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Anyone who uses a digital device of any kind will probably have noticed how easy it is accidently to duplicate—or worse, to delete—a file. But we now know that Nature is no different where her own quasi-digital medium is concerned. Duplicating or deleting DNA during copying generates what are known as copy number variations (CNVs, an example featuring duplication left). And as I have pointed out before in these posts, such multiplications or deletions of DNA are relevant to the imprinted brain theory because they can nullify or multiply the levels of expression of the genes in question, somewhat in the same way that imprinting (or silencing one or the other parent’s copy of a gene) does.
As a paper recently published in Translational Psychiatry explains,
DUF1220 is a protein domain encoded by genes on the long arm of chromosome 1. Copy number of DUF1220 has increased dramatically during primate evolution, with the most extreme increase found in humans. DUF1220 domains can be subdivided into conserved (CON) and human lineage-specific (HLS) subtypes based on sequence similarity:
Notably, the unique increase in copy number seen in humans compared with chimpanzees (290 versus 125) is due predominantly to an increase in the copy number of the HLS subtypes. This evolutionary increase in copy number has been linearly associated with an evolutionary increase in brain size and cortical neuron number, suggesting an evolutionary advantage associated with copy number expansion of the domain. Analyses of functional effects of CNV in human populations have shown that DUF1220 copy number is significantly associated with both healthy and pathogenic brain size variation, cognitive ability and severity of symptoms in autism.
As the imprinted brain theory’s diametric model predicts and this paper notes, “such duplications are enriched in individuals with autism and reciprocal deletions are enriched in those with schizophrenia.” Indeed, “One of the most striking and well-documented genomic findings suggests that schizophrenia and autism may be diametric opposites.”
CNVs in different genomic regions of chromosomes 1, 15, 16, 17, and 22 have been described in which duplications are significantly associated with one disorder while reciprocal deletions are associated with the other. In the case of the long arm of chromosome 1:
duplications are more frequently involved in autism, and reciprocal deletions more frequently involved in schizophrenia. Likewise, some disease phenotypes and neuropathologies exhibit inverse relationships between the two disorders. Autistic individuals often exhibit abnormally increased brain growth and in turn relatively increased brain size compared with controls, while schizophrenic individuals often have reduced brain volumes. Such findings imply that the dosage of key sequences within these CNVs contribute to both schizophrenia and autism but in opposite directions.
The study used DNA from 609 individuals diagnosed with schizophrenia, 120 controls, and 168 individuals with an autism spectrum disorder (ASD). Specifically, the researchers sought to determine whether DUF1220 is associated with features of schizophrenia. They report that schizophrenic individuals with predominantly "positive" symptoms (such as hallucinations and delusions) had significantly reduced CON1 copy number compared with schizophrenics with predominantly "negative" symptoms (for example, asociality and introversion). This difference was most pronounced in the male population, which also exhibited a significant reduction in CON1 copy number in predominantly positive symptom schizophrenics compared with ASD. Indeed, in the schizophrenic population as a whole, decreasing CON1 and HLS1 DUF1220 subtype copy number were each linearly associated with increasing positive symptoms. Contrariwise, increasing CON1 exhibited a significant association with increased negative symptoms in males.
The authors argue that “these results are relevant to refining the prevailing theories regarding the relationship between autism and schizophrenia … these theories include an overlapping phenotype theory, a subtype theory and a diametric opposites theory.”
Considering negative symptomology in schizophrenia, the association between increasing CON1 copy number and increasing negative symptoms in males lend support to a model in which negative symptoms of schizophrenia and symptoms of autism are similar and share genetic risk factors, in this case CON1 copy number increase. …
In contrast, though, is the highly significant linear association between both CON1 and HLS1 copy number and positive symptoms. Here, decreased copy number of either DUF1220 subtype is strongly associated with increased positive symptom severity. The association between CON1 copy number and positive symptoms lends support instead to the theory that at least some components of autism and schizophrenia represent diametric opposites of one another.
As the author's diagram above illustrates, they argue that their results support the previously proposed overlapping theory of autism and schizophrenia when discussing negative symptoms, but that their findings also confirm that “the diametric opposites theory is more likely when considering schizophrenia positive symptoms.” They go on to suggest that it is plausible that schizophrenia should be considered as a disease continuum, “where one end of the continuum features predominantly negative symptoms and clearly overlaps with autism, while the other end of the continuum features predominantly positive symptoms and exhibits no overlap with autism,” although it “may overlap with other diseases featuring similar symptoms.”
But as the diagram above illustrating the imprinted brain theory’s distinctive diametric model of mental illness suggests, non-imprinted genes and CNVs such as DUF1220 (not to mention environmental effects) could also contribute to the result, especially in the central, over-lapping area. And the fact that sex also plays a role would explain why increasing CON1 is particularly associated with increased negative, autistic-like, symptoms in males (for whom the point of balance is offset in the autistic direction as illustrated above). Furthermore, if you interpret schizophrenic "positive" symptoms as hyper-mentalistic and "negative" ones as hypo-mentalistic, the DUF1220 findings could be seen as not necessarily incompatible with the diametric model.
The authors conclude that they
have now implicated DUF1220 copy number in the symptoms of both autism and schizophrenia, supporting a new direction for research into the etiology and genetics of these pervasive and debilitating disorders. Finally, these findings lend further support to the view that autism and schizophrenia are harmful by-products of human brain evolution, resulting in part from the rapid and extreme evolutionary increase in DUF1220 copy number in the human genome.
(With thanks to Bernard Crespi for bringing this to my attention.)
