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Darwinian model. If the variability of gene expression is an essen-
tial biological parameter at the root of cell differentiation, and not
simply noise due to the way a deterministic genetic programme
functions, it should be possible to correlate the two phenomena,
and that correlation should be compatible with the Darwinian
model. Indeed, the latter predicts that during cell differentiation
the variability of expression between cells itself must vary quanti-
tatively. This variability may be expected to increase as long as the
cells are not adapted to their microenvironment, because the genetic
expression is not stable, and in contrast, decrease when the cells
differentiate to adapt to this microenvironment, since a particular
profile of genetic expression is selected and amplified corresponding
to the cell type selected. No such evolution in variability is expected
if the latter is the result of experimental noise independent of the
physiological state of the cells (Heams, 2004). We can make an
additional prediction concerning the molecular basis for this restric-
tion in variability: as we have indicated, in the Darwinian model,
signal transduction controls the variability of genetic expression via
protein phosphorylation. This phosphorylation can be experimen-
tally altered by various means, aiming, for example, at inhibiting or
activating, even over-activating, the phosphorylation and/or dephos-
phorylation enzymes. This treatment should also therefore alter the
restriction in variability of expression during cell differentiation and
disturb its occurrence.
The first of these two predictions has started to be validated.
When human embryonic cells cultured ex vivo multiply until they
saturate the culture dish, they undergo physiological transforma-
tion called contact inhibition which causes them to cease multiply-
ing. The variability of gene expression increases in this phenomenon
in the first instance when the cells arrive at saturation and certain
cells of the population are stabilised with a new gene expression
profile (Neildez-Nguyen et al ., 2008; Stockholm et al ., in press).
Thanks to the collaboration of several researchers with comple-
mentary skills, these predictions of the Darwinian model have
been greatly developed and are the subject of a specific experi-
mental research programme (Guillaume Beslon, INSA-Lyon; Olivier
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