Retroelements As Potential Pathogens in Neuropyschiatric
Diseases
H-S Kim, R Wadekar, J-Y Choi, B-H Hyun, H-M Kit, O Takenaks
and TJ Crow
The hypothesis that the predisposing gene has the structure of a
retrovirus or retrotransposon (Crow, 1984) explains some aspects of psychosis
(e.g. episodicity), and is susceptible to investigation through molecular
homologies. We have employed a combination of a PCR search based upon
known sequences and phylogenetic analysis of these sequences in Hopo sapiens and
hominoid primates to investigate this hypothesis. We have identified three
classes of element that have been subject to recent change in the course of
primate evolution and that include members that are specific to the human
genome: (1) the SINE.C2 element that has been associated with Fukuyama-type
muscular dystrophy (Kim et al, in press,a) and long terminal repeat (LTR)
structures associated with the human endogenous retroviruses (HERVs) in the (2)
HERV-K and (3) HERV-W classes (Kim et al, in press, b, c). Each of these
classes has the capacity to active adjacent genes and includes members that have
been subject to recent transposition in the human genome. We have
investigated elements in these classes that are present within the region of
Xq21.3/Yp region of homology that was generated by a transposition from the X to
the Y chromosome that occurred after the separation of the chimpanzee and Homo
sapiens lineages. These elements are of interest in relation to the
hypothesis that a gene for cerebral asymmetry is present within this region, and
is associated with variations that is relevant to predisposition to
neuropsychiatric diseases (Crow, 1999).
We envisage that a strategy that combines the phylogenetic
approach across primate species (to select those elements are are labile in
evolution) with what is know about the origin of the human capacity for language
(that it depended upon a change that allowed the brain to develop with an
asymmetrical torque across the fronto-occipital axis through a change in an X-Y
homologous gene) together with knowledge of the recent evolutionary history of
the sex chromosomes, may succeed in defining the critical genomic element when
these strategies pursued independently might fail.
Crow TJ. A re-evaluation of the viral hypothesis: is
psychosis the result of retroviral integration at a site close to the cerebral
dominance gene? Brit J Psychiat 1984;145:243-253.
Crow TJ. The case for an Xq21.3/Yp homologous locus in the
evolution of language and the origins of psychosis. Acta Neuropsychiatrica
1999;11:54-56.
Kim H-S, Wadekar T, Takenaka O, et al. SINE-R.C2 (a Homo
sapiens specific retroposon) is homologous to cDNA from post-mortem brain in
schizophrenia and to two loci in the Xq21.3/Yp block linked to handedness and
psychosis. Am J Med Genet (Neuropsychiatric Genetics) in press.
Kim H-S, Takenaka O, Crow TJ. Isolation and phylogeny of
endogenous retroviral sequences belonging to the HERV-W family in primate. J Gen
Virol (in press)
Kim H-S, Crow TJ. Identification and phylogeny ofnovel
human endogenous retroviral sequences belonging to the HERV-W family on the
human X chromosome. Arch Virol (in press).