Handedness, language lateralisation and anatomical asymmetry: relevance of protocadherin XY to hominid speciation and the aetiology of psychosis: Point of view

Sommer et al (2001) used meta-analyses to review the literatureon handedness, dichotic listening and anatomical asymmetryin schizophrenia and concluded that there was strong evidencefor decreased cerebral lateralisation. As they point out, theimplication is that finding the locus of the gene for cerebraldominance could unravel the genetic predisposition to schizophrenia.Procopio (2001) raises a number of points relevant to thefindings of Sommer et al and concludes that both genetic andenvironmental factors have to be accounted for — ‘theright shift is still only a hypothesis’. Procopio's comments focus on handedness and it is important to remind ourselves,as Sommer et al's review makes clear, that handedness is nomore than an indirect and developmentally labile index of anatomicalasymmetry and language lateralisation; it is this last variableand its genetic determination (Crow, 1998a,b) that is of greatestrelevance.

GENETIC AND ENVIRONMENTAL INFLUENCES

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GENETIC AND ENVIRONMENTAL...

Procopio (2001) rightly draws attention to the study by Steinmetzet al (1995) of asymmetry of the planum temporale in monozygotictwins concordant and discordant for handedness. Twins discordantfor handedness were more likely to be discordant for planumtemporale asymmetry (Fig. 1). Handedness and asymmetry arethus related, but if the underlying determinant is geneticwhy should monozygotic twins be discordant, as they often are,for either? Procopio proposes that an environmental influenceis relevant but the nature of such an influence is obscure (see below). The alternative is to assume that there are unaccountedfor (random or epigenetic) variations in development. The importanceof the study of Steinmetz et al is that it demonstrates thatsuch presently intangible variation is large in relation tothe component that, according to a simple view, can be attributedto sequence variation (i.e. that common to identical twins),as has always been implicit in Annett's (1999) right-shifttheory.

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Fig. 1 Distribution of direction and degree of planum temporale asymmetry in 20 pairs of monozygotic (MZ) twins. MZ concordant: twin pairs 1-10 concordant for handedness; MZ discordant: twin pairs 11-20 discordant for handedness (X-axis). Y-axis: negative values indicate left-ward, positive values right-ward planum temporale asymmetry (adapted from Steinmetz et al, 1995).

What environmental factor might influence the development ofcerebral asymmetry? Procopio points to the finding of Salvesenet al (1993) that children who had been screened by ultrasonographyin utero were more likely to be non-right-handed than thosewho had not. However, the difference was small (odds ratio1.32%; 95% CI 1.02-1.71). As Salvesen et al emphasise, non-right-handednesswas one of six initial hypotheses, and no association withimpaired neurological development was found. An effect of ultrasoundon cerebral dominance is a concern but the evidence is modest.

NATURE AND LOCATION OF THE ASYMMETRY FACTOR

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NATURE AND LOCATION OF...

The key question is the nature of the asymmetry factor itself.Unless this can be identified as more than a hypothetical gene,not much progress can be expected. That it is the key to understandingdisorders of development was suggested by Orton (1937) in relation to reading disability, and Annett (1985) in relationto cognitive development in general. Orton predicted deficitsat the point of equal hand skill and Annett, on the basis ofheterozygote advantage formulation, at the extremes of thehand skill continuum (see Annett, 1999). Our findings in theNational Child Development Study cohort (Crow et al, 1996, 1998; see also Leask & Crow, 2001), including that readingdisability is a precursor of psychosis (Crow et al, 1995), support Orton more strongly than Annett, but the important pointis that the dimension of lateralisation is a determinant ofthe human ability to handle symbols. Recent evidence reinforcesthe conclusion that directional asymmetry on a population basisis a human (or at least hominid) characteristic (Fig. 2). Whatthis evidence suggests is that at some point in hominid evolutionthere was a discrete genetic change (a saltation), and thatthis change was associated with cerebral lateralisation andplayed a role in the evolution of language. This hypothesiscan be related to the argument (e.g. Bickerton, 1995) thatlanguage is a relatively recent and abrupt acquisition in thehominid lineage and to evidence (e.g. Mellars, 1998) fromthe archaeological records that the ability to represent insymbols goes back no more than 90 000 years. These generalviews are consistent with the concept (Stringer & McKie, 1996)that the capacity for language is the characteristic that defines modern Homo sapiens as a species with an origin somewherein East Africa around 100 000 years ago. The question is unresolvedregarding whether lateralisation was introduced at this time,or whether it was present earlier, for example in Homo erectus (Steele, 1998) and was modified by a subsequent genetic change.The implication of this evolutionary perspective is that thegenetic changes that led to the evolution of language wererelatively simple and small in number.

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Fig. 2 Direction of hand preference for a range of daily activities in a population of Homo sapiens (data from Provins et al, 1982) and Pan troglodytes in the Gombe National Park (data from Marchant & McGrew, 1996). Each individual is assigned a point on the 100% left to 100% right scale. Medians and boundary values (horizontal bars) for 95% of the populations have been calculated from data on graphs in the original publications.

I have argued (Crow, 1993, 1994) that the pattern of verbaland spatial deficits associated with the sex chromosome aneuploidies indicates that the genetic determinant of asymmetry is in aregion of homology between the X and the Y chromosomes. Theevolutionary history of the sex chromosomes provides a pointerto its location (Lambson et al, 1992; Sargent et al, 1996, 2001; Schwartz et al, 1998): after the separation of the lineagesthat led to the chimpanzee and H. sapiens a translocation occurredfrom Xq21.3 to the Y chromosome short arm, and the translocatedblock was split by a subsequent paracentric inversion (Fig. 3).

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Fig. 3 The transposition from Xq21.3 and subsequent paracentric inversion on Yp, that generated the Xq21.3/Yp11 block of homology and its orientation in modern Homo sapiens. Vertical arrows indicate the orientation of the gene sequence. Yp, Y chromosome short arm; cross-bars on the X and Y chromosome icons indicate centromeres. PCDHX, protocadherinX; PCDHY, protocadherinY. (Adapted from Schwartz et al, 1998.)

Gene sequences within this block are present on the X and Ychromosomes in humans but only on the X in other primates.Within this region of homology a gene — protocadherinXY— has recently been described (Blanco et al, 2000) thatis a member of a class of cell adhesion molecules expressedin the brain that have a role in axonal guidance. It is thereforea candidate for H. sapiens-specific characteristics such ascerebral asymmetry (Crow, 2001). In that there are sequencedifferences between the X and Y copies, this gene can accountfor gender differences such as those observed in age of onsetof psychosis, lateralisation and the development of verbalability. According to the X—Y theory of cerebral asymmetry,the chromosomal re-arrangements that led to protocadherinXbeing represented on the Y as well as the X chromosome werespeciation events in hominid evolution (Crow, 2000).

EPIGENETICS OF ASYMMETRY

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EPIGENETICS OF ASYMMETRY

The particular interest of an X—Y homologous gene subjectto recent evolutionary change is its status with respect toX inactivation — the epigenetic process by which theexpression of most genes on one X chromosome in females isinhibited (Lyon, 1974, 1999). Genes with a copy on the Ychromosome are protected from this process, although the mechanismof this protection is obscure. It presumably applies to protocadherinXY.Genes that have recently translocated from the X to the Y arein a new environment; the Y copy escapes from X inactivationand there must be a process whereby the state of inactivationof the gene on the X chromosome changes (see Jegalian & Page, 1998).One possibility is that the protected sequencesare those that are able to pair in male meiosis with similarsequences on the Y (Burgoyne, 1982; Crow, 1991; but also see Burgoyne & McLaren, 1985). Determining the mechanism andrules that govern this process could be a necessary preludeto an understanding of the variability that is intrinsic to the species.

CONCLUSIONS

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CONCLUSIONS

ProtocadherinXY in the Xq21.3/Yp region of homology is a candidate determinant of cerebral asymmetry and therefore of the humancapacity for language. If the X—Y hypothesis is correct,a component of the variation with respect to this recent andspecies-specific evolutionary development is epigenetic ratherthan sequence-based, and it is this, rather than unidentifiedenvironmental factors, that accounts for variability of transmissionof handedness and psychosis.

REFERENCES

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