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Genetics Unit 9: Mutation, Repair and Chromosome Changes

Mutations are the raw material of variation and the cause of many diseases. This unit covers how DNA changes, how cells repair damage, and what happens when whole chromosomes change.

Covers: Types of point mutations, Spontaneous and induced mutation, The Ames test, DNA repair pathways, Chromosome rearrangements, Aneuploidy and polyploidy, Mutations and human disease

Study guide

A point mutation alters one or a few base pairs. Base substitutions are transitions (purine to purine or pyrimidine to pyrimidine) or transversions (purine to pyrimidine or the reverse). Their effect depends on the codon: a silent mutation keeps the amino acid, a missense mutation changes it, and a nonsense mutation creates a stop codon. Insertions or deletions of bases not in multiples of three cause frameshifts, which change every downstream codon and usually create an early stop. Missense effects range from mild (a conservative swap like leucine to isoleucine) to severe (a proline in a helix, or a change in an active site).

Mutations arise spontaneously and from mutagens. Spontaneous sources include replication errors, rare tautomeric forms of bases, depurination and deamination; deamination of 5-methylcytosine gives thymine, creating mutation hot spots. Chemical mutagens include base analogs such as 5-bromouracil, alkylating agents that add groups to bases, and intercalating agents that cause frameshifts. Ultraviolet light forms pyrimidine dimers, and ionizing radiation causes double-strand breaks. The Ames test screens chemicals by measuring reversion of His⁻ Salmonella to His⁺, with liver extract added because many carcinogens become mutagenic only after being metabolized.

Cells have several repair systems. Direct reversal, such as photolyase, undoes specific damage. Base excision repair removes a damaged base with a glycosylase, then replaces the nucleotide. Nucleotide excision repair cuts out a short stretch around bulky lesions such as UV dimers; its loss causes xeroderma pigmentosum. Mismatch repair fixes replication errors by identifying the new strand; its loss causes Lynch syndrome. Double-strand breaks are repaired accurately by homologous recombination using a sister chromatid, or quickly but with errors by non-homologous end joining. Mutations in repair genes raise mutation rates and cancer risk.

Chromosome rearrangements alter structure. Deletions remove segments, and duplications add them. Inversions flip segments: paracentric inversions exclude the centromere, and pericentric inversions include it. In an inversion heterozygote, crossing over inside the loop gives unbalanced or dicentric products, so recombinants are rarely recovered. Translocations move segments between nonhomologous chromosomes. Balanced carriers are usually healthy but produce some unbalanced gametes, leading to miscarriage or affected children. Robertsonian translocations fuse two acrocentric chromosomes, so carriers have 45 chromosomes.

Changes in chromosome number are aneuploidy (gain or loss of single chromosomes) or polyploidy (extra complete sets). Aneuploidy, usually from meiotic nondisjunction, includes trisomy 21 (Down syndrome), trisomy 18 and 13, Turner syndrome (45,X) and Klinefelter syndrome (47,XXY). Most autosomal aneuploidies are lethal because gene dosage is unbalanced. Polyploidy is common in plants. Autopolyploids come from one species; allopolyploids form when a sterile hybrid doubles its chromosomes, giving each chromosome a partner, restoring fertility and often creating a new species, as in wheat.

Key ideas

• Silent, missense and nonsense mutations differ by their effect on the codon's meaning.
• Frameshifts change every downstream codon and usually create early stops.
• Deamination, depurination and tautomeric shifts cause spontaneous mutations.
• UV makes pyrimidine dimers repaired by nucleotide excision repair.
• Mismatch repair, base excision repair and double-strand break repair each target different damage.
• Inversion and translocation carriers can be healthy but produce unbalanced gametes.
• Aneuploidy changes single chromosomes; polyploidy changes whole sets.

Formulas and rules

Common mistakes

• Calling any amino acid change a nonsense mutation.
• Thinking insertions of three bases cause frameshifts.
• Confusing aneuploidy (one chromosome) with polyploidy (whole sets).
• Assuming balanced translocation carriers have abnormal phenotypes or always pass on balanced sets.
• Matching the wrong repair pathway to the damage, such as mismatch repair for UV dimers.

Before the test, make sure you can

• Classify point mutations as silent, missense, nonsense or frameshift from codon changes.
• Explain how deamination, base analogs, intercalators and UV cause mutations.
• Interpret Ames test results.
• Match each DNA repair pathway to the damage it fixes and the disease caused by its loss.
• Describe deletions, duplications, inversions and translocations and their meiotic consequences.
• Calculate chromosome numbers for aneuploids, polyploids and allopolyploids.
• Explain dominant negative versus haploinsufficient mutations.

Words to know

Point mutation

A change in one or a few base pairs.

Transition

Substitution of a purine for a purine or a pyrimidine for a pyrimidine.

Transversion

Substitution of a purine for a pyrimidine or vice versa.

Silent mutation

A base change that does not change the amino acid.

Missense mutation

A base change that replaces one amino acid with another.

Nonsense mutation

A base change that creates a premature stop codon.

Frameshift

An insertion or deletion that changes the reading frame.

Deamination

Loss of an amino group from a base, such as cytosine becoming uracil.

Base analog

A chemical similar to a normal base that mispairs during replication.

Intercalating agent

A flat molecule that inserts between bases and causes frameshifts.

Pyrimidine dimer

Covalent link between adjacent pyrimidines caused by UV light.

Nucleotide excision repair

Removes a short strand segment around bulky damage.

Mismatch repair

Corrects mispaired bases left after replication.

Non-homologous end joining

Error-prone repair that directly rejoins broken DNA ends.

Inversion

A chromosome segment flipped in orientation.

Reciprocal translocation

Exchange of segments between nonhomologous chromosomes.

Robertsonian translocation

Fusion of the long arms of two acrocentric chromosomes.

Aneuploidy

Gain or loss of individual chromosomes.

Polyploidy

Having more than two complete chromosome sets.

Sample practice questions

30 more questions like these, from level 1 to 5, are in the practice set.