Abstract
BackgroundThe ability to discern ancestral relationships between individual human colon crypts is limited. Widely separated crypts likely trace their common ancestors to a time around birth, but closely spaced adult crypts may share more recent common ancestors if they frequently divide by fission to form clonal patches. Alternatively, adult crypts may be long-lived structures that infrequently divide or die.MethodsMethylation patterns (the 5' to 3' order of methylation) at CpG sites that exhibit random changes with aging were measured from isolated crypts by bisulfite genomic sequencing. This epigenetic drift may be used to infer ancestry because recently related crypts should have similar methylation patterns.ResultsMethylation patterns were different between widely separated ("unrelated") crypts greater than 15 cm apart. Evidence for a more recent relationship between directly adjacent or branched crypts could not be found because their methylation pattern distances were not significantly different than widely separated crypt pairs. Methylation patterns are essentially equally different between two adult human crypts regardless of their relative locations.ConclusionsMethylation patterns appear to record somatic cell trees. Starting from a single cell at conception, sequences replicate and may drift apart. Most adult human colon crypts appear to be long-lived structures that become mosaic with respect to methylation during aging.
Highlights
The ability to discern ancestral relationships between individual human colon crypts is limited
Methylation distances between cells from different crypts regardless of proximity, or between cells in branched crypts were not significantly different. These findings suggest two basic Y-shaped trees describe the majority of adult crypt cells
An approach based on methylation pattern comparisons can potentially infer ancestral relationships between human crypts
Summary
The ability to discern ancestral relationships between individual human colon crypts is limited. Adult crypts may be long-lived structures that infrequently divide or die. The human colon is a large, epithelial lined organ that develops from a simple tube [1]. Crypts form from this tube and subdivide the colon into millions of distinct clonal units maintained by stem cells [2]. Crypt fission is prominent in early development and declines with age [7]. The majority of adult crypts form early in life and subsequently survive a lifetime as independent clonal units. Branched crypts [presumed fission intermediates) are observed in normal adult human colons at low (
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