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Regular readers of these posts will have realized that an astonishing amount and range of factual findings now underpin the imprinted brain theory and its diametric model of the mind. Where the former is concerned, a huge Danish study has been by far the most remarkable confirmation of the theory’s predictions to date. Imprinted genes are expressed from one parent only, and the study used birth-size as a proxy for imprinting thanks to the fact that paternal genes tend to encourage growth while maternal ones restrict it. According to the imprinted brain theory, increased expression of paternal genes increases relative risk of autism spectrum disorder (ASD), while increased expression of maternal genes increases risk of psychotic spectrum disorder (PSD), and national mental health and birth-size data from Denmark stunningly showed that this was indeed so.
However, the Danish study did not directly detect expression of imprinted genes. Clearly, such evidence as birth size is circumstantial, and direct measures of imprinted gene expression in ASD as opposed to PSD remain to be undertaken. Nevertheless, one intriguing recent result does provide additional evidence (at least where ASD is concerned), and furthermore suggests how the Danish result might be explained at the genetic level.
Although patterns of gene expression in the brain of a living person cannot be directly assessed, some evidence can be gained from the culture of so-called organoids. In a new study of idiopathic autism (that is, autism without an apparent cause, graphical abstract above), skin cells from ASD subjects were converted back into undifferentiated stem cells like those in the embryo. Such cells are pluripotent, or in other words, capable of development into many tissue types. These induced pluripotent stem cells (iPSCs) were then in turn directed to develop into brain organoids: small groups of cells that resemble features of the embryonic structure from which the brain develops.
When compared with similar organoids derived from normal controls, those from the ASD patients showed up-regulated expression of genes involved in cell proliferation and neuronal development. ASD-derived organoids also exhibited an accelerated cell cycle and over-production of inhibitory neurons. Although the affected individuals did not share any underlying genetic mutations, all expressed a tendency to increased brain size: so-called macrocephaly. As the authors of this study comment,
we were able to identify perturbations in coherent programs of gene expression and associated features of altered neuro-development, namely up-regulation of cell proliferation, unbalanced inhibitory neuron differentiation, and exuberant synaptic development. … These findings are in accord with earlier hypotheses stating that abnormal control of cell proliferation and over-production of neurons might explain the accelerated brain growth in ASD.
The researchers found that one gene in particular, FOXG1, was over-expressed in the organoids of the ASD subjects. Altered expression of this gene and of gene network modules like those illustrated above were positively correlated with symptom severity. Indeed, the authors point out that “the alterations in the dynamics of brain growth and differentiation discovered using the organoid model represent a core feature of the disorder, rather than an incidental finding,” and add “that dysregulated gene expression in iPSC-derived organoids, and FOXG1 in particular, could be used as potential biomarkers of severe ASD.”
Down-regulation of FOXG1 is known to be linked to the opposite of macrocephaly, microcephaly, and reduced brain size is associated with PSD in much the same way that increased brain size is with ASD. Indeed, according to published findings by Randy Jirtle, also posted in his geneimprint blog, FOXG1, along with another gene implicated in ASD, DLGAP2, is predicted to be an imprinted paternally-active gene, just as the imprinted brain theory implies it should be.
As many women who have given birth know only too well, the size of a baby’s head rather than its body is critical where delivery is concerned, so it is perhaps not surprising that mothers may silence this brain-growth gene, leaving it to be expressed from the father's copy. And if the imprinted brain theory is correct, the opposite should be the case: maternally-active genes should be found to be up-regulated in the brain tissues of psychotics just as the X chromosome genes that so closely resemble them indeed are, as as I pointed out in a recent post. But paternal genes, by contrast, should be found to be correspondingly down-regulated, and future research on organoids from psychotics could presumably yield results testing this prediction, which is specific to the imprinted brain theory.
At the very least, this remarkable piece of research underlines the point I made in the previous post, namely that mental illness is now increasingly being revealed to be the result of variations in gene expression, rather than simply of inheritance of particular genes, just as the imprinted brain theory has always claimed. And clearly, if future research endorses this and similar findings, the implications of the Danish birth-size study will be underpinned with knowledge of the exact genes implicated in brain growth—or the lack of it—in both autism and psychosis.
(With thanks and acknowledgement to Randy Jirtle for bringing this study to my attention and sharing his unpublished findings with me.)
