D1.3 Mutation and gene editing

Mutation is the ultimate source of all genetic variation — without it there would be no new alleles for evolution to act on, but it is also the cause of many genetic diseases and of cancer. A mutation is a random change in the base sequence of DNA, and its effect depends on exactly what changes and where. D1.3 asks you to classify mutations, understand why most are neutral but some are harmful or beneficial, and appreciate the new technology of gene editing that lets us deliberately rewrite DNA. The classic case study tying it all together is sickle-cell anaemia.

What mutations are, and what causes them

A gene mutation is a change to the base sequence of a gene. The smallest kind is a base substitution (a point mutation), where one base is replaced by another; insertions and deletions of bases also occur and can shift how every following codon is read. Mutations are random and spontaneous — they can arise from uncorrected errors during DNA replication.

The rate of mutation is increased by mutagens: factors in the environment that damage DNA or interfere with replication. Examples include ionising radiation (such as X-rays, gamma rays and ultraviolet light) and certain chemicals (such as those in tobacco smoke). Many mutagens are also carcinogens because the mutations they cause can lead to cancer.

Consequences: neutral, harmful or beneficial

The effect of a mutation varies. Because the genetic code is degenerate, a base substitution may produce a codon that still codes for the same amino acid; such a silent (neutral) mutation has no effect on the protein. Other mutations change an amino acid and may alter the protein’s structure and function, or create a premature stop codon. The consequence can be:

• Harmful — the protein no longer works properly, as in many genetic diseases.
• Neutral — no noticeable effect, the most common outcome.
• Beneficial — rarely, the change improves survival or reproduction and may spread through a population by natural selection, providing the raw material for evolution.

It is important to be balanced in exam answers: mutations are not always bad. They are the source of the genetic variation on which evolution depends.

Somatic versus germline, and the sickle-cell example

Where a mutation happens determines whether it is inherited:

• A somatic mutation occurs in a body cell. It is passed on to that cell’s descendants within the individual (and can cause cancer) but is not passed to offspring.
• A germline mutation occurs in a cell that gives rise to gametes. It can be inherited by offspring and so enters the next generation.

The standard example is sickle-cell anaemia. A single base substitution in the gene for the beta-globin chain of haemoglobin changes one codon, so that the amino acid glutamic acid is replaced by valine. This single amino acid change alters the haemoglobin so that it distorts red blood cells into a sickle shape under low oxygen. The example is powerful because it traces a problem all the way from one DNA base to a whole-body condition — and because carriers of one copy gain some resistance to malaria, it also shows a mutation that is harmful in one context yet beneficial in another.

Gene editing with CRISPR

Gene editing is the deliberate, precise alteration of an organism’s DNA. The leading tool is CRISPR-Cas9, which uses a short guide RNA to locate a specific target sequence and the enzyme Cas9 to cut the DNA at that point; the cell’s repair machinery can then disable a gene or insert a new sequence. Compared with older methods it is fast, cheap and accurate.

The applications are far-reaching: correcting alleles that cause genetic diseases, engineering disease-resistant or higher-yielding crops, and research. But the technology raises serious ethical issues, especially the prospect of editing the germline of human embryos, which would pass changes to all future generations and could be misused for non-medical enhancement. The IB expects you to recognise both the benefits and the ethical concerns rather than taking a one-sided view.