.1 Classify the Philadelphia chromosome mutation using the four structural categories from the lesson. Justify with reference to which chromosomes are involved. 2 marks
3.2 Using the term breakpoint, explain how a translocation can create an entirely new fusion gene (BCR–ABL1) that does not exist in a typical cell. 3 marks
3.3 The lesson states that "moving a large DNA segment can change gene behaviour in ways a single codon substitution usually does not." Use the Philadelphia chromosome to explain — in your own words — exactly what this sentence means. 3 marks
4. Compare the three case studies
Complete the table below by filling in the empty cells. Then answer the synthesis question that follows. 7 marks
| Case study | Mutation category | What is changed at the chromosome level | Why phenotype is affected |
|---|---|---|---|
| Down syndrome | |||
| Cri-du-chat | |||
| Philadelphia chromosome (CML) |
4.1 Using all three case studies, justify the lesson's central claim that "chromosomal mutation can affect many genes at once". 4 marks
Q1.1 — Trisomy 21 classification (2 marks)
Trisomy 21 is a chromosome number change, not a structural deletion/duplication/inversion/translocation [1]. The structure of chromosome 21 itself is normal — what differs is that the cell carries three whole copies of it instead of two, an example of aneuploidy [1].
Q1.2 — Why an extra whole chromosome has broad effects (3 marks)
An extra chromosome 21 means every gene on that chromosome (hundreds of genes) is present in three copies rather than two [1]. The lesson's scale logic applies: the larger the genomic region affected, the more widespread the possible biological consequences — and a whole chromosome is a very large region [1]. A point mutation, by contrast, only changes a single base or a few bases inside one gene, so its effect is restricted to one protein at most [1].
Q1.3 — Gene dosage and trisomy 21 (3 marks)
Gene dosage is the number of copies of a gene present in a cell [1]. With three copies of every gene on chromosome 21 (instead of two), transcription of many of those genes runs at roughly 1.5× the typical rate, producing more of their gene products [1]. Several of these dosage-sensitive proteins control development (for example, the gene DYRK1A influences brain development), so over-production of multiple gene products during development can produce the wide-ranging phenotype associated with Down syndrome [1].
Q2.1 — Cri-du-chat classification (2 marks)
Cri-du-chat is a deletion [1]. A segment of the short arm of chromosome 5 (5p) is missing, so the genes inside that segment are absent from the karyotype [1].
Q2.2 — Why a multi-gene deletion has wider effects than a point mutation (3 marks)
The deleted segment removes several genes simultaneously, so multiple gene products and possibly regulatory regions are missing at the same time [1]. A single missense substitution in just one of those genes only alters one codon and thus one amino acid in one protein — the other genes are still made normally [1]. The cri-du-chat phenotype (developmental delay, laryngeal abnormality, facial features) reflects loss of multiple gene products at once, which a single-codon change in only one gene could not produce [1].
Q2.3 — Larger vs smaller deletions (2 marks)
Children with larger deletions are likely to show more symptoms [1]. Larger deletions remove more genes, so more gene products are lost simultaneously and more developmental pathways are disrupted — the lesson's scale logic again predicts broader phenotype with broader DNA loss [1].
Q3.1 — Philadelphia chromosome classification (2 marks)
The Philadelphia chromosome arises from a translocation [1]. Specifically a reciprocal translocation between chromosomes 9 and 22 — segments are exchanged between two non-homologous chromosomes, producing the small "derivative" chromosome 22 (the Philadelphia chromosome) [1].
Q3.2 — How translocation creates a fusion gene (3 marks)
A translocation breaks both donor chromosomes at specific breakpoints [1]. When the segments rejoin onto the wrong partner chromosome, a breakpoint that falls inside the coding sequence of ABL1 on chromosome 9 and a breakpoint inside BCR on chromosome 22 cause the two genes to be physically joined end-to-end at the new join [1]. The cell then transcribes them as a single fusion mRNA (BCR–ABL1) that does not exist in a normal genome, producing a fusion protein with new properties [1].
Q3.3 — Translocation changes behaviour a substitution cannot (3 marks)
A single codon substitution can at most change one amino acid in one existing protein — it cannot create a brand-new protein that does not exist in a normal cell [1]. The Philadelphia chromosome translocation creates a new BCR–ABL1 fusion protein that does not exist in a typical cell, with novel properties: it is a constitutively active tyrosine kinase that signals "divide" continuously [1]. This drives uncontrolled white-blood-cell proliferation and causes chronic myeloid leukaemia — a major phenotypic consequence that arose because a large DNA segment was moved, not because one base was substituted [1].
Q4 — Comparison table
Down syndrome — chromosome number change (trisomy 21); an extra whole copy of chromosome 21; all genes on chromosome 21 are present in 3 copies, so gene dosage is increased across hundreds of genes, disrupting development.
Cri-du-chat — deletion; a segment of the short arm of chromosome 5 (5p) is missing; multiple genes within that segment are absent, so their gene products are not produced, disrupting development (including laryngeal development).
Philadelphia chromosome (CML) — translocation (reciprocal, between chr 9 and chr 22); part of ABL1 from chr 9 is joined to part of BCR on chr 22 to form the Philadelphia chr; a new fusion gene BCR–ABL1 is created, encoding a constitutively active tyrosine kinase that drives uncontrolled cell division.
Q4.1 — Synthesis (4 marks)
All three cases support the claim that chromosomal mutation can affect many genes at once [1]. Down syndrome adds an extra whole chromosome, altering the dosage of hundreds of genes simultaneously [1]. Cri-du-chat deletes a multi-gene segment, removing several gene products in one event [1]. The Philadelphia chromosome fuses two normally separate genes into a single new gene with novel behaviour — a change in gene content and regulation that a single-base substitution cannot achieve [1]. Together they show that the scale of DNA involved (whole chromosome, multi-gene segment, or rearranged segment) is what drives the broader phenotypic consequences seen at the organism level.