Somatic Mosaicism — Glossary & Cheatsheet

Core Concepts

Somatic mutation — Any DNA change occurring after fertilisation (i.e. not inherited). Present only in descendant cells of the mutated cell, not in the germline. Contrast with germline mutation which is heritable.

Somatic mosaicism — The condition where a single organism contains cells with different genotypes, all derived from one original zygote. Every human is a somatic mosaic.

Chimerism — Similar to mosaicism but the distinct cell lines originate from different zygotes (e.g. organ transplant, twin absorption). Mosaicism = one zygote, chimerism = multiple.

Variant Allele Frequency (VAF) — The proportion of sequencing reads carrying a particular mutation. A VAF of 0.25 means ~25% of reads show the variant. Used to estimate what fraction of cells carry a mutation.

Clone / Clonal expansion — A population of cells all descended from a single mutated ancestor cell. When a mutation gives a cell a competitive advantage, it can expand to colonise tissue.

Driver mutation — A mutation that gives a cell a selective advantage (faster growth, resistance to apoptosis). Contrast with passenger mutation which is neutral and just along for the ride.

Mutational signature — A characteristic pattern of mutation types associated with specific mutational processes (e.g. UV damage, oxidative stress, ageing). Catalogued as SBS1, SBS5, SBS18, etc.

Key Terms

CHIP (Clonal Hematopoiesis of Indeterminate Potential) — Expanded blood cell clones carrying mutations in leukaemia driver genes at VAF ≥2%, in the absence of blood cancer. Extremely common in the elderly. Associated with increased cardiovascular disease risk and all-cause mortality, not just cancer.

Clonal hematopoiesis (CH) — Broader term for any clonal expansion in blood cells driven by somatic mutations. CHIP is a specific subset.

mTOR pathway — Signalling pathway controlling cell growth, proliferation, and metabolism. Somatic mutations here cause brain malformations (focal cortical dysplasia, hemimegalencephaly) and intractable epilepsy.

Hemimegalencephaly (HME) — Overgrowth of up to an entire brain hemisphere, caused by somatic mosaic mutations (often mTOR pathway). Higher VAF = more severe malformation.

Focal Cortical Dysplasia (FCD) — More localised brain malformation than HME, also caused by somatic mTOR mutations but at lower VAF. Often causes drug-resistant epilepsy.

Ramet — An individual stem/trunk in a clonal plant colony (e.g. one "tree" in Pando). Genetically part of the same organism (genet).

Genet — The entire genetic individual in a clonal organism. Pando is one genet comprising ~47,000 ramets.

Meristem — Plant growth tip where cell division occurs. Equivalent concept to stem cell niches in animals. Long-lived clonal plants may have mechanisms to preserve genetic integrity in meristems.

Immortal strand hypothesis — The idea that stem cells preferentially retain the original template DNA strand during division, passing newly-synthesised (potentially mutated) strands to differentiated daughter cells. Evidence suggests ~98% effective non-random strand segregation in adult human tissues.

Triploidy — Having three copies of each chromosome instead of two. Pando is triploid, which prevents sexual reproduction but may contribute to fitness and longevity.

Key Numbers

Disease Associations

The Pando Parallel

Pando and human bodies are both somatic mosaics — genetically non-uniform organisms where different regions carry slightly different mutations accumulated over time. The key parallels:

• Both accumulate mutations at tissue-specific rates (Pando: leaves > roots; humans: skin > bile ducts)
• Both appear to have mechanisms limiting mutation spread (Pando: modest spatial structure despite ages; humans: immortal strand hypothesis, DNA repair)
• Both show that "individual" and "clone" are blurry concepts at the genetic level
• The somatic mutations in both serve as molecular clocks for estimating age and tracing lineage history