DNA Methylation Drift: Maintenance Fidelity Simulator

Replication Enzymology

DNMT1 maintenance fidelity 96%

De novo (aberrant) gain rate 0.8%

TET active demethylation rate 0.5%

Population State

Cell division

Mean β (methylation)

50.0%

Drift entropy (mean CpG Shannon entropy)

0.00 bits

unmethylated βmethylated β

How it works

Each of 16 CpG dyads on this helix is tracked across a population of 200 simulated cell lineages. After every S-phase, replication leaves each dyad hemimethylated (only the parental strand still carries the mark). DNMT1 must recognise that hemimethylated site and copy the mark onto the new strand — it does this with maintenance fidelity p_m, not certainty:

methylated  → stays methylated with prob.  p_m · (1 − p_loss)
unmethylated → becomes methylated with prob. p_denovo

Per-site methylation level is a β value, the same quantity real bisulfite-sequencing epigenetic clocks (Horvath, Hannum) measure: β_j = (methylated copies at site j) / (population size). The drift readout is the population-averaged Shannon entropy per site,

H(β) = −[ β·log₂β + (1−β)·log₂(1−β) ]

which is 0 when a site is fixed (all-methylated or all-unmethylated across the population) and rises toward 1 bit as maintenance errors, de novo noise and active demethylation push the population toward a 50/50 mosaic. This stochastic accumulation of per-site heterogeneity — not any single "aging gene" — is the mechanistic basis for why methylation-based age predictors drift with true chronological/biological age.

Maintenance fidelity — real DNMT1 in vivo runs roughly 92–99% per division; drop it to see drift accelerate.
De novo gain — aberrant DNMT3A/3B activity slowly methylates sites that should stay open.
TET demethylation — active oxidation (5mC→5hmC→…) erodes existing marks, the other half of the tug-of-war.

Unmethylated CpG Methylated CpG

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