Mutations and variation

Why it matters

Genetic testing, cancer diagnostics, antibiotic resistance and vaccine updates all come down to mutations: changes in a DNA sequence. A molecular lab might sequence a tumour to find a mutation that guides treatment, or test bacteria for a resistance gene. To read such a result you need to know what kinds of mutation exist and what each does to the protein.

The core idea

A mutation is any change in the DNA base sequence. Because the protein is built by reading the DNA in codons (three-base words), the effect depends on how the change affects those words.

Mutations arise from:

• Copying errors during DNA replication (rare, because DNA polymerase proofreads).
• Mutagens: UV light, tobacco smoke chemicals, some radiation.
• Spontaneous chemical damage to bases.

Cells have repair systems that fix most damage. What remains can be harmful, neutral or, occasionally, useful.

Point mutations: one base changed

Take this stretch of mRNA and its protein:

mRNA:     AUG  GAG  UGG  AAA
Protein:  Met  Glu  Trp  Lys

Change one base at a time:

Worked example: sickle cell disease. In the β-globin gene of haemoglobin, one A is replaced by T in the DNA. The mRNA codon changes from GAG to GUG, so the sixth amino acid changes from glutamic acid to valine. This single missense change makes haemoglobin stick together when oxygen is low, distorting red cells into a sickle shape. One base, one amino acid, a serious disease. Labs detect it with haemoglobin electrophoresis, HPLC or DNA tests.

Insertions and deletions: frameshifts

Adding or removing bases that are not a multiple of three shifts the reading frame, so every codon after the change is different. An English analogy:

Original:          THE CAT ATE THE RAT
Delete one "A":    THE CTA TET HER AT...

mRNA:              AUG GAG UGG AAA
Delete first G:    AUG AGU GGA AA...
Protein:           Met Ser Gly ...   (every amino acid after the change is different)

Frameshifts usually produce a useless protein and often reach a premature stop codon. Deleting exactly three bases removes one amino acid without a frameshift. The most common cystic fibrosis variant, ΔF508, is a three-base deletion that removes one phenylalanine from the CFTR protein, causing it to misfold.

Larger changes

Mutations can also affect chromosomes: duplications, deletions of whole segments, or translocations where pieces of two chromosomes swap. The "Philadelphia chromosome" in chronic myeloid leukaemia is a translocation between chromosomes 9 and 22 that creates a fusion gene; detecting it guides treatment.

Where variation comes from

Mutation is the original source of all new alleles. Sexual reproduction then shuffles them:

• Independent assortment of chromosomes into gametes.
• Crossing over, where paired chromosomes swap segments during meiosis.
• Random fertilisation: any sperm with any egg.

Most variation between people is harmless. When a variant is common (found in more than about 1% of a population) it is often called a polymorphism. Clinical reports classify variants as pathogenic, likely pathogenic, of uncertain significance, likely benign or benign.

Mutations that occur in body cells (somatic) are not inherited but can cause cancer. Mutations in eggs or sperm (germline) can be passed to children.

Mutation and microbes

Bacteria and viruses reproduce quickly, so useful mutations spread fast. A mutation that lets a bacterium survive an antibiotic is selected when that antibiotic is used, and the resistant strain takes over. RNA viruses such as influenza mutate quickly, which is one reason flu vaccines are updated each year.

Common mistakes

• Assuming every mutation is harmful. Many are silent or neutral, and some are beneficial.
• Thinking a missense change is always mild. Sickle cell shows one amino acid can matter a lot.
• Calling any deletion a frameshift. Only deletions or insertions that are not multiples of three shift the frame.
• Mixing up somatic and germline. Only germline mutations are inherited.

Quick recap

• A mutation is a change in DNA sequence; repair fixes most damage.
• Silent: same amino acid. Missense: different amino acid. Nonsense: early stop.
• Insertions or deletions that are not a multiple of three cause frameshifts.
• Sickle cell is a single missense change; CF ΔF508 is a three-base deletion.
• Mutation creates new alleles; meiosis and fertilisation shuffle them.