Copy a 3-billion-letter book by hand and you will make mistakes. Your cells copy that much DNA every time they divide, and although they proofread carefully, an occasional error slips through. Most of these changes do nothing noticeable. A few, in the wrong place, can change a protein enough to cause a lifelong disorder: one wrong base out of billions is the entire difference between normal hemoglobin and sickle cell disease. Studying these changes explains why some disorders run in families, why some are common in certain populations, and why a disorder caused by a single faulty protein can sometimes be managed with something as simple as a change in diet.
What a mutation is
A mutation is a permanent change in the base sequence of DNA. Recall that a gene's bases are read in groups of three, called codons, and each codon specifies one amino acid in the protein the gene codes for. Change the bases and you may change the amino acids, and with them the protein's shape and function. Mutations arise from spontaneous copying errors during DNA replication, or from mutagens: agents such as UV light, X-rays and some chemicals in tobacco smoke that damage DNA. Where a mutation happens matters. A somatic mutation occurs in a body cell; it can contribute to cancer but is not passed to children. A germline mutation occurs in a cell that will become an egg or sperm, so it can be inherited and appear in every cell of the child. Not all mutations are harmful: many are neutral, and a few are beneficial, supplying the variation that natural selection acts on.
Substitutions, insertions and deletions
| Type | What happens | Sentence analogy (read in three-letter words) | Typical effect |
|---|---|---|---|
| Substitution (point mutation) | One base is replaced by another | THE CAT ATE THE RAT → THE BAT ATE THE RAT | Changes at most one codon: may be silent, may change one amino acid, or may create an early stop |
| Insertion | One or more bases are added | THE CAT ATE THE RAT → THE CAX TAT ETH ERA T | If not a multiple of 3, every codon after it is misread (frameshift) |
| Deletion | One or more bases are removed | THE CAT ATE THE RAT → THE ATA TET HER AT | If not a multiple of 3, causes a frameshift; deleting exactly 3 removes one amino acid |
The analogy shows why a frameshift is usually far worse than a substitution. A substitution is like one misspelled word; the rest of the sentence still reads correctly, and sometimes the new codon still codes for the same amino acid (a silent mutation), because most amino acids have more than one codon. An insertion or deletion of one or two bases shifts the reading frame, so every codon downstream is wrong, the protein is built from nonsense, and it usually stops early. The position also matters: a frameshift near the start of a gene garbles almost the whole protein, while one near the end changes only the last few amino acids. An insertion or deletion of exactly three bases keeps the frame, adding or removing a single amino acid.
Single-gene disorders
| Disorder | Gene and protein | Inheritance | Mutation | Effect |
|---|---|---|---|---|
| Cystic fibrosis | CFTR, a chloride ion channel in cell membranes | Autosomal recessive | Most common: deletion of 3 bases, removing one amino acid | Thick, sticky mucus in lungs and pancreas; lung infections; poor digestion |
| Sickle cell disease | HBB, part of hemoglobin | Autosomal recessive | Substitution: one base change swaps one amino acid | Red blood cells deform into sickles, block capillaries, and break down: pain and anemia |
| Huntington disease | HTT, the huntingtin protein | Autosomal dominant | Expanded repeat: extra copies of the codon CAG inserted | Gradual loss of brain cells, usually beginning in adulthood; movement, mood and memory decline |
| Phenylketonuria (PKU) | PAH, an enzyme that breaks down phenylalanine | Autosomal recessive | Various, often substitutions | Phenylalanine builds up and damages the developing brain unless diet is controlled |
| Tay-Sachs disease | HEXA, an enzyme that breaks down a fatty substance in nerve cells | Autosomal recessive | Various, including insertions | The substance builds up in nerve cells; the infant form is usually fatal in early childhood |
Cystic fibrosis is the most common life-threatening recessive disorder among Canadian children. In 1989 a team led by Lap-Chee Tsui at the Hospital for Sick Children in Toronto, working with John Riordan in Toronto and Francis Collins's group at the University of Michigan, identified the CFTR gene. Its protein normally lets chloride ions leave cells, and water follows them by osmosis, keeping mucus thin. In the most common mutation, three bases are deleted, so one amino acid is missing and the channel folds wrongly and never reaches the membrane. Without water drawn out, mucus becomes thick, traps bacteria in the lungs and blocks the ducts that carry digestive enzymes from the pancreas. Finding the gene made carrier testing and diagnosis possible and led to drugs that help faulty CFTR channels fold and open.
Sickle cell disease is caused by a single base substitution that swaps one amino acid in hemoglobin. When oxygen levels drop, the altered hemoglobin molecules stick together into stiff fibres that bend red blood cells into sickle shapes. Yet the allele is common in parts of Africa, the Middle East and South Asia. The reason is heterozygote advantage: carriers with one normal and one sickle allele (sickle cell trait) are usually healthy and are also more resistant to severe malaria, a disease caused by a protist, Plasmodium, that lives in red blood cells. Where malaria is common, carriers survive and reproduce more than either homozygote, so natural selection keeps the allele in the population. Huntington disease is dominant, so one copy of the allele is enough, but symptoms usually start between ages 30 and 50, often after a person has had children, which is how a harmful dominant allele can be passed on. Tay-Sachs alleles are more common in some populations, including Ashkenazi Jewish and some French-Canadian communities, an example of the founder effect, and carrier screening has made the disease much rarer.
Treatments: from diet to engineered plants
- Diet — a newborn with PKU, found by the heel-prick blood test done on newborns in Ontario, starts a low-phenylalanine diet (limiting protein and avoiding the sweetener aspartame). Started early, it prevents the brain damage entirely.
- Managing symptoms — people with cystic fibrosis use airway-clearing physiotherapy, inhaled medicines, antibiotics and digestive-enzyme capsules with meals.
- Drugs that target the faulty protein — CFTR modulator drugs help the mis-folded channel reach the membrane and open, greatly improving lung function for many patients.
- Replacing cells — a bone marrow (stem cell) transplant from a matched donor can cure sickle cell disease by supplying cells that make normal hemoglobin; gene therapies are now being developed and approved.
- Counselling and testing — carrier screening and genetic counselling help families understand risks; for Huntington disease, a predictive test can tell an adult whether they carry the allele, which raises difficult personal questions.