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M4

Module 4 · When things change

When things change

Mutations, DNA repair, cancer genetics, and epigenetic regulation: Module 4.

A mutation is a permanent change in the DNA sequence of a cell. Mutations can arise from errors during DNA copying, from chemical changes that happen on their own, or from exposure to mutagens such as UV light or certain chemicals. This section explores the main classes of mutation, how cells use several DNA repair systems to correct damage, and how mutations that escape repair can, over time, contribute to cancer.

What is a mutation?

A mutation is a permanent change in the DNA sequence of a cell. Mutations that arise in gametes (eggs or sperm) or the cells that form them are called germline mutations: they can be passed from parent to child.

Mutations that arise in any other body cell after fertilisation are somatic mutations. Somatic mutations are not inherited by offspring, but they accumulate in tissues throughout life and are central to the development of cancer.

Sources: errors, chemistry, and mutagens

Mutations have two main origins. Replication errors occur when DNA polymerase makes a copying mistake; most are corrected by proofreading enzymes, but a few escape. Spontaneous chemical changes: such as deamination, which converts cytosine to uracil, also alter bases without any external trigger.

Mutagens are physical or chemical agents that raise the mutation rate. UV light creates thymine dimers that distort the DNA strand; ionising radiation causes strand breaks; and chemicals called carcinogens can modify or cross-link bases. Most mutations are neutral or harmful; very rarely a mutation is beneficial and may be favoured by natural selection.

A mutation is a permanent change in the DNA sequence of a cell. Mutations can arise from errors during DNA copying, from chemical changes that happen on their own, or from exposure to mutagens such as UV light or certain chemicals. This section explores the main classes of mutation, how cells use several DNA repair systems to correct damage, and how mutations that escape repair can, over time, contribute to cancer.

What is a mutation?

A mutation is a permanent change in the DNA sequence of a cell. Mutations that arise in gametes (eggs or sperm) or the cells that form them are called germline mutations: they can be passed from parent to child.

Mutations that arise in any other body cell after fertilisation are somatic mutations. Somatic mutations are not inherited by offspring, but they accumulate in tissues throughout life and are central to the development of cancer.

Sources: errors, chemistry, and mutagens

Mutations have two main origins. Replication errors occur when DNA polymerase makes a copying mistake; most are corrected by proofreading enzymes, but a few escape. Spontaneous chemical changes: such as deamination, which converts cytosine to uracil, also alter bases without any external trigger.

Mutagens are physical or chemical agents that raise the mutation rate. UV light creates thymine dimers that distort the DNA strand; ionising radiation causes strand breaks; and chemicals called carcinogens can modify or cross-link bases. Most mutations are neutral or harmful; very rarely a mutation is beneficial and may be favoured by natural selection.

Epigenetic marks are chemical patterns on DNA and its packaging proteins. They regulate gene expression: which genes are read, without changing the DNA sequence itself. They turn genes on, off, or dim them in response to development, cell type, and environment. Think of it this way: the genome is the hardware. The epigenome is the software that tells each tissue which programs to run.

Beyond the DNA sequence

Epigenetics (from Greek, "above genetics") refers to changes in gene activity that do not involve altering the underlying A-T-G-C sequence. The same genome can produce vastly different expression profiles in muscle, liver, neurons, and immune cells because each cell type maintains its own epigenetic landscape.

This layering is essential for three interconnected processes: development (building an organism from a single cell), differentiation (cells becoming specialised), and environmental response (cells adjusting gene use in response to signals like hormones, stress, or nutrients).

In development, cells progressively restrict which genes they express. An early stem cell is flexible. It can become many types. As it differentiates, certain genes become permanently accessible and others are locked down by epigenetic marks. That commitment is maintained through cell divisions without needing to re-read developmental signals every time.

Environment can also leave lasting marks. Smoking, diet, stress, and toxin exposure all correlate with specific methylation changes at identifiable loci. Those changes can persist long after the exposure ends.

In short, epigenetics explains how one genotype supports hundreds of specialised cell types and how life experience can leave a molecular record.

Epigenetics vs genetics

Genetic changes alter the nucleotide sequence: creating different alleles that can change protein structure or how much of a protein is made. These changes are heritable, fixed in somatic cells, and usually detectable by sequencing.

Epigenetic changes work differently. They alter how accessible a gene is to the transcription machinery that reads it. A gene can be completely intact, correct sequence, correct promoter, and still be completely silenced by a dense layer of epigenetic marks that physically block access.

Key differences: epigenetic changes are often reversible (especially in response to drugs or environmental signals), they are tissue-specific (the same gene may be open in one cell type and closed in another), and they are dynamic across development and ageing.

Both layers affect phenotype. But through different routes: sequence determines what proteins can be built; epigenetics determines when, where, and how much. A variant that lies in a regulatory region might exert its effect by changing the local epigenetic landscape, blurring the line between the two.

You inherit a largely fixed DNA sequence. Most epigenetic patterns are rebuilt de novo during early development, although some persist or are re-established by genetic signals.

The epigenome is tissue-specific and dynamic

There is no single "the epigenome." Each of your roughly 200 cell types maintains a distinct pattern of open and closed chromatin, DNA methylation, and histone marks. These patterns are cell-type-specific and are actively maintained through every cell division.

That tissue-specificity creates a major challenge: measuring the epigenome in one accessible tissue (like blood) may not reflect what is happening in an inaccessible target tissue (like the brain). EWAS hits in blood must be interpreted cautiously when the phenotype of interest is neurological.

The epigenome also changes with time. Two major temporal dynamics operate: developmental programming (marks are established during differentiation and largely maintained) and age-associated drift (marks shift gradually over a lifetime). Epigenetic clocks, models built on methylation at a small set of CpG sites, can predict chronological or biological age with surprising accuracy, suggesting that ageing itself leaves a systematic epigenetic signature.

Epigenetics in disease and medicine

Because epigenetic marks control which genes are active, errors in those marks can have large consequences, sometimes as large as mutations.

In cancer, aberrant promoter hypermethylation silences tumour suppressor genes such as MLH1 (DNA mismatch repair), BRCA1, and CDKN2A (cell cycle control). This is a major driver of many cancers alongside sequence mutations. Similarly, global DNA hypomethylation in cancer cells can reactivate mobile transposable elements and proto-oncogenes.

In developmental disorders, errors in imprinting (see the Inheritance section) cause conditions like Angelman syndrome or Prader–Willi syndrome without any underlying mutation.

Critically, the reversibility of epigenetic marks makes them attractive drug targets. Enzymes that add or remove methyl groups or histone marks can be blocked by small molecules. HDAC inhibitors (e.g. vorinostat) and DNMT inhibitors (e.g. azacitidine) are already FDA-approved treatments for certain cancers. The field of epigenetic therapy is rapidly expanding.

Check your understanding

Six questions on mutations, repair, cancer, and epigenetics. Explanations follow any misses.

Select all mutation types named in this module. (Select all that apply.)

Substitutions (including silent, missense, nonsense)Insertions or deletions that can cause frameshiftsLarge chromosomal changes such as translocationsCrossing over during mitosis

Select all that apply.

An oncogene drives cell growth when it gains function. A tumour suppressor gene restrains growth and is lost. Which example fits an oncogene?

RAS (gain-of-function drives growth)TP53 (loss-of-function removes a brake)A gene that only repairs UV damageHistone proteins that package DNA

DNA methylation can reduce transcription of a gene without changing its base sequence.

TrueFalse

Defective mismatch repair is linked to which inherited cancer syndrome in this module?

Lynch syndromeSickle-cell diseaseDown syndromeCystic fibrosis only

What does XIST RNA do in female cells?

Coats one X chromosome to silence itBuilds ribosomesCopies DNA during S phaseRepairs double-strand breaks

Knudson's two-hit model explains why both copies of a tumour suppressor gene often must be lost.

TrueFalse

Answer every question to submit.