Inferring human stem cell behaviour from epigenetic drift

Although conventional experimental manipulations are impractical, it may be possible to infer human stem cell fates by 'reading' histories recorded within their genomes. Genomes are almost perfect copies of copies, and ancestries may be surreptitiously recorded by replication errors that inevitably accumulate. The greater the number of divisions, the greater the number of replication errors ('a molecular clock hypothesis'). Mutations rarely occur during a lifetime, but DNA methylation patterns are also copied after DNA replication and measurably drift with ageing at certain CpG sites in mitotic tissues, such as the colon. Such passenger methylation pattern variation may effectively function as 'epigenetic' somatic cell mitotic clocks. Replication errors can only accumulate in long-lived stem cell lineages, so methylation pattern drift largely records stem cell behaviour. How methylation patterns may encode stem cell ancestries is illustrated with two types of small reproductive units - colon crypt niches with continuous genealogies, and hair follicles with punctuated genealogies. Potentially, the genealogy of any human cell may be inferred by 'reading' its genome. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.