Reconstructing Contemporary Human Stem Cell Dynamics with Oscillatory Molecular Clocks

Cell histories can be reconstructed from their genomes by analysing 'molecular clocks' that accumulate heritable changes through time. Commonly used clocks, such as the accumulation of single nucleotide variants or DNA methylation, slowly change over decades, recording cell dynamics that occur over long timescales corresponding to the change accumulation (tick) rate. Faster clocks saturate and stop recording early in life, precluding the study of short-timescale cell dynamics such as renewal in adult tissues. Here we develop a new method that can measure contemporary adult cell dynamics with rapidly oscillating CpG DNA methylation, where like a pendulum, ongoing 'tick-tock' (de)methylation causes switching between 0, 50 and 100% methylation at each CpG locus in a diploid cell. In polyclonal cell populations, average oscillator methylation is ~50%, but “W-shaped” distributions with modal peaks at 0, 50 and 100% methylation are evident in clonal populations. The precise shape of the W-distribution is determined by the underlying dynamics of cell growth and replacement. Through our work, we've illustrated oscillator DNA methylation can be measured in many human tissues cheaply and routinely and enables the inference of otherwise elusive contemporary dynamics of normal and abnormal somatic cells.