GENE EXPRESSION AND ITS DISCONTENTS Developmental disorders as dysfunctions of epigenetic cognition



transmitted from one generation to the next in ways other
than through the base sequence of DNA. It can be transmit-
ted through cultural and behavioral means in higher animals,
and by epigenetic means in cell lineages. All of these transmis-
sion systems allow the inheritance of environmentally induced
variation. Such Epigenetic Inheritance Systems are the mem-
ory systems that enable somatic cells of different phenotypes
but identical genotypes to transmit their phenotypes to their
descendants, even when the stimuli that originally induced
these phenotypes are no longer present.

In chromatin-marking systems information is carried from
one cell generation to the next because it rides with DNA
as binding proteins or additional chemical groups that are
attached to DNA and influence its activity. When DNA is
replicated, so are the chromatin marks. One type of mark is
the methylation pattern a gene carries. The same DNA se-
quence can have several different methylation patterns, each
reflecting a different functional state. These alternative pat-
terns can be stably inherited through many cell divisions.

Epigenetic inheritance systems are very different from the
genetic system. Many variations are directed and predictable
outcomes of environmental changes. Epigenetic variants are,
in their view, frequently, although not necessarily, adaptive.
The frequency with which variants arise and their rate of re-
version varies widely and epigenetic variations induced by en-
vironmental changes may be produced coordinatedly at sev-
eral loci.

Parenthetically, Guerrero-Bosagna et al. (2005) disagree
with the assumption of adaptiveness, finding that input re-
sponsible for methylation effects simply produces phenotypic
variability that is then sub ject to selection. The matter re-
mains open.

Jablonka and Lamb (1998) conclude that epigenetic sys-
tems may therefore produce rapid, reversible, co-ordinated,
heritable changes. However such systems can also under-
lie non-induced changes, changes that are induced but non-
adaptive, and changes that are very stable.

What is needed, they feel, is a concept of epigenetic her-
itability comparable to the classical concept of heritability,
and a model similar to those used for measuring the effects of
cultural inheritance on human behavior in populations.

Following a furious decade of research and debate, this per-
spective received much empirical confirmation. Backdahl et
al. (2009), for example, write that epigenetic regulation of
gene expression primarily works through modifying the sec-
ondary and tertiary structures of DNA (chromatin), making
it more or less accessible to transcription. The sum and in-
teraction of epigenetic modifications has been proposed to
constitute an ‘epigenetic code’ which organizes the chromatin
structure on different hierarchical levels (Turner, 2000). Mod-
ifications of histones include acetylation, methylation, phos-
phorylation, ubiquitination, and sumoylation, but also other
modifications have been observed. Some such modifications
are quite stable and play an important part in epigenetic
memory although DNA methylation is the only epigenetic
modification that has maintenance machinery which preserves
the marks through mitosis. This argues for DNA methylation
to function as a form of epigenetic memory for the epigenome.

Codes and memory, we will show, are inherent to any cog-
nitive paradigm.

Jaenish and Bird (2003) argue that cells of a multicellu-
lar organism are genetically homogeneous but structurally
and functionally heterogeneous owing to the differential ex-
pression of genes. Many of these differences in gene expres-
sion arise during development and are subsequently retained
through mitosis. External influences on epigenetic processes
are seen in the effects of diet on long-term diseases such as
cancer. Thus, epigenetic mechanisms seem to allow an organ-
ism to respond to the environment through changes in gene
expression. Epigenetic modifications of the genome provide a
mechanism that allows the stable propagation of gene activity
states from one generation of cells to the next. Because epi-
genetic states are reversible they can be modified by environ-
mental factors, which may contribute to the development of
abnormal responses. What needs to be explained, from their
perspective, is the variety of stimuli that can bring about epi-
genetic changes, ranging from developmental progression and
aging to viral infection and diet.

Jaenish and Bird conclude that the future will see intense
study of the chains of signaling that are responsible for epige-
netic programming. As a result, we will be able to understand,
and perhaps manipulate, the ways in which the genome learns
from experience.

Indeed, our central interest precisely regards the manner
in which the asymptotic limit theorems of information theory
constrain such chains of signaling, in the same sense that the
Central Limit Theorem constrains sums of stochastic variates.

Crews et al. (2006, 2007) provide a broad overview of
induced epigenetic change in phenotype, as do Guerrero-
Bosagna et al. (2005), who focus particularly on early de-
velopment. They propose that changes arising because of al-
terations in early development processes, in some cases envi-
ronmentally induced, can appear whether or not such changes
could become fixed and prosper in a population. They recog-
nize two ways for this to occur, first by dramatically modifying
DNA aspects in the germ line with transgenerational conse-
quences - mutations or persistent epigenetic modifications of
the genome - or by inducing ontogenetical variation in every
generation, although not inheritance via the germ line. From
their perspective inductive environmental forces can act to
create, through these means, new conformations of organisms
which also implies new possibilities within the surrounding
environment.

Foley et al. (2009) take a very general perspective on
the prospects for epigenetic epidemiology. They argue that
epimutation is estimated to be 100 times more frequent than
genetic mutation and may occur randomly or in response to
the environment. Periods of rapid cell division and epigenetic
remodeling are likely to be most sensitive to stochastic or
environmentally medicated epimutation. Disruption of epige-
netic profile is a feature of most cancers and is speculated to
play a role in the etiology of other complex diseases includ-
ing asthma allergy, obesity, type 2 diabetes, coronary heart
disease, autism spectrum disorders and bipolar disorders and



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