What you'll learn
- How DNA is copied accurately before cell division.
- Why replication is described as semi-conservative.
- How mutations can alter proteins — or sometimes have no effect.
- How mutations in the CFTR gene cause cystic fibrosis symptoms.
1. DNA: the starting point
Deoxyribonucleic acid (DNA) is the hereditary molecule that stores genetic information. In eukaryotic cells, most DNA is found in the nucleus as long molecules packaged into chromosomes. A gene is a length of DNA that codes for a polypeptide or functional RNA.
Nucleotide
A nucleotide is the basic unit of DNA. Each DNA nucleotide contains a phosphate group, a deoxyribose sugar, and one nitrogenous base: adenine, thymine, cytosine, or guanine.
DNA has two strands twisted into a double helix. The bases pair in a specific way: adenine pairs with thymine, and cytosine pairs with guanine. This is called complementary base pairing. The paired bases are held together by hydrogen bonds, while each strand has a strong sugar-phosphate backbone.
Base pairing makes copying possible
Because each base only pairs with one partner, each original DNA strand can act as a template for building a new complementary strand.
2. Semi-conservative DNA replication
DNA must be copied before a cell divides, during the S phase of interphase. This ensures that each daughter cell receives a full copy of the genetic information.
Semi-conservative replication
Semi-conservative replication means that each new DNA molecule contains one original parental strand and one newly synthesised strand.
The overall process is:
- The DNA double helix unwinds.
- Hydrogen bonds between complementary bases break, separating the two strands.
- Each exposed strand acts as a template.
- Free DNA nucleotides line up by complementary base pairing.
- DNA polymerase, an enzyme, joins adjacent nucleotides by forming phosphodiester bonds in the sugar-phosphate backbone.
- Two identical DNA molecules are produced.
This diagram summarises the logic: the original strands are conserved, but each is paired with a new strand.
Finding the complementary new strand
Template strand: 3′-T A C G G A-5′
- Apply the DNA base-pairing rules: T pairs with A, A pairs with T, C pairs with G, and G pairs with C.
- Substitute base by base: T gives A, A gives T, C gives G, G gives C, G gives C, and A gives T.
- Write the new strand antiparallel to the template: 5′-A T G C C T-3′.
Semi-conservative is not conservative
Do not say the whole original DNA molecule stays together and a completely new molecule is made. That would be conservative replication, not semi-conservative replication.
3. Mutations: changes in DNA sequence
Mutation
A mutation is a permanent change in the base sequence of DNA.
Mutations can happen when DNA is copied and a wrong nucleotide is inserted. The chance is low because enzymes proofread and repair many errors, but it is not zero. Mutagens are agents that increase the mutation rate, such as ultraviolet radiation, ionising radiation, and some chemicals.
Mutations in body cells are called somatic mutations. They affect that individual cell line only. Mutations in gamete-producing cells can be inherited by offspring.
Types of gene mutation
Common gene mutations include:
- Substitution — one base is replaced by another.
- Insertion — one or more bases are added.
- Deletion — one or more bases are removed.
The effect depends on how the DNA sequence is read. A codon is a sequence of three bases that codes for one amino acid. A polypeptide is a chain of amino acids, and its amino acid sequence affects how it folds into a functional protein.
The genetic code is degenerate, meaning more than one codon can code for the same amino acid. This is why some mutations do not change the protein.
Possible effects include:
- Silent mutation — no change in amino acid sequence.
- Missense mutation — one amino acid is changed.
- Nonsense mutation — a stop codon is introduced early.
- Frameshift mutation — insertions or deletions not in multiples of three alter all later codons.
Classifying codon changes
Mini codon information: mRNA codons UUU and UUC code for phenylalanine, UUA codes for leucine, and UAA is a stop codon. The original coding DNA codon is 5′-TTT-3′.
- Convert the coding DNA codon to mRNA by replacing T with U: 5′-TTT-3′ becomes UUU, which codes for phenylalanine.
- If the DNA changes to 5′-TTC-3′, the mRNA codon is UUC. This still codes for phenylalanine, so it is a silent mutation.
- If the DNA changes to 5′-TTA-3′, the mRNA codon is UUA. This codes for leucine, so it is a missense mutation.
- If the DNA changes to 5′-TAA-3′, the mRNA codon is UAA. This is a stop codon, so it is a nonsense mutation.
Not every mutation is harmful
A mutation can be harmful, beneficial, or neutral. Its effect depends on whether it changes the amino acid sequence and whether that change alters the protein’s shape or function.
4. Cystic fibrosis and the CFTR gene
Cystic fibrosis is an inherited disorder caused by mutations in the CFTR gene, found on chromosome 7. CFTR stands for cystic fibrosis transmembrane conductance regulator. The CFTR protein is a chloride ion channel found in epithelial cell membranes.
Epithelial cell
An epithelial cell is a cell that lines a surface, such as the airways, pancreatic ducts, digestive tract, or reproductive tract.
In healthy airways, CFTR allows chloride ions to move into the airway surface liquid. Water follows by osmosis, keeping mucus thin enough for cilia to move it away.
In cystic fibrosis, defective CFTR reduces chloride ion movement. Less water enters the mucus, so the mucus becomes thick and sticky. Cilia cannot move it effectively, so bacteria are trapped and infections become more likely.
Gene to symptom chain
A CFTR mutation can change the CFTR protein’s structure, reducing chloride ion transport; this reduces water movement by osmosis, producing thick mucus that blocks ducts and traps bacteria.
The symptoms are not only in the lungs. Thick secretions can also block pancreatic ducts, reducing delivery of digestive enzymes to the small intestine. This can cause poor digestion and reduced absorption of nutrients.
The F508del mutation
One common CFTR mutation is F508del, where three DNA bases are deleted. This removes one amino acid, phenylalanine, from the CFTR protein. The altered protein may fold incorrectly and fail to reach the cell membrane properly.
A deletion is not always a frameshift
F508del removes three bases, so one whole codon is lost. Because the number of deleted bases is a multiple of three, it does not cause a frameshift.
5. Inheritance of cystic fibrosis
Cystic fibrosis is usually described as autosomal recessive. Autosomal means the gene is on a non-sex chromosome. Recessive means a person usually needs two disease-causing CFTR alleles to show the condition.
A person with one normal allele and one disease-causing allele is a carrier. Carriers usually do not have cystic fibrosis symptoms because they still produce enough functional CFTR protein.
Calculating cystic fibrosis inheritance risk
Use C for a normal CFTR allele and c for a disease-causing allele. Two carrier parents have genotypes Cc and Cc.
- Each carrier parent has a probability of 12\frac{1}{2}21 of passing on the c allele.
- A child is affected only if they inherit c from both parents, so multiply the independent probabilities: P(affected child)=12×12=14P(\text{affected child}) = \frac{1}{2} \times \frac{1}{2} = \frac{1}{4}P(affected child)=21×21=41.
- Therefore, for each pregnancy, the probability of an affected child is 25%, the probability of a carrier child is 50%, and the probability of a child with two normal alleles is 25%.
Link levels of biology
For cystic fibrosis explanations, move in order: DNA mutation → altered amino acid sequence → altered protein folding → faulty chloride channel → reduced osmosis → thick mucus → symptoms.
In the exam
- Use the exact phrase semi-conservative replication and explain that each new DNA molecule has one original strand and one new strand.
- For mutation questions, state the type of mutation and then link it to codons, amino acid sequence, protein shape, and protein function.
- For cystic fibrosis, avoid vague answers like “the mucus is wrong”; explain chloride ion movement and water movement by osmosis.
Check yourself
- Why does complementary base pairing make DNA replication accurate?
- How can a base substitution be silent in one case but harmful in another?
- How does a CFTR mutation lead to repeated lung infections?
