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Posted 1 November 2005
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Do Chimpanzees Suffer from Schizophrenia?
Jim Kennedy asks, "What if the group of schizophrenia risk genes all can be found in the relatively small group of genes that are different between chimpanzees and humans?" (See SRF's Idea Lab.)
This question was highly relevant to the Proceedings of the World Congress on Psychiatric Genetics recently held in Boston, and it is a question that I have been asking since 1988. It suggests an alternative to the widely popular linkage approach. By 1988 I had become convinced that cerebral asymmetry (the "torque," the bias, from wider right frontal to wider left occipital measurements across the anteroposterior axis) was the key to the brain changes in schizophrenia. This was based partly on our 1986 postmortem study (Brown et al., 1986) and more strongly on the findings of our second postmortem study (Crow et al., 1989a), and was spelt out in a review in the Schizophrenia Bulletin (Crow, 1990).
In various forms since then I have developed an evolutionary theory of the origins of schizophrenia. This is because, as I see it, we are dealing with an illness present within all populations, probably at similar rates. As far as we can see, it is genetic in origin but the nature of the gene(s) is obscure. As Huxley et al. (1964) pointed out, there is a problem—why do these genes not get selected out if they are associated with a biological disadvantage?
To account for the same-sex concordance effect, the hallmark of X-Y transmission (Crow et al., 1989b; Crow et al., 1990), I postulated that a single gene for asymmetry and brain growth was located in a region of homology between the X and the Y chromosomes. The first hypothesis that this was in the classical pseudoautosomal region (Crow, 1988b) was subsequently discounted by ourselves (Crow et al., 1994; DeLisi et al., 1994) and by others in linkage studies.
This exclusion of pseudoautosomal region 1 (PAR1) led to the more interesting hypothesis (Crow, 1993) that a gene for cerebral asymmetry and brain growth is located in a sex-specific region of homology. A number of blocks of homology outside the pseudoautosomal regions are now known. Such a location would explain a sex difference, which a pseudoautosomal gene would not. A linkage study along the X chromosome for handedness and psychosis (Laval et al., 1998) pointed to the Xq21.3 region of homology that is of particular interest because it is Homo sapiens-specific, that is, is not present on the Y chromosome in the chimpanzee or other primates, or indeed other mammals. In 1995 I became convinced [partly on the basis of reading Derek Bickerton's book on language and species, (1990)] that the faculty of language was the key human capacity that required explanation. It is a significant problem in its own right and arguably is a challenge to current formulations of evolutionary theory. In a series of papers (1995a; Crow, 1995b; 1995c; 1995d; 1996a; 1996b), I put forward the hypothesis that the genetic variation relating to psychosis arose in the event that gave rise to modern Homo sapiens as a species. From this concept developed the idea that language and psychosis are more closely related than is often thought—specifically, they have a common origin in the speciation event (Crow, 1997a; 1997b; 1998a; 1998b) and that the nuclear symptoms in particular are clues to the structure of language. This concept has its clearest expression in the aphorism that "schizophrenia is the price that Homo sapiens pays for language" (Crow, 1997a; 2000). The implication is that we are dealing with variation that is species-specific, that is, that is not present in non-human primates.
This conclusion has significant consequences for the search for psychosis genes. My view is that none of the candidates so far proposed, nor the linkages from which they were identified, can be regarded as reliably established. For example, there is little agreement on sites of linkage between the two largest sibling pair studies so far conducted (Crow 2006, in press). Enthusiasts for linkage believe that this is because many genes are involved and each of these is of small effect. Larger studies (maybe including tens of thousands of families) are needed to solve the problem. On the contrary, I suggest that a single gene is still feasible (after all, we don't yet have one) and that gene is of great interest to the species. To identify the gene, a simple strategy is feasible—comparison of the human and chimpanzee genomes. A number of differences are already known, and these include the region on the Y chromosome, to which we have already drawn attention, and pseudoautosomal region 2 (PAR2) at the telomeres of the long arms of the X and Y, which was discovered only in 1992 (Freije et al., 1992) and which, unlike PAR1, is present only in Homo sapiens.
Thus, the Xq21.3/Yp and PAR2 regions acquire particular significance (a) because these X-Y homologies were established by translocations in the course of hominid evolution, (b) because of the evidence that cerebral asymmetry is the characteristic that defines the human brain (Crow, 2004) and (c) because of the evidence from sex chromosome aneuploidies that the gene for cerebral asymmetry is in the X-Y homologous class (Crow, 1994). Therefore, I believe that it is still possible that there is "a continuum of psychosis, one human gene, and not much else" (Crow, 1995a), but the gene is the one that accounts for our capacity for language and humanity, and the critical change took place in the speciation event that separated us from the prior species Homo heidelbergensis. The species-specific variation associated with this event is, I believe, epigenetic in nature and therefore invisible to the linkage approach. If I am right, the problem will only be solved by focusing on human-great ape genome comparisons.
In 1988 I wrote that "a promising strategy is to make use of the hypothesis that psychosis is specific to man…. The concept is consistent with the notion that psychosis is a disturbance of genetic mechanisms…subject to recent evolutionary change…. Thus, if we were able to identify those regions of DNA which distinguish man from the chimpanzee and gorilla, we might assume that it is in this segment of the genome that the psychosis gene is to be found…" (Crow, 1988a).
"An even more specific hypothesis…that psychosis is a disorder of cerebral development…derives support from a recent analysis of a CT scan study (Johnstone et al., 1989)…in addition to the well-established finding of a degree of ventricular enlargement, brain area in…schizophrenia was reduced. This seems more likely to be the result of a failure of development than a process of atrophy…age of onset was relevant to asymmetries in the posterior part of the brain: Patients with early onset had significantly smaller asymmetries by comparison both with schizophrenic patients of later onset and patients with non-schizophrenic disorders…. Most convincing are the findings of a study in which the ventricle has been assessed in postmortem material by a radiological technique (Crow et al., 1989a)…of particular interest is the finding of a significant (p <0.001) (side) by diagnosis interaction, the increase being greater on the left side in the schizophrenic patients. It seems, therefore, that schizophrenia may indeed be a disorder of the mechanisms which control the development of cerebral lateralisation…there is reason to suppose that asymmetry of function and structure in the brain is a relatively late evolutionary development, and may either have been a specifically human departure or have developed greatly in man" (Crow, 1988a).
Bickerton,D., 1990. Language and Species University of Chicago, Chicago.
Brown R, Colter N, Corsellis JA, Crow TJ, Frith CD, Jagoe R, Johnstone EC, Marsh L. Postmortem evidence of structural brain changes in schizophrenia. Differences in brain weight, temporal horn area, and parahippocampal gyrus compared with affective disorder. Arch Gen Psychiatry. 1986 Jan;43(1):36-42. Abstract
Crow TJ. Temporal lobe asymmetries as the key to the etiology of schizophrenia. Schizophr Bull. 1990;16(3):433-43. Review. Abstract
Crow TJ. Sexual selection, Machiavellian intelligence, and the origins of psychosis. Lancet. 1993 Sep 4;342(8871):594-8. Review. Abstract
Crow TJ. Sex chromosomes and psychosis. The case for a pseudoautosomal locus. Br J Psychiatry. 1988 Nov;153:675-83. Abstract
Crow TJ. 2004. Directional asymmetry is the key to the Origin of Modern Homo sapiens (the Broca-Annett axiom). Response to Lesley Rogers. Laterality. 9, 233-242.
Crow TJ. 1994. The case for an X-Y homologous determinant of cerebral asymmetry. Cytogenet Cell Genet. 67, 393-394.
Crow TJ. A continuum of psychosis, one human gene, and not much else--the case for homogeneity. Schizophr Res. 1995 Oct;17(2):135-45. Review. Abstract
Crow TJ. A Darwinian approach to the origins of psychosis. Br J Psychiatry. 1995 Jul;167(1):12-25. Review. Erratum in: Br J Psychiatry 1995 Sep;167(3):414. Abstract
Crow TJ. A theory of the evolutionary origins of psychosis. Eur Neuropsychopharmacol. 1995;5 Suppl:59-63. Review. Abstract
Crow TJ. Constraints on concepts of pathogenesis. Language and the speciation process as the key to the etiology of schizophrenia. Arch Gen Psychiatry. 1995 Dec;52(12):1011-4; discussion 1019-24. No abstract available. Abstract
Crow TJ. 1996a. Language and psychosis: common evolutionary origins. Endeavour. 20(3), 105-109.
Crow TJ. 1996b. Sexual selection as the mechanism of evolution of Machiavellian intelligence: a Darwinian theory of the origins of psychosis. J Psychopharmacol. 10(1), 77-87.
Crow TJ. 1988a. Aetiology of psychosis: the way ahead. In: Bebbington P. and McGuffin P. (Eds.), Schizophrenia: The Major Issues, Heinemann, Oxford, pp. 127-134.
Crow TJ. Is schizophrenia the price that Homo sapiens pays for language? Schizophr Res. 1997 Dec 19;28(2-3):127-41. Abstract
Crow TJ. From Kraepelin to Kretschmer leavened by Schneider: thextransition from categories of psychosis to dimensions of variation intrinsic to homo sapiens. Arch Gen Psychiatry. 1998 Jun;55(6):502-4. No abstract available. Abstract
Crow TJ. Nuclear schizophrenic symptoms as a window on the relationship between thought and speech. Br J Psychiatry. 1998 Oct;173:303-9. Abstract
Crow TJ. Schizophrenia as the price that homo sapiens pays for language: a resolution of the central paradox in the origin of the species. Brain Res Brain Res Rev. 2000 Mar;31(2-3):118-29. Review. Abstract
Crow TJ. Schizophrenia as failure of hemispheric dominance for language. Trends Neurosci. 1997 Aug;20(8):339-43. Review. Abstract
Crow TJ, Ball J, Bloom SR, Brown R, Bruton CJ, Colter N, Frith CD, Johnstone EC, Owens DG, Roberts GW. Schizophrenia as an anomaly of development of cerebral asymmetry. A postmortem study and a proposal concerning the genetic basis of the disease. Arch Gen Psychiatry. 1989 Dec;46(12):1145-50. Abstract
Crow TJ, DeLisi LE, Johnstone EC. Concordance by sex in sibling pairs with schizophrenia is paternally inherited. Evidence for a pseudoautosomal locus. Br J Psychiatry. 1989 Jul;155:92-7. Abstract
Crow TJ, Delisi LE, Johnstone EC. In reply ... a locus closer to the telomere? Br J Psychiatry. 1990 Mar;156:416-20. No abstract available. Abstract
Crow TJ, Delisi LE, Lofthouse R, Poulter M, Lehner T, Bass N, Shah T, Walsh C, Boccio-Smith A, Shields G, et al. An examination of linkage of schizophrenia and schizoaffective disorder to the pseudoautosomal region (Xp22.3) Br J Psychiatry. 1994 Feb;164(2):159-64. Abstract
DeLisi LE, Devoto M, Lofthouse R, Poulter M, Smith A, Shields G, Bass N, Chen G, Vita A, Morganti C, et al. Search for linkage to schizophrenia on the X and Y chromosomes. Am J Med Genet. 1994 Jun 15;54(2):113-21. Abstract
Freije D, Helms C, Watson MS, Donis-Keller H. Identification of a second pseudoautosomal region near the Xq and Yq telomeres. Science. 1992 Dec 11;258(5089):1784-7. Abstract
Huxley J, Mayre E, Osmond H, Hoffer A. Schizophrenia as a genetic morphism. Nature. 1964 Oct 17;204:220-1. No abstract available. Abstract
Johnstone EC, Owens DG, Bydder GM, Colter N, Crow TJ, Frith CD. The spectrum of structural brain changes in schizophrenia: age of onset as a predictor of cognitive and clinical impairments and their cerebral correlates. Psychol Med. 1989 Feb;19(1):91-103. Abstract
Laval SH, Dann JC, Butler RJ, Loftus J, Rue J, Leask SJ, Bass N, Comazzi M, Vita A, Nanko S, Shaw S, Peterson P, Shields G, Smith AB, Stewart J, DeLisi LE, Crow TJ. Evidence for linkage to psychosis and cerebral asymmetry (relative hand skill) on the X chromosome. Am J Med Genet. 1998 Sep 7;81(5):420-7. Abstract