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Brain Research Reviews 31 2000.

118129
www.elsevier.comrlocaterbres

Interactive report

Schizophrenia as the price that Homo sapiens pays for language: a


resolution of the central paradox in the origin of the species 1
T.J. Crow

POWIC, Warneford Hospital, Uniersity Department of Psychiatry, OX3 7JX Oxford, UK


Accepted 30 June 1999

Abstract
The central paradox of schizophrenia is that the condition, apparently genetic in origin, persists in spite of a substantial fecundity
disadvantage. The hypothesis is proposed that the predisposition to schizophrenia is a component of Homo sapiens-specific variation
associated with the capacity for language. A genetic change the speciation event, predicted to be related to the Xq21.3 to Yp
chromosomal transposition that separates Homo sapiens from the great apes. allowed the hemispheres to develop with a cerebral torque,
reflected particularly in association cortex, from right frontal to left occipital. Variations in the dimension of lateralization are associated
with differences in the rate at which verbal and non-verbal ability develops. The nuclear symptoms of schizophrenia can be understood as
a failure to establish dominance for a key component the phonological sequence of language in one hemisphere, with consequent
disruption of the mechanism of indexicality that allows the speaker to distinguish his thoughts from the speech output that he generates
and the speech input that he receives and decodes from others. q 2000 Elsevier Science B.V. All rights reserved.
Keywords: Language; Schizophrenia; Evolution; Homo sapiens; XY homology; Speciation

Contents
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1.

The central paradox

2.

Universality of schizophrenia

3.

The origin of the genetic variation

4.

Lateralization as the critical change .

5.

Relative hand skill as a predictor of academic ability

6.

Anatomical deviations in schizophrenia .

7.

Functional asymmetries in schizophrenia .

8.

Nuclear symptoms as disorders of language

9.

The nature of the gene .

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10. Conclusions
References

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Corresponding author. Tel.: q44-1865-226474; Fax: q44-1865-244990; E-mail: tim.crow@psychiatry.oxford.ac.uk


Published on the World Wide Web on 5 November 1999.

0165-0173r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 1 6 5 - 0 1 7 3 9 9 . 0 0 0 2 9 - 6

T.J. Crowr Brain Research Reiews 31 (2000) 118129

1. The central paradox


The central paradox of schizophrenia that a condition
apparently genetic in origin, survives in the population in
spite of a substantial fecundity disadvantage was first
clearly identified by Huxley et al. w63x. The disadvantage is
well documented. Individuals who develop schizophrenia
are much less likely than others to marry and have children
w49,58,82,101,118,122x and the effect is greater probably
three-fold. in males. The deficit presumably is due to the
difficulty these individuals have in establishing a pair
bond. The magnitude is such that any genetic predisposition would be eliminated from the population within a few
generations. But it is not. There must be a genetic advantage, Huxley et al. argued that might be present in those
who carry the gene but not its pathological expression. that
balances the disadvantage associated with schizophrenia.
The first two authors Huxley and Mayr. are amongst a
small group Simpson and Dhobzhansky are others. described as architects of the evolutionary synthesis the
accommodation of Mendelian genetics with Darwinian
evolutionary theory in the 1940s w87x. But the answer they
gave to the question that they had raised that the
advantage was a genetically based resistance to wound
shock and stress was implausible, as Kuttner et al. w75x
pointed out. It makes no sense to postulate a balance in a
function that is unrelated to the dysfunction that has to be
explained. If the disability lies in psychological symptoms
and behaviour then, at least in the first place, one should
look in this area of function for the balancing advantage.
On the assumption that schizophrenia is a condition that is
in some way related to being human, Kuttner et al. w75x
offered three functions the capacity for complex social
relations, intelligence, and language as candidates and
argued for the first. These three must surely be inter-related. Here I argue that the third language is the most
characteristically human ability, and that when language
in the broader sense of an ability to communicate with the
use of symbols. is seen as the focus, new approaches to the
orgins and pathophysiological basis of the symptoms open
up.

2. Universality of schizophrenia
This issue should be considered in relation to what is
known of the epidemiology of psychosis. Kraepelin travelled to Java and considered that the form of psychotic
illness he saw there was the same as he had described in
his patient populations in Germany. From investigations
amongst the Yoruba of Nigeria and the Eskimo Inuit,
Murphy w94x concluded that the phenomena of psychosis
were essentially independent of the social structure of the
population. Features typical of schizophrenia e.g., the
nuclear symptoms. are well documented in the Australian
aboriginal population w92x and the African Bantu w105x,

119

peoples that have been separated for 50 000 years, and


have recently been described in the tribes of central Borneo w6x. On the basis of the most systematic cross cultural
comparison yet conducted Jablensky et al. w64x concluded
that "schizophrenic illnesses are ubiquitous, appear with
similar incidence in different cultures and have features
that are more remarkable by their similarity across cultures
than by their difference".
The evidence points to the singular conclusion that,
contrary to almost any other common condition, the incidence of schizophrenia is independent of the environment
and a characteristic of human populations. Perhaps it is the
human condition.

3. The origin of the genetic variation


If the condition is genetic, as in some way it appears
that it must be, the question arises of when the variation
arose. If the condition is now present in populations that
have been separated for 50 000 years it seems that either
the origin of the variation, or the mechanism by which it is
generated e.g., a mutation hotspot., must have preceded
the separation of these populations. The origin must be
before or coincident with the genetic change the speciation event. that preceded the diaspora of modern Homo
sapiens across the surface of the globe w31x.
According to a congruence of genetic and palaeontological evidence the transition from an earlier hominid species
took place at some point in East Africa some time between
100 and 150 000 years ago w119x. The genetic change is of
great intrinsic interest as it must somehow account for the
extraordinary biological success of the species, its increase
in population size, the spread into diverse ecological niches
and its ability to transform the environment in a way that
no other vertebrate species has achieved.
What physiological function accounted for this success?
The list of candidates see e.g., Bickerton w8x. resembles
those enumerated by Kuttner et al. w75x, that is the capacity
for complex social interactions, intelligence and language,
with the possible addition of consciousness. From this
list language stands out as the most biologically relevant,
and the one that can be most readily understood in terms
of neural function. Ability to communicate is necessary for
survival in a socially organised species, and must be
closely related to intelligence, which is otherwise difficult to define. Consciousness could be an epi-phenomenon
w8x of the secondary representational capacity that it is
necessary to invoke to account for the phenomena of
language.
Distinctive characteristics of human language are the
arbitrariness of the association between the sign word.
and what it signifies w112x, and its generativity w15x as
represented by the apparently infinite number of sentences
that can be generated and recognised by a competent
speaker of a given language. To account for these innova-

120

T.J. Crowr Brain Research Reiews 31 (2000) 118129

tions a mechanism of universal grammar has been postulated as a unique feature of the human brain w15,16x. But
what is striking in the evolutionary record is the recency of
the evidence for symbolic representation that might parallel the acquisition of the capacity for language. Such
evidence, as instanced by rock art, goes back perhaps
50 000 years but not more w8,96x. But by the same argument deployed above in relation to the incidence of
schizophrenia, if this capacity is now present in each of the
populations that make up humanity either it, or a change
that made its development inevitable, must have been
present at the time of the species transition. A parsimonious conclusion is that the function that characterises the
species language was introduced by the genetic change
the speciation event that initiated the transition.
But what could this change conceivably have been?
What could account for the de novo ability to generate
sentences of indeterminate length, that nevertheless can be
understood because they have a reference and a grammatical structure that can be decoded by a competent hearer?
As demonstrated by sign language these syntactic-semantic
capacities are independent of the phonological and acoustic modalities w5,54,59x. They must relate to the brain as a
whole.
It is necessary to postulate some radical change in brain
function. MaynardSmith and Szathmary w86x characterised the origin of language in Homo sapiens as the
seventh of the major transitions in evolution. The facts
challenge the gradualist concept of speciation, the notion
that species originate by a process of multiple and cumulative genetic change in populations that are geographically
separated, over long periods of time. This notion the
biological or isolation concept. has been opposed by
the theory of punctuated equilibria e.g., Eldredge and
Gould, w48x; Eldredge w47x. although a genetic mechanism
for the latter is lacking. The case of Homo sapiens is
relevant. What is required is a change that is simple, that
could be accounted for by a modification in a single gene,
and that enabled a relatively rapid transformation.

4. Lateralization as the critical change


Only one change has been plausibly suggested, a possibility known since Dax w43x and then Broca w11x discovered that some component of language was confined to
one hemisphere. Something lateralised, or lateralised in a
way that was not previously the case. What was this
component, and what were the consequences of the process of lateralisation? In the answers to these questions lies
a solution to the neural basis of language and, according to
the present thesis, an understanding of the origins of
psychosis.
CrichtonBrowne w21x was one of the first to interpret
the findings in the light of evolutionary theory, and he also
thought they might be relevant to mental illness suppos-

ing that "the regions of the brain which are latest evolved
and which are located on the left side of the brain might
suffer first in insanity". Eberstaller w46x and Cunningham
w42x described anatomical asymmetries the length of the
Sylvian fissure was longer on the left in most individuals
the speciation event had left an imprint on the surface of
the brain. These anatomical asymmetries were almost forgotten until those of the planum temporale were re-discovered by Geschwind and Levitsky w53x in 1964.
That there are asymmetries of brain function has long
been apparent from the phenomena of handedness w22x and
the notion that these could be accounted for in terms of a
genetic influence that is specific to Homo sapiens has been
developed by Annett w2x and Corballis w19x. This case is
strengthened by the observations of Marchant and McGrew w84x that at least in the wild directional handedness
on a population basis is absent in chimpanzees, and of
Buxhoeveden and Casanova w14x that asymmetries of the
columnar structure of the planum temporale are present in
man but absent in the chimpanzee.

5. Relative hand skill as a predictor of academic ability


If cerebral lateralization is what distinguishes Homo
sapiens as a species from its precursors this mechanism
must account for what is most characteristic in brain
function. The capacity for language, it is argued, is the
core function; other aspects of intelligence must also be
related. Annett w2x proposed that transmission of handedness within families could be accounted for by a single
gene the right shift factor. and that the variation in the
population associated with this gene represents a balanced
polymorphism with respect to intelligence that is to say
that heterozygotes for the right shift factor are at an
advantage in intelligence relative to those at the extremes
e.g., strong left- and right-handers. of the right shift
continuum. This hypothesis is the focus of significant
controversy w4,90,98,104x.
My colleagues and I investigated this question in the
UK National Development Study archive w39x. In this
archive an item of test performance number of squares
checked with the right and left hands in one minute. is
recorded on approximately 12 000 children at the age of 11
years that allows us to derive an index of relative hand
skill and to examine it as a predictor of verbal and
non-verbal as well as mathematical and reading ability.
The findings give general support to the concept that
relative hand skill is a determinant perhaps the major
determinant. of the development of academic ability, but
only partial support to Annetts balanced polymorphism
hypothesis.
With respect to verbal ability ability to select the fourth
in a sequence of four given the first three words, and a
template of four words with phonological, semantic or
logical associations to match against. there is a substantial

T.J. Crowr Brain Research Reiews 31 (2000) 118129

sex difference at the age of 11 girls do much better than


boys. but within each sex relative hand skill is a powerful
predictor of ability. There are modest deficits of ability at
the extremes both left and right. of relative hand skill but
these are small relative to the deficits that are seen close to
the point of equal hand skill, that we refer to as the point
of hemispheric indecision. Individuals who are close to
this point are delayed in developing verbal ability, and this
is particularly so in those in whom there is a discrepancy
between relative hand skill and writing hand left hand
writers with positive, and right hand writers with negative
relative hand skill.. A similar pattern of deficits is also
present for non-verbal ability although the deficits at the
extremes are greater and the sex difference is absent., and
for reading ability and mathematical skill. For reading
ability males have a modest advantage except at the point
of hemispheric indecision; males close to this point read
less well than females, a finding that has obvious relevance
to the excess of males with dyslexia.
We interpret these findings as consistent with the view
that degree of lateralisation is the major determinant of the
rate at which verbal ability develops in one hemisphere.
From Fig. 1 it appears that dominance, say for word
finding, develops in one or the other hemisphere, and that
there is an optimum, approximately equi-distant from the
zero left s right. on either side. For non-verbal ability,
perhaps developing at a slower pace and in the non-dominant hemisphere, the optimum is less than for verbal
ability.
Perhaps there is a balance between verbal and non-verbal
ability, and this reflects the rate at which dominance
develops. Females are more strongly right-handed at least
at this age. and are less likely to be left-handed w39x than
males. Whatever factor is influencing the development of

121

dominance is acting more strongly or earlier in females as


a group than in males.
What type of gene might account for these relationships? Annetts balanced polymorphism hypothesis does
not account for the deficits that are seen at the point of
hemispheric indecision. It is also necessary to explain the
sex difference. Sex differences have been noted in the
literature on handedness w3,89x, but transmission has generally been thought to follow an autosomal pattern. However
a gene within a non-recombining i.e., sex-specific. region
of homology between the X and Y chromosomes has the
potential to explain a sex difference together with an
autosomal pattern of transmission. The psychological
deficits associated with the sex chromosome aneuploidies
are consistent with the presence of a gene for cerebral
asymmetry within this class w26,30,32,95x. Individuals with
Turners syndrome XO. have deficits in spatial i.e.,
non-verbal. ability, while individuals with an extra X
chromosome Klinefelters XXY or triple X syndrome.
have verbal deficits. These findings can be explained by an
XY homologous gene for asymmetry, protected from X
inactivation, that is associated with a range of variation
that is modestly different on the two chromosomes.
As Corballis w20x has pointed out, because the Y chromosome, outside the pseudo-autosomal regions, does not
recombine a balanced polymorphism will not be maintained. Therefore, if indeed there is an XY homologous
gene for cerebral asymmetry, it must be supposed that the
associated variation is due either to instability in the gene,
i.e., that the gene is a mutation hotspot, or that it arises
from epigenetic modification see Section 9..
XY homologies have arisen at various points in the
course of mammalian evolution, generally as a result of X
to Y translocations w1,76x. Of greatest interest is the Yp11.2
block that arose as a translocation from Xq21.3 sometime
after the separation of the chimpanzee and hominid lineages w93,110x, and that was subject to a subsequent
paracentric inversion w114x. The region distinguishes Homo
sapiens from other primates including the great apes. No
genes have yet been identified within this 3.54 Mb block.

6. Anatomical deviations in schizophrenia

Fig. 1. Verbal ability in approximately 12 000 11 yr old children subdivided by sex and writing hand in relation to relative hand skill. The test
of verbal ability required the child to fill in the fourth in a logical,
semantic or phonological sequence of four words when presented with
the first three together with a template sequence of four words to be
matched. Relative hand skill was calculated from the function RyLrRq
LU 100 from the number of squares checked in one minute with the left
and right hands in an array of squares on a printed sheet. The curves are
iteratively smoothed w39x.

The concept of serious mental illness as a Homo sapiens specific condition was entertained by CrichtonBrowne
w21x, Southard w117x, Miskolczy w91x and Parfitt w99x. The
prediction is that such anatomical deviations as are present
will be seen in relation to those regions of the cerebral
cortex that have evolved most recently. The best established changes are a degree of ventricular enlargement
w66,124x and a modest reduction in cortical w126x and brain
w12x mass. The changes are compatible with a failure of
development but are non-specific. More informative is a
loss of asymmetry. In a post-mortem study Luys w81x
reported a reduction in mass on the left side but this was

122

T.J. Crowr Brain Research Reiews 31 (2000) 118129

Fig. 2. The fronto-occipital axis of asymmetry in the human brain. A


relative but inter-individually variable. increase in the development of
the right frontal hetero-modal cortex relative to the left, and of the left
occipito-parieto-temporal association cortex relative to the right implies a
convergence of callosal fibres from left-to-right in sensory posterior.
association cortex and right-to-left in motor anterior. association cortex.
The intra-hemispheric antero-posterior commisural connections carry reciprocal convergences and divergences w35x.

scan study Crow et al. w38x reported diminished width


asymmetries in cases with an early age of onset, a finding
recently replicated by Maher et al. w83x. The general
finding of a loss of width asymmetries in patients with
schizophrenia as a group has been documented by Falkai
et al. w51x.
Of particular interest in view of the above studies of
handedness is the question of a sex difference. In a study
of the lengths across the superior cortical surface on
post-mortem brain a sex difference in asymmetry, to the
right in males and to the left in females, was present in
normal controls but reversed in patients with schizophrenia
w61x. The density of fibres in the corpus callosum, that
probably relates to asymmetries in the cortex was increased relative to controls in males and decreased in
females w62x. Asymmetries of the temporal lobe gyri referred to above were differentially related to age of onset
in the two sexes, becoming more anomalous in males and
less so in females w88x with increasing age of onset. An
explanation of these sex differences requires a more detailed anatomical understanding of the cortical asymmetries.

7. Functional asymmetries in schizophrenia


not replicated by CrichtonBrowne w21x. Southard w117x
considered the changes he saw were more pronounced in
the left hemisphere. In the CT scan era Luchins et al. w80x
reported a reversal of width asymmetries in a sub-group of
patients, but this was unconfirmed in a later study by
Luchins and Meltzer w79x.
Given that the asymmetries of the human brain are
probably differentially distributed within areas of association cortex, and cross the antero-posterior axis from right
frontal to left occipital w7x, their topology and deviations in
disease may not be easily detected. A relatively robust
p - 0.005 for the diagnosis by side interaction. change
was seen in a post-mortem radiographic study of the
temporal horn w37x, suggesting loss of substance in
schizophrenia within the left temporal lobe. This has been
confirmed and localised to the parahippocampal, fusiform
and superior temporal gyri in a more recent study w60,88x.
Changes in the superior temporal gyrus that are relatively
selective to the left side have been reported in some e.g.,
Shenton, w115x MRI studies.. One interpretation w100x,
consistent with the sapiens-specific concept, is that it is
areas of hetero-modal association cortex that have most
recently evolved that are affected. Loss or reversal of
asymmetry of the planum temporale was reported in a
post-mortem study by Falkai et al. w50x, and in some
w102,108x but not all w74x MRI studies.
Other studies relate to frontal as well as occipito-temporal lobes see Fig. 2.. In MRI studies of first episodes of
psychosis Bilder et al. w9x reported loss of the fronto-occipital torque in coronal section volumes and DeLisi et al.
w44x found loss of frontal and occipital widths. In a CT

Gur w57x first reported that individuals with schizophrenia are less strongly right-handed than the population as a
whole. This is consistent with the concept that it is degree
rather than direction of handedness that is anomalous w56x
and the finding that the incidence of ambiguous or inconsistent handedness is increased. In the National Child
Development cohort pre-schizophrenic children were more
likely to be reported as ambidextrous for writing hand at
the age of 7 years p - 0.005. Table 1., and were less
strongly lateralised on the index of relative hand skill
p - 0.01. at age 11 years w41x Table 2.. Each of these
findings is consistent with the concept that on the contin-

Table 1
Hand preference: age 7 assessments by mother each patient group
compared with normal controls.
RH

LH

Ambidextrous
%.

x2

df

p
Pearson.

Schizophrenia
narrow.

20

8 25.8.

16.09

0.0003

Schizophrenia
broad.

34

11 22.4.

16.58

0.00025

Affective
psychosis

21

5 17.9.

4.9

0.08

Neurosis

57

4 6.1.

0.36

0.8

Controls

1241

140

103 6.9.

T.J. Crowr Brain Research Reiews 31 (2000) 118129

123

Table 2
Relative hand skill age 11 years: mean number of squares marked in 1 min
n

Schizophrenia
narrow.
Schizophrenia
broad.
Affective
psychosis
Neurosis
Controls

RH

LH

Relhand

95% CI for mean

low

high

22

79.9

72.7

4.2

y4.2

12.6

0.008

36

81.9

71.3

6.1

0.4

11.8

0.01

25

89.9

67.6

13.9

8.8

18.6

NS

60
1302

88.3
89.0

67.7
69.2

13.7
12.9

11.2
12.1

16.2
13.7

NS

uum of lateralisation those predisposed to psychosis are


closer to the point of hemispheric indecision than the
population as a whole. In this respect they resemble individuals with reading difficulties, and indeed a finding
consistent at the ages of 7, 11 and 16 years in the
pre-schizophrenic population in the National Child Development cohort is an impairment in reading ability relative
to controls w41x. Thus in terms of relative hand skill and its
academic correlates individuals at risk of psychosis are
pre-disposed to problems in inter-hemispheric integration.
Recent MEG studies document these problems from a
neurophysiological perspective. Reite et al. w103x found
that the relative location of the primary auditory evoked
potential in the two hemispheres is changed in patients
with schizophrenia and that the change differs in the two
sexes. Tiihonen et al. w120x and Sauer et al. w111x have
reported similar findings. With the use of a whole head
magnetometer Rockstroh et al. w107x examined the size of
the N100 potential and found that the asymmetry in normal controls was lost in patients with schizophrenia p 0.001..

8. Nuclear symptoms as disorders of language


Schneider w113x drew attention to what he described as
the first rank or nuclear symptoms. When these symptoms are present he suggested we can agree that these are
illnesses that we wish to identify with the label of schizophrenia. The symptoms fall into two main groups
primary experiences concerning ones thoughts that
thoughts, that nevertheless are ones own, are inserted into
or removed from ones mind by an outside agency, or that
ones thoughts are broadcast to others and certain types
of auditory hallucination hearing ones thoughts spoken
aloud, a running commentary on ones thoughts or actions,
or voices that speak about one in the third person. What is
distinctive about these symptoms is their incomprehensibility. To someone who has not experienced the symptom the
notion that one could have a thought that was not ones
own is arresting, if not a contradiction in the use of terms.
A thought by definition is surely ones own. How could
it be under the control of anyone or -thing other than

oneself? How could ones thoughts be available to or


commented upon by anyone else? Thoughts are internal
to ones mind; they are to be distinguished from speech,
the form of message that is presented to, and received
from, the community outside.
Yet these are the symptoms that inform us that the
problem is universal w64,94x, and that it occurs in all
populations independent of the specific language structures
the populations have adopted. These symptoms tell us that
the problem is intrinsic to the human capacity for language, and that this faculty is variable between individuals.
I have suggested that the nuclear symptoms of schizophrenia represent language at the end of its tether w31x; they
provide a window on the transition between speech and
thought w35x.
Thus one should consider these symptoms in the context that the capacity for language originated in the speciation event. That genetic change did no more than give a
nudge to the rate of development of one hemisphere
relative to the other, in one direction in the frontal lobes,
and in the other in the occipito-parieto-temporal regions.
Each of the features that has been claimed as specific to
language de Saussurean arbitrariness of the association
between the signifier and its signifieds, and Chomskyan
generativity, for example must somehow be attributable
to this change w33x. One component of language became
localised to one hemisphere, and as a consequence other
components could be localised elsewhere.
Why any function should be localised to one hemisphere was explained in terms of the time constraints on
inter-hemispheric transmission by Ringo et al. w106x
these limits will be avoided if the neural apparatus necessary to perform each high resolution time critical task is
gathered in one hemisphere. The neural representation of
words de Saussures w112x signifiers, Chomskys w16x
phonetic form. that gives rise to the phonological output is
just such a sequence. This representation must surely be
what is localised in Brocas speech area in the dominant
hemisphere. The speech output is serially organised and
this accounts for its structure according to de Saussure
w112x a primary characteristic of the spoken word is its
linearity, in itself it is simply a line, a continuous ribbon of
sound. But the corollorary is that other associations and

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T.J. Crowr Brain Research Reiews 31 (2000) 118129

organisation become possible in the non-dominant hemisphere.


According to Cooks w18x bi-hemispheric concept the
two hemispheres contribute to language according to different principles. The principle of the non-dominant hemisphere it seems is the contribution of a paradigmatic
component of de Saussures linguistic mechanism, the
potential for each element in the syntagmatic structure the
sentence. to be substituted by an alternative element with
its different associations. If within the dominant frontal
lobe the associations between elements occur in series,
while the associations that each of these elements has in
the non-dominant hemisphere is in parallel, there is a
mechanism which has relevance to de Saussures arbitrariness of the association between the signifier dominant
frontal. and its signifieds non-dominant frontal. as well
as, indirectly, to Chomskys generativity the ability to
generate an effectively infinite diversity of strings of symbols.
But for the strings to have meaning it is also necessary
for them to have structure, and to be relevant to a specific
act of communication. Here the nuclear symptoms of
schizophrenia have their particular significance w35x. What
these tell us is that when the process of hemispheric
differentiation is incomplete the dysfunction that results is
a loss of the distinction between thought and speech, and
in particular of the distinction between messages that are
generated by the individual as speaker and those that he
receives as a hearer. To make these distinctions what is
required is a system of neural reference that relates not
only to the output and input, that is to the encoding and
decoding of phonological sequences, but also to their
generation and interpretation in terms of the associative
networks that the individual already possesses. Herein lie
the distinctions between what might be said thoughts. and
what actually is said speech output., and between what is
heard speech input. and how it is interpreted its meanings., and the further and less tangible distinction between
sensory meanings and motor thoughts.
For any of these distinctions to be made what the
individual requires, as Buehler w13x emphasised, is a deictic frame of reference, a coordinate system that relates the
phonological output, and what has led up to it, to the I of
the speaker, to the present moment in time now. and to
the location of the speaker in space here.. Thus defined
the zero of the reference system can be contrasted with the
you of the hearer that the speaker intends to influence, at
a point distant from that of the speaker, and future in time.
It is the failure of this reference system that is exemplified in the nuclear symptoms of schizophrenia. Neural
activity is generated that has the characteristic of thought,
but lacks its autonomy, either in that it has acquired a
characteristic of the phonological input thought insertion.,
or of the phonological output thought broadcast., or that it
becomes dissociated from the reference point of the I
thought withdrawal.. This group of symptoms one might

suppose arises at least in part in relation to the transition


between thought and speech that normally occurs between
non-dominant and dominant frontal association areas. Conversely the auditory hallucinations may be supposed to
arise in relation to the transition between phonological
input and its interpretation in the non-dominant occipitoparieto-temporal regions. Neural activity with the characteristic of speech input is entrained by activity in the
non-dominant thoughts spoken aloud. or dominant running commentary. frontal lobes, or by activity that arises
in the non-dominant occipito-parieto-temporal region third
person voices.. In each case activity that one may suppose
to be normally confined to one quadrant of hetero-modal
association cortex loses its sequestration, with the consequence that one or more of the boundaries, defined by the
deictic origin, between the I of the speaker and his
interface with the rest of the linguistic community, is lost.

9. The nature of the gene


That there is a genetic contribution to psychosis was
suspected by Kraepelin and documented by Rudin w109x in
the period preceding the evolutionary synthesis of
Mendelian genetics and Darwinian theory. Dominant and
recessive models of transmission have been considered
w55x, modified by a penetrance factor to allow for incomplete concordance in MZ twins, with a rather poor fit to
either model. Further limitations of current conceptions of
the genetic predisposition to psychosis are, i. the assumption that the Kraepelinian separation of schizophrenic and
manic-depressive psychoses identifies true categories of
disease, and ii. failure to take account of the distinctive
epidemiology of psychosis, i.e., its universality in human
populations, and iii. lack of an explanation of the central
paradox noted above. The difficulties of the Kraepelinian
binary system were appreciated early w73x and have been
extensively discussed in the recent literature w17,25,
27,34,68,85x. No categorical system of classification has
been validated; it seems that a dimensional description is
more appropriate, but the identity of the dimensions themselves which according to the present formulation are the
dimensions of linguistic competence. remain obscure. Underlying variables of possible pathophysiological relevance
w34x are the rate of brain development and the degree of
hemispheric specialisation.
One possibility to be considered is that a number of
genes contribute independently to pre-disposition, either in
combination or separately within different families. Against
the latter version of the polygene hypothesis must be set
a failure to observe families within which the form of the
psychosis breeds true, and against both versions of the
hypothesis must be weighed the relative uniformity of the
brain changes, the constancy of incidence across populations, and the problem posed by the central paradox. In
each of these cases it seems that the difficulties of achiev-

T.J. Crowr Brain Research Reiews 31 (2000) 118129

ing an adequate genetic formulation are exacerbated rather


than reduced by the assumption that more than one gene is
involved.
The attempt to cut through the theoretical difficulties by
a linkage approach has contributed no consistent findings.
For each claim for linkage most systematic scans have
yielded a failure of replication; amongst the three genome
scans with samples of over 100 sibships there is no
agreement between any two studies on any one of the
positive claims w40x
Some explanation for this failure of linkage, particularly
in the face of the case for a homogeneous genetic influence w29x, is required. One possibility is that the relevant
locus is a high mutation site as suggested by Book w10x.
Another is that the familial influence in psychosis is not
strictly genetic but epigenetic, i.e., that it represents a
modification of gene expression, e.g., by methylation, that
is transmitted. It has been suggested that it is particularly
those processes that distinguish one species from another
w121,123x, that are subject to epigenetic control, and that
these mechanisms have particular relevance to recent evolutionary developments in the brain w69x.
In the absence of strong evidence for linkage progress
may depend upon developing and eliminating hypotheses.
The hypothesis w26,28x that a gene for asymmetry is in the
class that is present in homologous form on the X and Y
chromosomes has the potential to explain the sex difference in age of onset of psychosis as well as the sex
differences that have recently emerged in the brain changes.
In a linkage study in 178 sib-pairs with schizophrenia or
schizo-affective psychosis w78x a modest excess of allele
sharing was observed in brotherbrother pairs at the locus
DXS8032 on the proximal long arm of the X chromosome,
and rather stronger evidence of linkage to degrees of
handedness at DXS990 centered on the Xq21.3rYp11.2
region of homology referred to above. In psychosis Norton
et al. w97x have reported allele sharing in malemale sib
pairs at DXS8092 which is approximately 3cM proximal
to the centromeric boundary of this region. These findings
constitute no more than weak evidence. If indeed there is a
gene in this region one explanation for the modest size of
the linkage result might be that a major contribution to
susceptibility arises from epigenetic modification.
An XY homologous gene has relevance to speciation
theory. Because outside the pseudo-autosomal regions the
gene sequence on the Y may differ from that on the X
there is the possibility that the characteristic the gene
encodes will be subject to sexual selection, i.e., differential
modification in the two sexes. This opens up the potential
for a runaway accentuation of the characteristic that is the
focus of mate selection w52,76,77x a process that could be
relevant to the apparently rapid changes in brain structure
and function that have occurred in hominid evolution. It
has been suggested w45,67,125x that sexual selection and
speciation are linked. Specifically it appears that a primary
genetic change in a mate recognition system could be

125

followed by a process of sexual selection on the relevant


characteristics, and that this might account for the differentiation of species.
Blocks of XY homology have sometimes arisen in
mammalian evolution as a result of translocations from the
X to the Y chromosome w1x. When this occurs a gene
within the translocated segment, previously present only
on the X and subject to inactivation in females, will be
expressed at double dosage in males. In general one must
suppose that an abrupt change in gene dose will be disadvantageous and that such chromosomal rearrangements
will be rapidly selected out of the population. But consider
the case that such a gene has an influence on a bodily
characteristic e.g., body size, ornamentation. that is regarded by females as attractive in a mate, or that is an
advantage to a male in the competition for females that
Y chromosome will increase its representation in successive generations. There will be a change in the population
that is confined to males. But because the gene is already
present on the X chromosome, there is the possibility of a
subsequent modification in response to the change in
males. of the same characteristic in females. Particularly if
the influence of the gene is quantitative e.g., on an aspect
of growth. one can see that such a doubling of gene
dosage in males will create the potential for an evolutionary escalation w32,36x.
Jegalian and Page w65x describe differences between
mammalian orders in the pattern of inactivation on the X
of genes common to X and Y chromosomes and propose a
mechanism that depends on successive changes their figure 4. in response to selective pressures unspecified. on
first male and then female fitness. These selective pressures could be those that arise between the sexes, and in
relation to the speciation process. In man variation in
expression of the phenomena associated with Turners
syndrome is in part dependent upon the parent of origin of
the single X w116x, suggesting that a process of imprinting
or X inactivation is involved. This variability of expression
of genes that evolved late in the hominid sequence could
contribute critically to individual differences and to predisposition to psychosis. Of particular interest is the fact that
the variability of the phenomena of Turners syndrome
relates to aspects of social ability that differentiate the
sexes, and less to those aspects of verbal and non-verbal
ability that may relate directly to cerebral asymmetry and
language. One can ask the question is there one or more
than one gene on the X relating to Homo sapiens specific
abilities? Is there for example one gene for social ability
and another for language, or are these abilities related to a
single genetic mechanism that is differentially modified in
the two sexes?
Given the difficulties of the linkage strategy how is
such a gene to be found? The hypothesis of an XY
homologous gene and the approach through evolutionary
history points to the Xq21.3rYp11.2 region as of the
greatest interest w33x. Genes within this region and also

126

T.J. Crowr Brain Research Reiews 31 (2000) 118129

10. Conclusions

Fig. 3. Regions of homology between X and Y chromosomes adapted


from w1x.. The regions of homology are labeled from a Yp PAR1 short
arm pseudo-autosomal region. to k Yq PAR2 long arm pseudo-autosomal region. in sequence on the Y chromosome. Of particular interest is
the region in Xq21.3 that transposed to the Y some time after the
separation of the chimpanzee and hominid lines and was subsequently
split in a paracentric inversion on the Y. ZFY zinc finger protein on the
Y: AMG-amelogenin; RSP4Y ribosomal protein on the Y...

within pseudo-autosomal region 2. whose location andror


control may differentiate the human from the chimpanzee
are prime candidates. A second and complementary approach is through hypotheses of the nature of the gene
itself. To account for the anatomical findings as well as the
disorganization of function within episodes of illness it
was suggested w23,24x that the gene could be an unstable
element a retrovirus or retrotransposon. that in the course
of human evolution had become associated with a growth
factor the cerebral dominance gene. that determined the
asymmetry of the brain see Fig. 3..
The location of such elements within the genome and
their phytogenetic histories can be investigated w7072x. Of
focal interest is the possibility that an integration event
involving one such mobile element played a critical role in
human evolution by generating or modifying an association between a growth factor and a regulator or promoter
sequence, and that this event generated the variability in
relative hemispheric development that allowed language to
evolve. In other words that such a change was the speciation event itself.

The central paradox of schizophrenia can be resolved in


the conclusion that the variation of which predisposition to
schizophrenia is a part of variation that crosses the population as a whole, that is Homo sapiens-specific, and is
associated with the capacity for language that defines the
species. The genetic change the speciation event. that
enabled the transition from a precursor hominid species
allowed the two hemispheres to develop with a degree of
independence across the antero-posterior axis from right
frontal to left occipital., is reflected in anatomical asymmetries in late-developing association cortex. The dimension
of symmetry-asymmetry is associated with significant variation in verbal and other abilities as demonstrated in data
from the UK National Child Development cohort specific disabilities including predisposition to dyslexia and
psychosis are associated with values of relative hand skill
close to zero. The nuclear symptoms of schizophrenia can
be understood as a failure to establish dominance for a key
component the phonological sequence of language in
the dominant hemisphere, with consequent disruption of
the mechanism of indexicality that allows the speaker to
distinguish his thoughts from the speech output that he
generates and that which he receives from others. Sex
differences in relative hand skill, verbal ability, age of
onset and brain changes associated with psychosis are
pointers to a gene in a region of XY homology, and
reflections of a role for sexual selection in refining the
change brought about by the speciation event. The
Xq21.3rYp11.2 region of homology that was generated by
a translocation and subsequent paracentric inversion on the
Y, between the separation of the chimpanzee and hominid
lineages, and a gene in the retrovirusrretrotransposon
class, are candidates. The most recent change that is
universal to human populations is predicted to be the key
to the inter-related problems of the origins of language, the
speciation of Homo sapiens and the predisposition to
psychosis.

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