Ž .Brain Research Reviews 31 2000 118–129www.elsevier.comrlocaterbres

Interactive report

Schizophrenia as the price that Homo sapiens pays for language: aresolution of the central paradox in the origin of the species 1

T.J. Crow )

POWIC, Warneford Hospital, UniÕersity 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 fecunditydisadvantage. The hypothesis is proposed that the predisposition to schizophrenia is a component of Homo sapiens-specific variation

Žassociated 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 associatedwith differences in the rate at which verbal and non-verbal ability develops. The nuclear symptoms of schizophrenia can be understood asa failure to establish dominance for a key component – the phonological sequence – of language in one hemisphere, with consequentdisruption of the mechanism of ‘indexicality’ that allows the speaker to distinguish his thoughts from the speech output that he generatesand 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; X–Y homology; Speciation

Contents

1. The central paradox . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

2. Universality of schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

3. The origin of the genetic variation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

4. Lateralization as the critical change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

5. Relative hand skill as a predictor of academic ability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

6. Anatomical deviations in schizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

7. Functional asymmetries in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

8. Nuclear symptoms as disorders of language . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

9. The nature of the gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

) Corresponding author. Tel.: q44-1865-226474; Fax: q44-1865-244990; E-mail: tim.crow@psychiatry.oxford.ac.uk1 Published on the World Wide Web on 5 November 1999.

0165-0173r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.Ž .PII: S0165-0173 99 00029-6

( )T.J. CrowrBrain Research ReÕiews 31 2000 118–129 119

1. The central paradox

The central paradox of schizophrenia – that a conditionapparently genetic in origin, survives in the population inspite of a substantial fecundity disadvantage – was first

w xclearly identified by Huxley et al. 63 . The disadvantage iswell documented. Individuals who develop schizophreniaare much less likely than others to marry and have childrenw x Ž49,58,82,101,118,122 and the effect is greater probably

.three-fold in males. The deficit presumably is due to thedifficulty these individuals have in establishing a pairbond. The magnitude is such that any genetic predisposi-tion would be eliminated from the population within a fewgenerations. But it is not. There must be a genetic advan-

Žtage, 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.Ž .The first two authors Huxley and Mayr are amongst a

Ž .small group Simpson and Dhobzhansky are others de-scribed as ‘architects of the evolutionary synthesis’ – theaccommodation of Mendelian genetics with Darwinian

w xevolutionary theory in the 1940s 87 . But the answer theygave to the question that they had raised – that theadvantage was a genetically based resistance to wound

w xshock and stress – was implausible, as Kuttner et al. 75pointed out. It makes no sense to postulate a balance in afunction that is unrelated to the dysfunction that has to beexplained. If the disability lies in psychological symptomsand behaviour then, at least in the first place, one shouldlook in this area of function for the balancing advantage.On the assumption that schizophrenia is a condition that is

w xin some way related to being human, Kuttner et al. 75offered three functions – the capacity for complex socialrelations, intelligence, and language – as candidates andargued for the first. These three must surely be inter-re-lated. Here I argue that the third – language – is the mostcharacteristically human ability, and that when languageŽin the broader sense of an ability to communicate with the

.use of symbols is seen as the focus, new approaches to theorgins and pathophysiological basis of the symptoms openup.

2. Universality of schizophrenia

This issue should be considered in relation to what isknown of the epidemiology of psychosis. Kraepelin trav-elled to Java and considered that the form of psychoticillness he saw there was the same as he had described inhis patient populations in Germany. From investigationsamongst the Yoruba of Nigeria and the Eskimo Inuit,

w xMurphy 94 concluded that the phenomena of psychosiswere essentially independent of the social structure of the

Žpopulation. Features typical of schizophrenia e.g., the.nuclear symptoms are well documented in the Australian

w x w xaboriginal population 92 and the African Bantu 105 ,

peoples that have been separated for 50 000 years, andhave recently been described in the tribes of central Bor-

w xneo 6 . On the basis of the most systematic cross culturalw xcomparison yet conducted Jablensky et al. 64 concluded

that "schizophrenic illnesses are ubiquitous, appear withsimilar incidence in different cultures and have featuresthat are more remarkable by their similarity across culturesthan by their difference".

The evidence points to the singular conclusion that,contrary to almost any other common condition, the inci-dence of schizophrenia is independent of the environmentand a characteristic of human populations. Perhaps it is thehuman condition.

3. The origin of the genetic variation

If the condition is genetic, as in some way it appearsthat it must be, the question arises of when the variationarose. If the condition is now present in populations thathave been separated for 50 000 years it seems that eitherthe origin of the variation, or the mechanism by which it is

Ž .generated e.g., a mutation ‘hotspot’ , must have precededthe separation of these populations. The origin must be

Žbefore or coincident with the genetic change the ‘specia-.tion event’ that preceded the diaspora of modern Homo

w xsapiens across the surface of the globe 31 .According to a congruence of genetic and palaeontolog-

ical evidence the transition from an earlier hominid speciestook place at some point in East Africa some time between

w x100 and 150 000 years ago 119 . The genetic change is ofgreat intrinsic interest as it must somehow account for theextraordinary biological success of the species, its increasein population size, the spread into diverse ecological nichesand its ability to transform the environment in a way thatno other vertebrate species has achieved.

What physiological function accounted for this success?Ž w x.The list of candidates see e.g., Bickerton 8 resembles

w xthose enumerated by Kuttner et al. 75 , that is the capacityfor complex social interactions, intelligence and language,with the possible addition of ‘consciousness’. From thislist language stands out as the most biologically relevant,and the one that can be most readily understood in termsof neural function. Ability to communicate is necessary forsurvival in a socially organised species, and must beclosely related to ‘intelligence’, which is otherwise diffi-cult to define. Consciousness could be an epi-phenomenonw x8 of the ‘secondary representational capacity’ that it isnecessary to invoke to account for the phenomena oflanguage.

Distinctive characteristics of human language are theŽ .arbitrariness of the association between the sign word

w x w xand what it signifies 112 , and its generativity 15 asrepresented by the apparently infinite number of sentencesthat can be generated and recognised by a competentspeaker of a given language. To account for these innova-

( )T.J. CrowrBrain Research ReÕiews 31 2000 118–129120

tions a mechanism of ‘universal grammar’ has been postu-w xlated as a unique feature of the human brain 15,16 . But

what is striking in the evolutionary record is the recency ofthe evidence for symbolic representation that might paral-lel the acquisition of the capacity for language. Suchevidence, as instanced by rock art, goes back perhaps

w x50 000 years but not more 8,96 . But by the same argu-ment deployed above in relation to the incidence ofschizophrenia, if this capacity is now present in each of thepopulations that make up humanity either it, or a changethat made its development inevitable, must have beenpresent at the time of the species transition. A parsimo-nious conclusion is that the function that characterises thespecies – 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 generatesentences of indeterminate length, that nevertheless can beunderstood because they have a reference and a grammati-cal structure that can be decoded by a competent hearer?As demonstrated by sign language these syntactic-semanticcapacities are independent of the phonological and acous-

w xtic modalities 5,54,59 . They must relate to the brain as awhole.

It is necessary to postulate some radical change in brainw xfunction. Maynard–Smith and Szathmary 86 charac-

terised the origin of language in Homo sapiens as theseventh of the major transitions in evolution. The factschallenge the gradualist concept of speciation, the notionthat species originate by a process of multiple and cumula-tive genetic change in populations that are geographically

Žseparated, over long periods of time. This notion the.‘biological’ or ‘isolation’ concept has been opposed by

Žthe theory of punctuated equilibria e.g., Eldredge andw x w x.Gould, 48 ; Eldredge 47 although a genetic mechanism

for the latter is lacking. The case of Homo sapiens isrelevant. What is required is a change that is simple, thatcould 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 possi-w x w xbility known since Dax 43 and then Broca 11 discov-

ered that some component of language was confined toone hemisphere. Something lateralised, or lateralised in away that was not previously the case. What was thiscomponent, and what were the consequences of the pro-cess of lateralisation? In the answers to these questions liesa solution to the neural basis of language and, according tothe present thesis, an understanding of the origins ofpsychosis.

w xCrichton–Browne 21 was one of the first to interpretthe findings in the light of evolutionary theory, and he alsothought they might be relevant to mental illness – suppos-

ing that "the regions of the brain which are latest evolvedand which are located on the left side of the brain might

w xsuffer first in insanity". Eberstaller 46 and Cunninghamw x42 described anatomical asymmetries – the length of theSylvian fissure was longer on the left in most individuals –the speciation event had left an imprint on the surface ofthe brain. These anatomical asymmetries were almost for-gotten until those of the planum temporale were re-dis-

w xcovered by Geschwind and Levitsky 53 in 1964.That there are asymmetries of brain function has long

w xbeen apparent from the phenomena of handedness 22 andthe notion that these could be accounted for in terms of agenetic influence that is specific to Homo sapiens has been

w x w xdeveloped by Annett 2 and Corballis 19 . This case isstrengthened by the observations of Marchant and Mc-

w xGrew 84 that at least in the wild directional handednesson a population basis is absent in chimpanzees, and of

w xBuxhoeveden and Casanova 14 that asymmetries of thecolumnar structure of the planum temporale are present inman but absent in the chimpanzee.

5. Relative hand skill as a predictor of academic ability

If cerebral lateralization is what distinguishes Homosapiens as a species from its precursors this mechanismmust account for what is most characteristic in brainfunction. The capacity for language, it is argued, is thecore function; other aspects of ‘intelligence’ must also be

w xrelated. Annett 2 proposed that transmission of handed-ness within families could be accounted for by a single

Ž .gene the ‘right shift factor’ and that the variation in thepopulation associated with this gene represents a balancedpolymorphism with respect to intelligence – that is to saythat heterozygotes for the right shift factor are at anadvantage in intelligence relative to those at the extremesŽ .e.g., strong left- and right-handers of the right shiftcontinuum. This hypothesis is the focus of significant

w xcontroversy 4,90,98,104 .My colleagues and I investigated this question in the

w xUK National Development Study archive 39 . In thisŽarchive an item of test performance number of squares

.checked with the right and left hands in one minute isrecorded on approximately 12 000 children at the age of 11years that allows us to derive an index of relative handskill and to examine it as a predictor of verbal andnon-verbal as well as mathematical and reading ability.The findings give general support to the concept that

Žrelative hand skill is a determinant perhaps the major.determinant of the development of academic ability, but

only partial support to Annett’s balanced polymorphismhypothesis.

ŽWith respect to verbal ability ability to select the fourthin a sequence of four given the first three words, and atemplate of four words with phonological, semantic or

.logical associations to match against there is a substantial

( )T.J. CrowrBrain Research ReÕiews 31 2000 118–129 121

Žsex 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 atŽ .the extremes both left and right of relative hand skill but

these are small relative to the deficits that are seen close tothe point of equal hand skill, that we refer to as the ‘pointof hemispheric indecision’. Individuals who are close tothis point are delayed in developing verbal ability, and thisis particularly so in those in whom there is a discrepancy

Žbetween relative hand skill and writing hand left handwriters with positive, and right hand writers with negative

.relative hand skill . A similar pattern of deficits is alsoŽpresent for non-verbal ability although the deficits at the

.extremes are greater and the sex difference is absent , andfor reading ability and mathematical skill. For readingability males have a modest advantage except at the pointof hemispheric indecision; males close to this point readless well than females, a finding that has obvious relevanceto the excess of males with dyslexia.

We interpret these findings as consistent with the viewthat degree of lateralisation is the major determinant of therate at which verbal ability develops in one hemisphere.From Fig. 1 it appears that dominance, say for wordfinding, develops in one or the other hemisphere, and thatthere is an optimum, approximately equi-distant from the

Ž .zero left s right on either side. For non-verbal ability,perhaps developing at a slower pace and in the non-domi-nant hemisphere, the optimum is less than for verbalability.

Perhaps there is a balance between verbal and non-verbalability, and this reflects the rate at which dominance

Ždevelops. Females are more strongly right-handed at least. w xat this age and are less likely to be left-handed 39 than

males. Whatever factor is influencing the development of

Fig. 1. Verbal ability in approximately 12000 11 yr old children subdi-vided by sex and writing hand in relation to relative hand skill. The testof verbal ability required the child to fill in the fourth in a logical,semantic or phonological sequence of four words when presented withthe first three together with a template sequence of four words to bematched. Relative hand skill was calculated from the function RyLrRqLU 100 from the number of squares checked in one minute with the leftand right hands in an array of squares on a printed sheet. The curves are

w xiteratively smoothed 39 .

dominance is acting more strongly or earlier in females asa group than in males.

What type of gene might account for these relation-ships? Annett’s balanced polymorphism hypothesis doesnot account for the deficits that are seen at the point ofhemispheric indecision. It is also necessary to explain thesex difference. Sex differences have been noted in the

w xliterature on handedness 3,89 , but transmission has gener-ally been thought to follow an autosomal pattern. However

Ž .a gene within a non-recombining i.e., sex-specific regionof homology between the X and Y chromosomes has thepotential to explain a sex difference together with an‘autosomal’ pattern of transmission. The psychologicaldeficits associated with the sex chromosome aneuploidiesare consistent with the presence of a gene for cerebral

w xasymmetry within this class 26,30,32,95 . Individuals withŽ . ŽTurner’s syndrome XO have deficits in spatial i.e.,

.non-verbal ability, while individuals with an extra XŽ .chromosome Klinefelter’s XXY or triple X syndrome

have verbal deficits. These findings can be explained by anX–Y homologous gene for asymmetry, protected from Xinactivation, that is associated with a range of variationthat is modestly different on the two chromosomes.

w xAs Corballis 20 has pointed out, because the Y chro-mosome, outside the pseudo-autosomal regions, does notrecombine a balanced polymorphism will not be main-tained. Therefore, if indeed there is an X–Y homologousgene for cerebral asymmetry, it must be supposed that theassociated variation is due either to instability in the gene,i.e., that the gene is a mutation hotspot, or that it arises

Ž .from epigenetic modification see Section 9 .X–Y homologies have arisen at various points in the

course of mammalian evolution, generally as a result of Xw xto Y translocations 1,76 . Of greatest interest is the Yp11.2

block that arose as a translocation from Xq21.3 sometimeafter the separation of the chimpanzee and hominid lin-

w xeages 93,110 , and that was subject to a subsequentw xparacentric inversion 114 . The region distinguishes Homo

sapiens from other primates including the great apes. Nogenes have yet been identified within this 3.5–4 Mb block.

6. Anatomical deviations in schizophrenia

The concept of serious mental illness as a Homo sapi-ens specific condition was entertained by Crichton–Brownew x w x w x w x21 , Southard 117 , Miskolczy 91 and Parfitt 99 . Theprediction is that such anatomical deviations as are presentwill be seen in relation to those regions of the cerebralcortex that have evolved most recently. The best estab-lished changes are a degree of ventricular enlargementw x w x66,124 and a modest reduction in cortical 126 and brainw x12 mass. The changes are compatible with a failure ofdevelopment but are non-specific. More informative is a

w xloss of asymmetry. In a post-mortem study Luys 81reported a reduction in mass on the left side but this was

( )T.J. CrowrBrain Research ReÕiews 31 2000 118–129122

Fig. 2. The fronto-occipital axis of asymmetry in the human brain. AŽ .relative but inter-individually variable increase in the development of

the right frontal ‘hetero-modal’ cortex relative to the left, and of the leftoccipito-parieto-temporal association cortex relative to the right implies a

Ž .convergence of callosal fibres from left-to-right in sensory posteriorŽ .association cortex and right-to-left in motor anterior association cortex.

The intra-hemispheric antero-posterior commisural connections carry re-w xciprocal convergences and divergences 35 .

w x w xnot replicated by Crichton–Browne 21 . Southard 117considered the changes he saw were more pronounced in

w xthe left hemisphere. In the CT scan era Luchins et al. 80reported a reversal of width asymmetries in a sub-group ofpatients, but this was unconfirmed in a later study by

w xLuchins and Meltzer 79 .Given that the asymmetries of the human brain are

probably differentially distributed within areas of associa-tion cortex, and cross the antero-posterior axis from right

w xfrontal to left occipital 7 , their topology and deviations indisease may not be easily detected. A relatively robustŽ .p-0.005 for the diagnosis by side interaction changewas seen in a post-mortem radiographic study of the

w xtemporal horn 37 , suggesting loss of substance inschizophrenia within the left temporal lobe. This has beenconfirmed and localised to the parahippocampal, fusiform

w xand superior temporal gyri in a more recent study 60,88 .Changes in the superior temporal gyrus that are relatively

Žselective to the left side have been reported in some e.g.,w x . w xShenton, 115 MRI studies . One interpretation 100 ,

consistent with the sapiens-specific concept, is that it isareas of hetero-modal association cortex that have mostrecently evolved that are affected. Loss or reversal ofasymmetry of the planum temporale was reported in a

w xpost-mortem study by Falkai et al. 50 , and in somew x w x102,108 but not all 74 MRI studies.

Other studies relate to frontal as well as occipito-tem-Ž .poral lobes see Fig. 2 . In MRI studies of first episodes of

w xpsychosis Bilder et al. 9 reported loss of the ‘fronto-oc-cipital’ torque in coronal section volumes and DeLisi et al.w x44 found loss of frontal and occipital widths. In a CT

w xscan study Crow et al. 38 reported diminished widthasymmetries in cases with an early age of onset, a finding

w xrecently replicated by Maher et al. 83 . The generalfinding of a loss of width asymmetries in patients withschizophrenia as a group has been documented by Falkai

w xet al. 51 .Of particular interest in view of the above studies of

handedness is the question of a sex difference. In a studyof the lengths across the superior cortical surface onpost-mortem brain a sex difference in asymmetry, to theright in males and to the left in females, was present innormal controls but reversed in patients with schizophreniaw x61 . The density of fibres in the corpus callosum, thatprobably relates to asymmetries in the cortex was in-creased relative to controls in males and decreased in

w xfemales 62 . Asymmetries of the temporal lobe gyri re-ferred to above were differentially related to age of onsetin the two sexes, becoming more anomalous in males and

w xless so in females 88 with increasing age of onset. Anexplanation of these sex differences requires a more de-tailed anatomical understanding of the cortical asymme-tries.

7. Functional asymmetries in schizophrenia

w xGur 57 first reported that individuals with schizophre-nia are less strongly right-handed than the population as awhole. This is consistent with the concept that it is degree

w xrather than direction of handedness that is anomalous 56and the finding that the incidence of ambiguous or incon-sistent handedness is increased. In the National ChildDevelopment cohort pre-schizophrenic children were morelikely to be reported as ambidextrous for writing hand at

Ž . Ž .the age of 7 years p-0.005 Table 1 , and were lessstrongly lateralised on the index of relative hand skillŽ . Žw x .p-0.01 at age 11 years 41 – Table 2 . Each of thesefindings is consistent with the concept that on the contin-

Table 1ŽHand preference: age 7 assessments by mother each patient group

.compared with normal controls2RH LH Ambidextrous x df p

Ž . Ž .% Pearson

Ž .Schizophrenia 20 3 8 25.8 16.09 2 0.0003Ž .narrow

Ž .Schizophrenia 34 4 11 22.4 16.58 2 0.00025Ž .broad

Ž .Affective 21 2 5 17.9 4.9 2 0.08psychosis

Ž .Neurosis 57 5 4 6.1 0.36 2 0.8

Ž .Controls 1241 140 103 6.9

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

n RH LH Relhand 95% CI for mean p

low high

Schizophrenia 22 79.9 72.7 4.2 y4.2 12.6 0.008Ž .narrowSchizophrenia 36 81.9 71.3 6.1 0.4 11.8 0.01Ž .broadAffective 25 89.9 67.6 13.9 8.8 18.6 NSpsychosisNeurosis 60 88.3 67.7 13.7 11.2 16.2 NSControls 1302 89.0 69.2 12.9 12.1 13.7

uum of lateralisation those predisposed to psychosis arecloser to the point of hemispheric indecision than thepopulation as a whole. In this respect they resemble indi-viduals with reading difficulties, and indeed a findingconsistent at the ages of 7, 11 and 16 years in thepre-schizophrenic population in the National Child Devel-opment cohort is an impairment in reading ability relative

w xto controls 41 . Thus in terms of relative hand skill and itsacademic correlates individuals at risk of psychosis arepre-disposed to problems in inter-hemispheric integration.

Recent MEG studies document these problems from aw xneurophysiological perspective. Reite et al. 103 found

that the relative location of the primary auditory evokedpotential in the two hemispheres is changed in patientswith schizophrenia and that the change differs in the two

w x w xsexes. Tiihonen et al. 120 and Sauer et al. 111 havereported similar findings. With the use of a whole head

w xmagnetometer Rockstroh et al. 107 examined the size ofthe N100 potential and found that the asymmetry in nor-

Žmal controls was lost in patients with schizophrenia p-.0.001 .

8. Nuclear symptoms as disorders of language

w xSchneider 113 drew attention to what he described asthe first rank or ‘nuclear’ symptoms. When these symp-toms are present he suggested we can agree that these areillnesses that we wish to identify with the label of ‘schi-zophrenia’. The symptoms fall into two main groups –primary experiences concerning one’s thoughts – thatthoughts, that nevertheless are one’s own, are inserted intoor removed from one’s mind by an outside agency, or thatone’s thoughts are broadcast to others – and certain typesof auditory hallucination – hearing one’s thoughts spokenaloud, a running commentary on one’s thoughts or actions,or voices that speak about one in the third person. What isdistinctive about these symptoms is their incomprehensibil-ity. To someone who has not experienced the symptom thenotion that one could have a thought that was not one’sown is arresting, if not a contradiction in the use of terms.A thought ‘by definition’ is surely one’s own. How couldit be under the control of anyone or -thing other than

oneself? How could one’s thoughts be available to orcommented upon by anyone else? ‘Thoughts’ are internalto one’s mind; they are to be distinguished from speech,the form of message that is presented to, and receivedfrom, the community outside.

Yet these are the symptoms that inform us that thew xproblem is universal 64,94 , and that it occurs in all

populations independent of the specific language structuresthe populations have adopted. These symptoms tell us thatthe problem is intrinsic to the human capacity for lan-guage, and that this faculty is variable between individuals.I have suggested that the nuclear symptoms of schizophre-

w xnia represent ‘language at the end of its tether’ 31 ; theyprovide a window on the transition between speech and

w xthought 35 .Thus one should consider these symptoms in the con-

text that the capacity for language originated in the specia-tion event. That genetic change did no more than give anudge to the rate of development of one hemisphererelative 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 tolanguage – de Saussurean arbitrariness of the associationbetween the signifier and its signifieds, and Chomskyangenerativity, for example – must somehow be attributable

w xto this change 33 . One component of language becamelocalised to one hemisphere, and as a consequence othercomponents could be localised elsewhere.

Why any function should be localised to one hemi-sphere was explained in terms of the time constraints on

w xinter-hemispheric transmission by Ringo et al. 106 –these limits will be avoided if ‘the neural apparatus neces-sary to perform each high resolution time critical task isgathered in one hemisphere’. The neural representation of

Ž w x w xwords de Saussure’s 112 signifiers, Chomsky’s 16.phonetic form that gives rise to the phonological output is

just such a sequence. This representation must surely bewhat is localised in Broca’s speech area in the dominanthemisphere. The speech output is serially organised andthis accounts for its structure – according to de Saussurew x112 ‘a primary characteristic of the spoken word is itslinearity, in itself it is simply a line, a continuous ribbon ofsound’. But the corollorary is that other associations and

( )T.J. CrowrBrain Research ReÕiews 31 2000 118–129124

organisation become possible in the non-dominant hemi-sphere.

w xAccording to Cook’s 18 bi-hemispheric concept thetwo hemispheres contribute to language according to dif-ferent principles. The principle of the non-dominant hemi-sphere it seems is the contribution of a paradigmaticcomponent of de Saussure’s linguistic mechanism, the

Žpotential for each element in the syntagmatic structure the.sentence to be substituted by an alternative element with

its different associations. If within the dominant frontallobe the associations between elements occur in series,while the associations that each of these elements has inthe non-dominant hemisphere is in parallel, there is amechanism which has relevance to de Saussure’s arbitrari-

Žness of the association between the signifier dominant. Ž .frontal and its signifieds non-dominant frontal as well

as, indirectly, to Chomsky’s generativity – the ability togenerate an effectively infinite diversity of strings of sym-bols.

But for the strings to have meaning it is also necessaryfor them to have structure, and to be relevant to a specificact of communication. Here the nuclear symptoms of

w xschizophrenia have their particular significance 35 . Whatthese tell us is that when the process of hemisphericdifferentiation is incomplete the dysfunction that results isa loss of the distinction between thought and speech, andin particular of the distinction between messages that aregenerated by the individual as speaker and those that hereceives as a hearer. To make these distinctions what isrequired is a system of neural reference that relates notonly to the output and input, that is to the encoding anddecoding of phonological sequences, but also to theirgeneration and interpretation in terms of the associativenetworks that the individual already possesses. Herein lie

Ž .the distinctions between what might be said thoughts andŽ .what actually is said speech output , and between what is

Ž . Žheard speech input and how it is interpreted its mean-.ings , and the further and less tangible distinction between

sensory ‘meanings’ and motor ‘thoughts’.For any of these distinctions to be made what the

w xindividual requires, as Buehler 13 emphasised, is a deic-tic frame of reference, a coordinate system that relates thephonological output, and what has led up to it, to the ‘I’ of

Ž .the speaker, to the present moment in time ‘now’ and toŽ .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, ata point distant from that of the speaker, and future in time.

It is the failure of this reference system that is exempli-fied in the nuclear symptoms of schizophrenia. Neuralactivity is generated that has the characteristic of thought,but lacks its autonomy, either in that it has acquired a

Ž .characteristic of the phonological input thought insertion ,Ž .or of the phonological output thought broadcast , or that it

becomes dissociated from the reference point of the ‘I’Ž .thought withdrawal . This group of symptoms one might

suppose arises at least in part in relation to the transitionbetween thought and speech that normally occurs betweennon-dominant and dominant frontal association areas. Con-versely the auditory hallucinations may be supposed toarise in relation to the transition between phonologicalinput and its interpretation in the non-dominant occipito-parieto-temporal regions. Neural activity with the charac-teristic of speech input is entrained by activity in the

Ž . Žnon-dominant thoughts spoken aloud or dominant run-.ning commentary frontal lobes, or by activity that arises

Žin 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-modalassociation cortex loses its sequestration, with the conse-quence that one or more of the boundaries, defined by thedeictic origin, between the ‘I’ of the speaker and hisinterface with the rest of the linguistic community, is lost.

9. The nature of the gene

That there is a genetic contribution to psychosis wasw xsuspected by Kraepelin and documented by Rudin 109 in

the period preceding the evolutionary ‘synthesis’ ofMendelian genetics and Darwinian theory. Dominant andrecessive models of transmission have been consideredw x55 , modified by a ‘penetrance’ factor to allow for incom-plete concordance in MZ twins, with a rather poor fit toeither model. Further limitations of current conceptions of

.the genetic predisposition to psychosis are, i the assump-tion that the Kraepelinian separation of schizophrenic andmanic-depressive psychoses identifies true categories of

.disease, and ii failure to take account of the distinctiveepidemiology of psychosis, i.e., its universality in human

.populations, and iii lack of an explanation of the centralparadox noted above. The difficulties of the Kraepelinian

w xbinary system were appreciated early 73 and have beenwextensively discussed in the recent literature 17,25,

x27,34,68,85 . No categorical system of classification hasbeen validated; it seems that a dimensional description ismore appropriate, but the identity of the dimensions them-

Žselves which according to the present formulation are the.dimensions of linguistic competence remain obscure. Un-

derlying variables of possible pathophysiological relevancew x34 are the rate of brain development and the degree ofhemispheric specialisation.

One possibility to be considered is that a number ofgenes contribute independently to pre-disposition, either incombination or separately within different families. Againstthe latter version of the ‘polygene’ hypothesis must be seta failure to observe families within which the form of thepsychosis ‘breeds true’, and against both versions of thehypothesis must be weighed the relative uniformity of thebrain changes, the constancy of incidence across popula-tions, and the problem posed by the central paradox. Ineach of these cases it seems that the difficulties of achiev-

( )T.J. CrowrBrain Research ReÕiews 31 2000 118–129 125

ing an adequate genetic formulation are exacerbated ratherthan reduced by the assumption that more than one gene isinvolved.

The attempt to cut through the theoretical difficulties bya linkage approach has contributed no consistent findings.For each claim for linkage most systematic scans haveyielded a failure of replication; amongst the three genomescans with samples of over 100 sibships there is noagreement between any two studies on any one of the

w xpositive claims 40Some explanation for this failure of linkage, particularly

in the face of the case for a homogeneous genetic influ-w xence 29 , is required. One possibility is that the relevant

w xlocus is a high mutation site as suggested by Book 10 .Another is that the familial influence in psychosis is notstrictly genetic but epigenetic, i.e., that it represents amodification of gene expression, e.g., by methylation, thatis transmitted. It has been suggested that it is particularlythose processes that distinguish one species from anotherw x121,123 , that are subject to epigenetic control, and thatthese mechanisms have particular relevance to recent evo-

w xlutionary developments in the brain 69 .In the absence of strong evidence for linkage progress

may depend upon developing and eliminating hypotheses.w xThe hypothesis 26,28 that a gene for asymmetry is in the

class that is present in homologous form on the X and Ychromosomes has the potential to explain the sex differ-ence in age of onset of psychosis as well as the sexdifferences that have recently emerged in the brain changes.In a linkage study in 178 sib-pairs with schizophrenia or

w xschizo-affective psychosis 78 a modest excess of allelesharing was observed in brother–brother pairs at the locusDXS8032 on the proximal long arm of the X chromosome,and rather stronger evidence of linkage to degrees ofhandedness at DXS990 centered on the Xq21.3rYp11.2region of homology referred to above. In psychosis Norton

w xet al. 97 have reported allele sharing in male–male sibpairs at DXS8092 which is approximately 3cM proximalto the centromeric boundary of this region. These findingsconstitute no more than weak evidence. If indeed there is agene in this region one explanation for the modest size ofthe linkage result might be that a major contribution tosusceptibility arises from epigenetic modification.

An X–Y homologous gene has relevance to speciationtheory. Because outside the pseudo-autosomal regions thegene sequence on the Y may differ from that on the Xthere is the possibility that the characteristic the geneencodes will be subject to sexual selection, i.e., differentialmodification in the two sexes. This opens up the potentialfor a runaway accentuation of the characteristic that is the

w xfocus of mate selection 52,76,77 a process that could berelevant to the apparently rapid changes in brain structureand function that have occurred in hominid evolution. It

w xhas been suggested 45,67,125 that sexual selection andspeciation are linked. Specifically it appears that a primarygenetic change in a mate recognition system could be

followed by a process of sexual selection on the relevantcharacteristics, and that this might account for the differen-tiation of species.

Blocks of X–Y homology have sometimes arisen inmammalian evolution as a result of translocations from the

w xX to the Y chromosome 1 . When this occurs a genewithin the translocated segment, previously present onlyon the X and subject to inactivation in females, will beexpressed at double dosage in males. In general one mustsuppose that an abrupt change in gene dose will be disad-vantageous and that such chromosomal rearrangementswill be rapidly selected out of the population. But considerthe case that such a gene has an influence on a bodily

Ž .characteristic e.g., body size, ornamentation that is re-garded by females as attractive in a mate, or that is anadvantage to a male in the competition for females – thatY chromosome will increase its representation in succes-sive generations. There will be a change in the populationthat is confined to males. But because the gene is alreadypresent on the X chromosome, there is the possibility of a

Žsubsequent modification in response to the change in.males of the same characteristic in females. Particularly if

Žthe 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 evolution-w xary escalation 32,36 .

w xJegalian and Page 65 describe differences betweenmammalian orders in the pattern of inactivation on the Xof genes common to X and Y chromosomes and propose a

Žmechanism that depends on successive changes their fig-. Ž .ure 4 in response to selective pressures unspecified on

first male and then female fitness. These selective pres-sures could be those that arise between the sexes, and inrelation to the speciation process. In man variation inexpression of the phenomena associated with Turner’ssyndrome is in part dependent upon the parent of origin of

w xthe single X 116 , suggesting that a process of imprintingor X inactivation is involved. This variability of expressionof genes that evolved late in the hominid sequence couldcontribute critically to individual differences and to predis-position to psychosis. Of particular interest is the fact thatthe variability of the phenomena of Turner’s syndromerelates to aspects of social ability that differentiate thesexes, and less to those aspects of verbal and non-verbalability that may relate directly to cerebral asymmetry andlanguage. One can ask the question is there one or morethan one gene on the X relating to Homo sapiens specificabilities? Is there for example one gene for social abilityand another for language, or are these abilities related to asingle genetic mechanism that is differentially modified inthe two sexes?

Given the difficulties of the linkage strategy how issuch a gene to be found? The hypothesis of an X–Yhomologous gene and the approach through evolutionaryhistory points to the Xq21.3rYp11.2 region as of the

w x Žgreatest interest 33 . Genes within this region and also

( )T.J. CrowrBrain Research ReÕiews 31 2000 118–129126

ŽFig. 3. Regions of homology between X and Y chromosomes adaptedw x. Žfrom 1 . The regions of homology are labeled from a Yp PAR1 – short

. Žarm pseudo-autosomal region to k Yq PAR2 – long arm pseudo-auto-.somal region in sequence on the Y chromosome. Of particular interest is

the region in Xq21.3 that transposed to the Y some time after theseparation of the chimpanzee and hominid lines and was subsequentlysplit 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 androrcontrol may differentiate the human from the chimpanzeeare prime candidates. A second and complementary ap-proach is through hypotheses of the nature of the geneitself. To account for the anatomical findings as well as thedisorganization of function within episodes of illness it

w xwas suggested 23,24 that the gene could be an unstableŽ .element a retrovirus or retrotransposon that in the course

of human evolution had become associated with a growthŽ .factor the ‘cerebral dominance gene’ that determined the

Ž .asymmetry of the brain see Fig. 3 .The location of such elements within the genome and

w xtheir phytogenetic histories can be investigated 70–72 . Offocal interest is the possibility that an integration eventinvolving one such mobile element played a critical role inhuman evolution by generating or modifying an associa-tion between a growth factor and a regulator or promotersequence, and that this event generated the variability inrelative hemispheric development that allowed language toevolve. In other words that such a change was the specia-tion event itself.

10. Conclusions

The central paradox of schizophrenia can be resolved inthe conclusion that the variation of which predisposition toschizophrenia is a part of variation that crosses the popula-tion as a whole, that is Homo sapiens-specific, and isassociated with the capacity for language that defines the

Ž .species. The genetic change the ‘speciation event’ thatenabled the transition from a precursor hominid speciesallowed the two hemispheres to develop with a degree of

Žindependence across the antero-posterior axis from right.frontal to left occipital , is reflected in anatomical asymme-

tries in late-developing association cortex. The dimensionof symmetry-asymmetry is associated with significant vari-ation in verbal and other abilities as demonstrated in datafrom the UK National Child Development cohort – spe-cific disabilities including predisposition to dyslexia andpsychosis are associated with values of relative hand skillclose to zero. The nuclear symptoms of schizophrenia canbe understood as a failure to establish dominance for a keycomponent – the phonological sequence – of language inthe dominant hemisphere, with consequent disruption ofthe mechanism of indexicality that allows the speaker todistinguish his thoughts from the speech output that hegenerates and that which he receives from others. Sexdifferences in relative hand skill, verbal ability, age ofonset and brain changes associated with psychosis arepointers to a gene in a region of X–Y homology, andreflections of a role for sexual selection in refining thechange brought about by the speciation event. TheXq21.3rYp11.2 region of homology that was generated bya translocation and subsequent paracentric inversion on theY, between the separation of the chimpanzee and hominidlineages, and a gene in the retrovirusrretrotransposonclass, are candidates. The most recent change that isuniversal to human populations is predicted to be the keyto the inter-related problems of the origins of language, thespeciation of Homo sapiens and the predisposition topsychosis.

References

w x1 N. Affara, C. Bishop, W. Brown, H. Cooke, P. Davey, N. Ellis,J.M. Graves, M. Jones, M. Mitchell, G. Rappold, C. Tyler-Smith,P. Yen, Y.-F.C. Lau, Report of the second international workshopon Y chromosome mapping 1995, Cytogenet. Cell Genet. 73Ž .1996 33–76.

w x2 M. Annett, Left, Right, Hand and Brain: The Right Shift Theory,Lawrence Erlbaum, London, 1985.

w x3 M. Annett, Handedness as a continuous variable with dextral shift:sex, generation and family handedness in subgroups of left and

Ž .righthanders, Behav. Genet. 24 1994 51–63.w x4 M. Annett, The right shift theory of a genetic balanced polymor-

phism for cerebral dominance and cognitive processing, CahierŽ .Psychol. Cogn.rCurr. Psychol. Cogn. 14 1995 427–480.

w x5 D.F. Armstrong, W.C. Stokoe, S.E. Wilcox, Gesture and the Natureof Language, Cambridge University Press, Cambridge, 1995.

( )T.J. CrowrBrain Research ReÕiews 31 2000 118–129 127

w x6 R.J. Barrett, K. Schneider in Borneo: do first rank symptoms ofŽ .schizophrenia apply to the Iban? abstract , American Anthropolog-

ical Association, 96th Annual Meeting, 1997, pp. 84-85.w x7 D.M. Bear, D. Schiff, J. Saver, M. Greenberg, R. Freeman, Quanti-

tative analysis of cerebral asymmetry; fronto-occipital correlation,sexual dimorphism and association with handedness, Arch. Neurol.

Ž .43 1986 598–603.w x8 D. Bickerton, Language and Human Behavior, University of Wash-

ington, Seattle, WA, 1995.w x9 R.M. Bilder, H. Wu, B. Bogerts, G. Degreef, M. Ashtari, J.M.J.

Alvir, P.J. Snyder, J.A. Lieberman, Absence of regional hemi-spheric volume asymmetries in first episode schizophrenia, Am. J.

Ž .Psychiatry 151 1994 1437–1447.w x10 J.A. Book, Schizophrenia as a gene mutation, Acta Genet. Stat.

Ž .Med. 4 1953 133–139.w x11 P. Broca, Remarques sur la siege de la faculte du langue, Bull. Soc.´ ´

Ž .Anatomiq. 6 1861 330–357.w x12 R. Brown, N. Colter, J.A.N. Corsellis, T.J. Crow, C.D. Frith, R.

Jagoe, E.C. Johnstone, L. Marsh, Postmortem evidence of struc-tural brain changes in schizophrenia. Differences in brain weight,temporal horn area, and parahippocampal gyrus compared with

Ž .affective disorder, Arch. Gen. Psychiatry 43 1986 36–42.w x Ž13 K. Buehler, Sprachtheorie translated by D.W. Goodwin as: Theory

.of Language: The Representational Function of Language, 1990 , J.Benjamins, Amsterdam, 1934.

w x14 D. Buxhoeveden, M. Casanova, Comparative lateralization patternsin the language area of normal human, chimpanzee, and rhesus

Ž .monkey brain, Laterality, 1998 in press.w x15 N. Chomsky, Knowledge of Language: Its Nature, Origin and Use,

Praeger, New York, 1985.w x16 N. Chomsky, The Minimalist Program, MIT Press, Hong Kong,

1995.w x17 C.R. Cloninger, Pro: tests of alternative models of the relationship

of schizophrenic and affective psychoses, in: E.S. Gershon andŽ .C.R. Cloninger Eds. , Genetic Approaches to Mental Disorders,

American Psychiatric Press, Washington, 1994, pp. 149-162.w x18 N.D. Cook, The Brain Code: Mechanisms for Information Transfer

and the Role of the Corpus Callosum, Methuen, London, 1986.w x19 M.C. Corballis, The Lop-sided Ape: Evolution of the Generative

Mind, Oxford University Press, New York, 1991.w x20 M.C. Corballis, The genetics and evolution of handedness, Psychol.

Ž .Rev. 104 1997 714–727.w x21 J. Crichton-Browne, On the weight of the brain and its component

Ž .parts in the insane, Brain 2 1879 42–67.w x22 J. Crichton-Browne, Dexterity and the bend sinister, Proc. Roy.

Ž .Inst. G.B. 18 1907 623–652.w x23 T.J. Crow, A re-evaluation of the viral hypothesis: is psychosis the

result of retroviral integration at a site close to the cerebralŽ .dominance gene?, Br. J. Psychiatry 145 1984 243–253.

w x24 T.J. Crow, Left brain, retrotransposons, and schizophrenia, Br.Ž .Med. J. 293 1986 3–4.

w x25 T.J. Crow, Nature of the genetic contribution to psychotic illness -Ž .a continuum viewpoint, Acta Psychiatr. Scand. 81 1990 401–408.

w x26 T.J. Crow, Sexual selection, Machiavellian intelligence and theŽ .origins of psychosis, Lancet 342 1993 594–598.

w x27 T.J. Crow, Con: The demise of the Kraepelinian binary system as aprelude to genetic advance, in: E.S. Gershon and C.R. CloningerŽ .Eds. , Genetic Approaches to Mental Disorders, American Psychi-atric Press, Washington, 1994, pp. 163-192.

w x28 T.J. Crow, The case for an X-Y homologous determinant ofŽ .cerebral asymmetry, Cytogenet. Cell Genet. 67 1994 393–394.

w x29 T.J. Crow, A continuum of psychosis, one human gene and notŽ .much else - the case for homogeneity, Schiz. Res. 17 1995

135–145.w x30 T.J. Crow, The case for an X-Y homologous gene, and the possible

role of sexual selection in the evolution of language, Curr. Psychol.Ž . Ž .Cogn. 14 6 1995 775–781.

w x31 T.J. Crow, Is schizophrenia the price that Homo sapiens pays forŽ .language?, Schiz. Res. 28 1997 127–141.

w x32 T.J. Crow, Sexual selection, timing and the descent of man: atheory of the genetic origins of language., Cahier Psychol.

Ž .Cogn.rCurr. Psychol. Cogn. 17 1998 1079–1114.w x33 T.J. Crow, Did Homo sapiens speciate on the Y chromosome?,

Ž .Psycoloquy, 1999 in press.w x34 T.J. Crow, From Kraepelin to Kretschmer leavened by K Schnei-

der: the transition from categories of psychosis to dimensions ofvariation intrinsic to Homo sapiens, Arch. Gen. Psychiatry 55Ž .1998 502–504.

w x35 T.J. Crow, Nuclear schizophrenic symptoms as a window on therelationship between thought and speech, Brit. J. Psychiatry 173Ž .1998 103–109.

w x36 T.J. Crow, Why cerebral asymmetry is the key to the origin ofHomo sapiens: how to find the gene or eliminate the theory, Cahier

Ž .Psychol. Cogn.rCurr. Psychol. Cogn. 17 1998 1237–1277.w x37 T.J. Crow, J. Ball, S.R. Bloom, R. Brown, C.J. Bruton, N. Colter,

C.D. Frith, E.C. Johnstone, D.G. Owens, G.W. Roberts,Schizophrenia as an anomaly of development of cerebral asymme-try. A postmortem study and a proposal concerning the genetic

Ž .basis of the disease, Arch. Gen. Psychiatry 46 1989 1145–1150.w x38 T.J. Crow, N. Colter, C.D. Frith, E.C. Johnstone, D.G.C. Owens,

Developmental arrest of cerebral asymmetries in early onsetŽ .schizophrenia, Psychiatry Res. 29 1989 247–253.

w x39 T.J. Crow, L.R. Crow, D.J. Done, S.J. Leask, Relative hand skillpredicts academic ability: global deficits at the point of hemi-

Ž .spheric indecision, Neuropsychologia 36 1998 1275–1282.w x40 T.J. Crow, L.E. DeLisi, The chromosome workshops at the 5th

International Congress of Psychiatric Genetics: the weight of theŽ .evidence from genome scans, Psychiatr. Genet. 8 1998 59–61.

w x41 T.J. Crow, D.J. Done, A. Sacker, Cerebral lateralization is delayedŽ .in children who later develop schizophrenia, Schiz. Res. 22 1996

181–185.w x42 D.J. Cunningham, Contribution to the Surface Anatomy of the

Cerebral Hemispheres, Academy House, Dublin, 1892.w x43 M. Dax, Lesions de la moitie gauche de l’encephale coincident´ ´ ´

avec l’oubli des signes de la pensee, Gaz. Hebdom. Med. Chirurg.´ ´Ž . Ž11 1865 259–260, Read at congres meridional at Montpelier in´ ´.1836 .

w x44 L.E. DeLisi, M. Sakuma, M. Kushner, D.L. Finer, A.L. Hoff, T.J.Crow, Anomalous cerebral asymmetry and language processing in

Ž .schizophrenia, Schiz. Bull. 23 1997 255–271.w x45 W.J. Dominey, Effects of sexual selection and life histories on

speciation: species flocks in African cichlids and HawaiianŽ .Drosophila, in: A.A. Echelle and I. Kornfield Eds. , Evolution of

Fish Species Flocks, Orino Press, Maine, 1984, pp. 231-249.w x46 O. Eberstaller, Zur oberflachenanatomie des grosshirnhemispharen,¨ ¨

Ž .Wien. Med. Blat. 7 1884 479–482.¨w x47 N. Eldredge, The Pattern of Evolution, Freeman, New York, 1998.w x48 N. Eldredge, S.J. Gould, Punctuated equilibria: an alternative to

Ž .phyletic gradualism, in: T.M. Schopf Ed. , Models in Palaeobiol-ogy, Freeman Cooper, San Francisco, CA, 1972, pp. 82-115.

w x49 E. Essen-Moller, Mating and fertility patterns in families withŽ .schizophrenia, Eugen. Quart. 6 1959 142–147.

w x50 P. Falkai, B. Bogerts, T. Schneider, B. Greve, U. Pfeiffer, K. Pilz,C. Gonsiorzcyk, C. Majtenyi, I. Ovary, Disturbed planum tempo-rale asymmetry in schizophrenia. A quantitative post-mortem study,

Ž .Schiz. Res. 14 1995 161–176.w x51 P. Falkai, T. Schneider, B. Greve, E. Klieser, B. Bogerts, Reduced

frontal and occipital lobe asymmetry on the CT scans ofschizophrenic patients: its specificity and clinical significance, J.

Ž .Neural Transm. - General Section 99 1995 63–77.w x52 R.A. Fisher, The Genetical Theory of Natural Selection, Oxford

University Press, Oxford, 1930.w x53 N. Geschwind, W. Levitsky, Left-right asymmetry in temporal

Ž .speech region., Biol. Psychiatry 29 1991 159–175.

( )T.J. CrowrBrain Research ReÕiews 31 2000 118–129128

w x54 S. Goldin-Meadow, D. McNeill, J. Singleton, Silence is liberating:removing the handcuffs on grammatical expression in the manual

Ž .modality, Psychol. Rev. 103 1996 34–55.w x55 I.I. Gottesman, J. Shields, Schizophrenia; the Epigenetic Puzzle,

Cambridge University Press, Cambridge, 1982.w x56 M.F. Green, P. Satz, C. Smith, L.D. Nelson, Is there atypical

Ž .handedness in schizophrenia?, J. Abnorm. Psychol. 98 198957–61.

w x57 R.E. Gur, Motoric laterality imbalance in schizophrenia, Arch.Ž .Gen. Psychiatry 34 1977 33–37.

w x58 F. Haverkamp, P. Propping, T. Hilger, Is there an increase inreproductive rates in schizophrenics? Critical review of the litera-

Ž .ture, Arch. Psychiat. Nervenkrankh. 232 1982 439–450.w x59 G. Hickok, U. Bellugi, E. Klima, The neurobiology of sign lan-

guage and its implications for the neural basis of language, NatureŽ .381 1996 699–702.

w x60 J.R. Highley, B. McDonald, M.A. Walker, M.M. Esiri, T.J. Crow,The temporal lobes, asymmetry and schizophrenia: a post mortem

Ž .stereological study of tissue, Brit. J. Psychiatry 175 1999 127–134.w x61 J.R. Highley, M.M. Esiri, M. Cortina-Borja, B. McDonald, S.J.

Cooper, B. Herron, T.J. Crow, Anomalies of cerebral asymmetry inschizophrenia interact with gender and age of onset: a post mortem

Ž .study, Schiz. Res. 34 1998 13–25.w x62 J.R. Highley, M.M. Esiri, B. McDonald, M. Cortina-Borja, B.

Herron, S.J. Cooper, T.J. Crow, The size and fibre composition ofthe corpus callosum with respect to gender and schizophrenia: A

Ž .post mortem study, Brain 122 1999 99–110.w x63 J. Huxley, E. Mayr, H. Osmond, A. Hoffer, Schizophrenia as a

Ž .genetic morphism, Nature 204 1964 220–221.w x64 A. Jablensky, N. Sartorius, G. Ernberg, M. Anker, A. Korten, J.E.

Cooper, R. Day, A. Bertelsen, Schizophrenia: manifestations, inci-dence and course in different cultures. A World Health Organiza-

Ž .tion Ten Country Study, Psychol. Med. Suppl. 20 1992 1–97.w x65 K. Jegalian, D.C. Page, A proposed mechanism by which genes

common to mammalian X and Y chromosomes evolve to becomeŽ .X inactivated, Nature 394 1998 776–780.

w x66 E.C. Johnstone, T.J. Crow, C.D. Frith, J. Husband, L. Kreel,Cerebral ventricular size and cognitive impairment in chronic

Ž .schizophrenia, Lancet ii 1976 924–926.w x67 K.Y. Kaneshiro, Sexual isolation, speciation and the direction of

Ž .evolution, Evolution 34 1980 437–444.w x68 K.S. Kendler, L.M. Karkowski, D. Walsh, The structure of psy-

chosis: latent class analysis of probands from the RoscommonŽ .family study, Arch. Gen. Psychiatry 55 1997 492–499.

w x69 E.B. Keverne, Genomic imprinting in the brain, Curr. Opin. Neuro-Ž .biol. 7 1997 463–468.

w x70 H.-S. Kim, T.J. Crow, Isolation of novel human endogenousretrovirus HC2-like elements in human chromosomes, AIDS Res.

Ž .Hum. Retroviruses 15 1999 299–302.w x71 H.-S. Kim, R.V. Wadekar, O. Takenaka, B-H. Hyun, T.J. Crow,

Phylogenic analysis of a retroposon family in African great apes, J.Molec. Evol., in press.

w x72 H.-S. Kim, R.V. Wadekar, O. Takenaka, F. Mitsunaga, T.Kageyama, B.-H. Hyun, C.A. Sargent, N.A. Affara, T.J. Crow,

Ž .SINE-R.C2 a Homo Sapiens specific retroposon is homologous tocDNA from post-mortem brain in schizophrenia and to two loci inthe Xq21.3rYp block linked to handedness and psychosis, Am. J.

Ž . Ž .Med. Genet. Neuropsychiatric Genet. 88 1999 560–566.w x73 E. Kraepelin, Die Erscheinungsformen des Irreseins, Zeit. Gesam.

Ž .Neurol. Psychiatrie, Vol. 62 1920 1-29. Translated by H. Mar-shall, as: Patterns of mental disorder, in: Themes and Variations in

Ž .European Psychiatry, Eds. S.R. Hirsch and M. Shepherd, Wright,Bristol, 1974, pp. 7-30.

w x74 J.J. Kulynych, K. Vladar, B.D. Fantic, D.W. Jones, D.R. Wein-berger, Normal asymmetry of the planum temporale in patients

with schizophrenia: three dimensional cortical morphometry withŽ .MRI., Brit. J. Psychiatry 166 1995 742–749.

w x75 R.E. Kuttner, A.B. Lorincz, D.A. Swan, The schizophrenia geneŽ .and social evolution, Psychol. Rep. 20 1967 407–412.

w x76 R. Lande, Models of speciation by sexual selection on polygenicŽ . Ž .traits, Proc. Natl. Acad. Sci. USA 78 1981 3721–3762.

w x77 R. Lande, Genetic correlations between the sexes in the evolutionof sexual dimorphism and mating preferences, in: J.W. Bradbury

Ž .and M.B. Anderson Eds. , Sexual Selection: Testing the alterna-tives, J. Wiley, Chicester, 1987, pp. 83-94.

w x78 S.H. Laval, J. Dann, R.J. Butler, J. Loftus, J. Rue, S.J. Leask, N.Bass, M. Comazzi, A. Vita, S. Nanko, S. Shaw, P. Peterson, G.Shields, A.B. Smith, J. Stewart, L.E. DeLisi, T.J. Crow, Evidence

Žfor linkage to psychosis and cerebral asymmetry relative hand. Žskill on the X chromosome., Am. J. Med. Genet. Neuropsychi-

. Ž .atric Genet. 81 1998 420–427.w x79 D.J. Luchins, H.Y. Meltzer, A blind, controlled study of occipital

Ž .asymmetry in schizophrenia, Psychiatry Res. 10 1983 87–95.w x80 D.J. Luchins, D.R. Weinberger, R.J. Wyatt, Schizophrenia evi-

dence for a subgroup with reversed cerebral asymmetry, Arch. Gen.Ž .Psychiatry 36 1979 1309–1311.

w x81 J.B. Luys, Contribution a l’etude d’une statistique sur les poids des` ´hemispheres cerebraux a l’etat normal et a l’etat pathologique,´ ´ ` ´ `

Ž .Encephale 1 1881 644–646.w x82 K. MacSorley, An investigation into the fertility rates of mentally

Ž .ill patients, Ann. Hum. Gen. 27 1964 247–256.w x83 B.A. Maher, T.C. Manschreck, D.A. Yurgelun-Todd, M.T. Tsuang,

Hemispheric asymmetry of frontal and temporal grey matter andŽ .age of onset in schizophrenia, Biol. Psychiatry 44 1998 413–417.

w x84 L.F. Marchant, W.C. McGrew, Laterality of limb function in wildchimpanzees of Gombe National Park: comprehensive study of

Ž .spontaneous activities, J. Hum. Evol. 30 1996 427–443.w x Ž .85 A. Marneros, N.C. Andreasen, M.T. Tsuang Eds , Psychotic Con-

tinuum, Springer, Berlin, 1995.w x86 J. Maynard-Smith, E. Szathmary, The Major Transitions in Evolu-

tion, W.H. Freeman, Oxford, 1995.w x87 E. Mayr, W.B. Provine, The Evolutionary Synthesis, Harvard

University Press, Cambridge, MA, 1998.w x88 B. McDonald, J.R. Highley, M.A. Walker, B. Herron, S.J. Cooper,

M.M. Esiri and T.J. Crow, Anomalous asymmetry of fusiform andparahippocampal gyrus grey matter in schizophrenia: a post-mortem

Ž .study, Amer. J. Psychiatry, 1999 in press.w x89 I.C. McManus, The inheritance of left-handedness, in: Q.R. Bock

Ž . Žand J. Marsh Eds. , Biological Asymmetry and Handedness CIBA.Foundation Symposium 162 , Wiley, Chichester, 1991, pp. 251-281.

w x90 I.C. McManus, S. Shergill, M.P. Bryden, Annett’s theory thatindividuals heterozygous for the right shift gene are intellectuallyadvantaged: theoretical and empirical findings., Br. J. Psychol. 84Ž .1993 517–537.

w x91 D. Miskolczy, Uber das anatomische korrelat der schizophrenie,Ž .Zeitschr. Neurol. 147 1933 509–544.

w x92 B.J. Mowry, D.P. Lennon, C.N. De Felice, Diagnosis ofschizophrenia in a matched sample of Australian aborigines, Acta

Ž .Psychiatr. Scand. 90 1994 337–341.w x93 S. Mumm, B. Molini, J. Terrell, A. Srivastava, D. Schlessinger,

Evolutionary features of the 4Mb Xq21.3 XY homology regionŽ .revealed by a map at 60-kb resolution, Genome Res. 7 1997

307–314.w x94 J.M. Murphy, Psychiatric labelling in a cross-cultural perspective,

Ž .Science 191 1976 1019–1028.w x95 C.T. Netley, Sex chromosome aneuploidy and cognitive develop-

Ž .ment, Cahier Psychol. Cogn.rCurr. Psychol. Cogn 17 19981190–1197.

w x96 W. Noble I. Davidson, Human Evolution, Language and Mind,Cambridge University Press, Cambridge, 1996.

( )T.J. CrowrBrain Research ReÕiews 31 2000 118–129 129

w x97 N. Norton, N.M. Williams, M.I. Rees, P. Holmans, I. Fenton, A.C.Cardno, K.C. Murphy, L.A. Jones, R.D. Sanders, P. Asherson, P.McGuffin, M.J. Owen, An affected sib pair study for schizophrenia

Žon the X chromosome, Am. J. Med. Genet. Neuropsychiatric. Ž .Genet. 81 1998 529.

w x98 R.E. Palmer, M.C. Corballis, Predicting reading ability from hand-Ž .edness measures, Brit. J. Psychiatry 87 1996 609–620.

w x99 D.N. Parfitt, The neurology of schizophrenia, J. Ment. Sci. 102Ž .1956 671–718.

w x100 G.D. Pearlson, P.E. Barta, T.E. Schlaepfer, R.G. Petty, A.Y. Tien,I.K. McGilchrist, Heteromodal association cortex in schizophrenia -

Ž .Grey matter changes and clinical correlates, Schiz. Res. 15 19951–2.

w x101 L.S. Penrose, Survey of cases of familial mental illness, Eur. Arch.Ž .Psychiatry. Neurol. Sci. 240 1991 315–324.

w x102 R.G. Petty, P.E. Barta, G.D. Pearlson, R.W. Lewis, A.Y. Tien, A.Pulver, D.D. Vaughan, M.F. Casanova, R.E. Powers, Reversal ofasymmetry of the planum temporale in schizophrenia, Am. J.

Ž .Psychiatry 152 1995 715–721.w x103 M. Reite, J. Sheeder, P. Teale, M. Adams, D. Richardson, J.

Simon, R.H. Jones, D.C. Rojas, Magnetic source imaging evidenceof sex differences in cerebral lateralization in schizophrenia, Arch.

Ž .Gen. Psychiatry 54 1997 433–440.w x104 F. Resch, J. Haffner, P. Parzer, U. Pfueller, U. Strehlow, C.

Zerahn-Hartung, Testing the hypothesis of relationships betweenlaterality and ability according to Annett’s right-left theory: find-ings in an epidemiological sample of young adults, Brit. J. Psychol.

Ž .88 1997 621–635.w x105 B.P. Riley, S. Rajagopalan, M. Mogudi-Carter, T. Jenkins, R.

Williamson, No evidence for linkage of chromosome 6p markers toschizophrenia in Southern African Bantu-speaking families, Psychi-

Ž .atr. Genet. 6 1996 41–49.w x106 J.L. Ringo, R.W. Doty, S. Demeter, P.Y. Simard, Time is of the

essence: a conjecture that hemispheric specialisation arises fromŽ .interhemispheric conduction delay, Cereb. Cort. 4 1994 331–343.

w x107 B. Rockstroh, B. Clements, C. Pantev, L.D. Blumenfeld, A. Sterr,T. Elbert, Failure of dominant left-hemispheric activation to right

Ž .ear stimulation in schizophrenia, Neuroreport 9 1998 3819–3822.w x108 A. Rossi, P. Stratta, P. Mattei, M. Cupillari, A. Bozzao, M.

Gallucci, M. Casacchia, Planum temporale in schizophrenia: aŽ .magnetic resonance study, Schiz. Res. 7 1992 19–22.

w x109 E. Rudin, Studien uber Vererbung und Entstehung geistiger¨ ¨Storungen; I. Zur Verebung und Neuentstehung der Dementia¨Praecox, Springer, Berlin, 1916.

w x110 C.A. Sargent, H. Briggs, I.J. Chalmers, B. Lambson, E. Walker,N.A. Affara, The sequence organization of Yprproximal Xq ho-mologous regions of the human sex chromosomes is highly con-

Ž .served, Genomics 32 1996 200–209.w x111 H. Sauer, T. Rosburg, I. Kreitschmann-Andermahr, H.P. Voltz, R.

Huonker, H. Nowak, M. Hajek, Sex-specific differences in hemi-spheric lateralization in schizophrenia? an MEG-MRI study, Nerve-

Ž .narzt 69 1998 249–256.

w x Ž112 F. de Saussure, Course in General Linguistics translated by R..Harris and published by Open Court, Illinois, 1983 , Payot, Paris,

1916.w x113 K. Schneider, Primare und Sekundare Symptome bei der

ŽSchizophrenie translated by H. Marshall, as: Primary and sec-ondary symptoms in schizophrenia, in: Themes and Variations in

Ž .European Psychiatry, S.R. Hirsch, M. Shepherd Eds. Wright,.Bristol, 1974, pp. 40-44 Fortsschritte der Neurologie und Psychia-

trie, 25, 1957, 487-490.w x114 A. Schwartz, D.C. Chan, L.G. Brown, R. Alagappan, D. Pettay, C.

Disteche, B. McGillivray, A. De la Chapelle, D.C. Page, Recon-structing hominid Y evolution: X-homologous block, created byX-Y transposition, was disrupted by Yp inversion through LINE-

Ž .LINE recombination, Hum. Mol. Genet. 7 1998 1–11.w x115 M.E. Shenton, R. Kikinis, F. Jolesz, S.D. Pollak, M. Le May, C.G.

Wible, H. Hokama, J. Martin, D. Metcalf, M. Coleman, R.W.McCarley, Abnormalities of the left temporal lobe and thought

Ž .disorder in schizophrenia, N. Engl. J. Med. 327 1993 604–612.w x116 D.H. Skuse, R.S. James, D.V.M. Bishop, B. Coppin, P. Dalton, G.

Aamodt-Leeper, M. Bacarese-Hamilton, C. Cresswell, R. McGurk,P.A. Jacobs, Evidence from Turner’s syndrome of an imprinted

Ž .X-linked locus affecting cognitive function, Nature 387 1997705–708.

w x117 E.E. Southard, On the topographical distribution of cortex lesionsand anomalies in dementia praecox, with some account of their

Ž .functional significance, Amer. J. Insanity 71 1915 603–671.w x118 B.C. Stevens, Marriage and Fertility of Women Suffering from

Schizophrenia and Affective Disorders, Oxford University Press,London, 1969.

w x119 C. Stringer, R. McKie, African Exodus: the Origins of ModernHumanity, J. Cape, London, 1996.

w x120 J. Tiihonen, H. Katila, E. Pekkonen, I.P. Jaaskelainen, M. Huoti-lainen, H.J. Aronen, R.J. Ilmoniemi, P. Rasanen, J. Virtanen, E.Salli, J. Karhu, Reversal of cerebral asymmetry in schizophrenia

Ž .measured with magnetoencephalography, Schiz. Res. 30 1998209–219.

w x121 S. Varmuza, Gametic imprinting as a speciation mechanism inŽ .mammals, J. Theor. Biol. 164 1993 1–13.

w x122 H.P. Vogel, Fertility and sibship size in a psychiatric patientŽ .population, Acta Psychiatr. Scand. 60 1979 483–503.

w x123 P.B. Vrana, X.-J. Guan, S.M. Tilghman, Genomic imprinting isŽ .disrupted in interspecific hybrids, Nat. Genet. 20 1998 362–365.

w x124 D.R. Weinberger, E.F. Torrey, A.N. Neophytides, R.J. Wyatt,Lateral cerebral ventricular enlargement in chronic schizophrenia,

Ž .Arch. Gen. Psychiatry 36 1979 735–739.w x125 M.J. West-Eberhard, Sexual selection, social competition and spe-

Ž .ciation, Q. Rev. Biol. 58 1983 155–183.w x126 R.B. Zipursky, K.O. Lim, E.V. Sullivan, B.W. Brown, A. Pfeffer-

baum, Widespread cerebral grey matter volume deficits inŽ .schizophrenia, Arch. Gen. Psychiatry 49 1992 195–205.