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STEM CELLS: TISSUE RENEWAL 267

once off the template with one new mutation. At the steady state, the
transit lineage always receives a strand copied from the template that
carries one new mutation; replication in the transit cell adds another
mutation.
Figure 12.10b shows the opposite pattern, in which the newest strand
always segregates to the stem lineage along the bottom. The newer
strand always has one additional mutation, so the stem lineage accrues
one new mutation in each generation.
By the standard view of DNA replication and mitosis, strands segre-
gate randomly to daughter cells. If so, then the pattern by which muta-
tions accumulate would follow a stochastic process between case (a), in
which the stem lineage always gets the older strand, and (b), in which
the stem lineage always gets the newer strand. Stochastic segregation
would, on average, cause mutations to accumulate in the stem lineage
at one-half the rate at which mutations arise on newly copied strands.
Cairns (1975) called the pattern in Figure 12.10a “immortal strand-
ing.” Any tendency away from purely random segregation and toward
immortal stranding would lower the rate at which mutations accumulate
in the stem line.
Immortal stranding requires asymmetric stem cell division, in which
the fate of the daughters is determined during mitosis, before segrega-
tion occurs. Any evidence for immortal stranding also provides evidence
for asymmetric stem cell division.
Several recent studies support Cairns’ hypothesis of immortal strand-
ing in stem cell lineages. Potten et al. (2002) marked DNA strands
in mouse small intestine crypts with tritiated thymidine, then labeled
newly synthesized strands with a different label, bromodeoxyuridine.
Over time, only a few cells in crypt positions 3–7 retained the initial la-
bel; those cell positions delineate the crypt location in which stem cells
reside (Figure 12.7). When the second label was removed, the putative
stem cells that retained tritiated thymidine lost the second label, bro-
modeoxyuridine, showing that those cells did pass through the mitotic
cycle.
Smith (2005) similarly showed that cells with stem lineage properties
in mouse mammary glands retain immortal strands through epithelial
tissue renewal.
Studies of asymmetrically dividing cells in tissue culture also demon-
strate conditions under which immortal stranding occurs (Merok et al.