Dear Sir or Madame,
A recent article by Muhle et al. in this journal (1) summarizes
available evidence on the genetics of autism. In general, single-gene
disorders (e.g., Fragile X, Rett, and Zellweger’s syndrome) in psychiatry
are rare. Arguably, a corollary to this observation is the scant
evidence of behavioral abnormalities when single genes are “knocked-out”
in mice models. The majority of mental disorders, including autism, are
defined by a large number of interactions between multiple predisposing
gene variants and the environment. This concept is now subsumed under the
concept of a “complex trait”. This is an important concept to bear in
mind when instituting putative medical interventions and analyzing
association/linkage studies.
Thus far there have been no speculations as to why mental disorders,
and more specifically, autism, tend to be complex traits. We propose that
genetic complexity is a consequence of encephalization and evolution.
Encephalization is a measure of brain size corrected for body size. In
humans, encephalization quotients are higher than in the case of other
mammalian species of similar body size. Brain size is therefore a marker
of the fast pace at which genetic novelties have been introduced into the
Homo lineage. Genetic variability is mandatory for rapid evolution to
occur (2).
The brain is a complicated organ consisting of some 1010 neurons,
103–104 connections per neuron, and about 50 different neurotransmitters.
Furthermore humans, as other larger mammals, have long generation cycles
and few offsprings. At first glance large mammals and complex brains
should lag in the evolutionary race. How has our species been able to
evolve at such a rapid pace? A possible answer is that large brains serve
to accumulate genetic variation (3). Novel genetic changes introduced
into a receptive brain (e.g., one with appropriate connectivity or number
of neurons) can be easily appropriated by natural selection. Genetic
variability thus allows the brain to adapt in unison to changing
environmental conditions. This may help explain a contrasting fact
between megalencephaly and micrencephaly: cognitive impairment is more
commonly seen in conditions related to smaller rather than larger brains.
According to the radial unit hypothesis, the neocortex consists of
arrays of ontogenetic columns (4). Brain growth (cortical expansion) has
occurred through the addition of supernumerary ontogenetic columns. For
normal function, once these (mini)columns have been established,
connectivity among them approximates the order of 1000. Encephalization
has consequently provided for a disproportionate increase in white matter
as compared to gray matter. There may be a functional asymptote to
overall cortical expansion (5). This suggests that pathology may flourish
as we approach the limits of cortical expansion.
We think that minicolumnopathies constitute a suite of mental
disorders that are the consequence of cortical expansion. It is therefore
noteworthy that in autism, brains are on average larger than normal and
have an increased white:gray matter ratio. Unsurprisingly, recent
neuropathological studies have reported minicolumnar abnormalities in the
brains of autistic patients (6). In these cases minicolumns have been
noted to be more numerous and narrower while preserving normal cellular
density.
Another potential sequel of encephalization characterized by
plasticity and redundancy of neuronal networks is generalized relaxation
of selective pressures for genetic components expressed in the brain.
This model predicts an accumulation of selectively neutral or slightly
deleterious genetic factors (3). The significance of this for
understanding the origin of autism, is that due to population history (7)
or cultural practices, there can be an increase in the frequency of
individuals carrying gene complexes in similar environments: It follows
that any estimate of a parameter measuring genetic association may be
inflated.
References
1. Muhle R, Trentacoste SV, Rapin I. The genetics of autism.
Pediatrics 2004; 113(5):472-486.
2. Lipp H-P. Non-mental aspects of encephalization: the brain as a
playground of mammalian evolution. Hum Evol 1989; 4:45-53.
3. Lipp H-P, Wolfer DP. Big brains for bad genes: nonmental
correlates of encephalization. Evolutionary Anthropology 2003; Suppl 1:
126-131.
4. Rakic P, Kornack DR. Neocortical expansion and elaboration during
primate evolution: a view from neuroembryology. In Dean Falk and Kathleen
R. Gibson editors: Evolutionary Anatomy of the Primate Cerebral Cortex.
Cambridge University Press, New York, NY, 2001; chapter 2, pages 30-56.
5. Ringo JL. Neuronal interconnection as a function of brain size.
Brain, Behavior & Evolution 1991;38:1-6.
6. Casanova MF, Buxhoeveden D, Switala A, Roy E. Minicolumnar
pathology in autism. Neurology 2002; 58:428-432.
7. Wang N, Akey JM, Zhang K, Chakraborty R, Jin L. Distribution of
recombination crossovers and the origin of haplotype blocks: the interplay
of population history, recombination, and mutation. Am J Hum Genet 2002;
71(5):1227-34.
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