Evolution of schizophrenia

The balancing selection hypothesis suggests that balancing selection, an evolutionary mechanism, has allowed for the persistence of certain schizophrenia genes. This mechanism is defined as maintaining multiple alleles of a gene in the gene pool of a population despite having selective pressures.[3] Heterozygote advantage, a mechanism of balancing selection, is when the presence of both the dominant and recessive allele for a particular gene allow for greater fitness in an individual as compared to if the individual only expressed one type of allele.^[4] This mechanism can be seen in the carriers for the schizophrenia gene who express both the dominant and recessive allele. These carriers may express certain advantageous traits that would allow the schizophrenia gene to be selected for.^[3] Evidence has suggested a carrier of the schizophrenia gene could experience selective advantage due to their expression of advantageous traits as compared to those who do not express the schizophrenia gene.^[5] Studies have shown that some of the carriers for the schizophrenia gene may express adaptive benefits such as a decreased frequency of viral infections.^[5] Additional beneficial traits may include a higher IQ, increased creativity, and mathematical reasoning.^[3] Due to the presence of these beneficial traits, the schizophrenia gene has not been selected against and has remained prevalent in human development over numerous generations. While the idea of balancing selection hypothesis sounds plausible, there is no substantial evidence in support of this hypothesis. Within the studies that found a positive correlation between specific favorable characteristics and the schizophrenia gene, only a few carriers were tested, meaning that there is no sufficient evidence to assume a direct correlation between these advantageous traits and the carriers of schizophrenia.^[5] Although this hypothesis has not yet been substantiated, the advantageous traits that these carriers express could provide a reasonable explanation for why the genes for schizophrenia have not been eliminated.^[6]

Positive selection is another mechanism that has allowed for the selection of genes contributing to the presence of schizophrenia. Positive selection is a mechanism of natural selection in which beneficial traits are selected for and become prevalent over time in a population.^[7] In a study conducted using phylogeny-based maximum-likelihood (PAML), a method that was used to test for positive selection, significant evidence of positive selection was found in the genes associated with schizophrenia.^[8] An example of a beneficial trait that has been selected for through positive selection is creativity. Three allelic variants of creativity genes that are also associated with schizophrenia include SLC6A4, TPH1 and DRD2.^[8] The high inheritance of creative and cognitive characteristics by these allelic variants in individuals expressing schizophrenia confirms evidence of positive selection within some schizophrenia genes. Additional studies conducted using SNP analysis on the SLC39A8 gene, a gene associated with schizophrenia, found that the T-allele on the gene was associated with reduced blood pressure and a decreased risk of hypertension.^[9] These beneficial traits associated with schizophrenia genes provide an explanation for selection of these genes in human development.^[9] While promising evidence persists, additional evidence claims that the effect of positive selection may not play a significant role in the presence of schizophrenia. Studies conducted through the use of FST and methods based on sample frequency spectrum (SFS) failed to find convincing signals of positive selection on the CGC-type of the ST8SIA2 gene, another gene associated with schizophrenia.^[10]

Social brain hypothesis

A social brain refers to the higher

As schizophrenia is foremost a disorder of the consciousness, it has been suggested that schizophrenia exists as an unwanted byproduct of the evolution of the prefrontal cortex and other brain regions constituting the social brain.^[12] Under increasingly selective pressure induced by increasingly complex social living, the regions of the brain have grown as a means of accommodation and in turn have given rise to vulnerable neural systems.^[12] One hypothesis suggests this vulnerability in neural systems has made it possible for changes in genes associated with the social brain that affect neurogenesis, neuronal migration, arborisation, or apoptosis.^[15] Although it is unclear which of these factors have exhibited gene changes, it is likely that these changes have contributed to the defect in neurodevelopment seen in schizophrenia patients. A second hypothesis suggests that disturbance in the brain's frontal circuits, a region that largely constitutes the social brain, can lead to a lack of regulation in cognitive control and processing.^[15] This defect in regulation could increase the susceptibility for a social disorder like schizophrenia.^[15]

Social advantage hypothesis

This hypothesis refers to the worship of psychics and seers in the times of early civilization; the hallucinatory behavior and delusions brought by schizophrenia may have been highly regaled and allowed the individual to be conferred the title of saint or prophet, raising him on the social spectrum and allowing for social selection to act on the behalf of the disorder.^[2] This hypothesis lacks evidence and has not aided in explaining the continued persistence of schizophrenia in modern-day society where people showing symptoms of schizophrenia are typically not identified as saints or prophets.^[2]

Physiological advantage hypothesis

This hypothesis maintains that people with schizophrenia possess a physiological advantage in the form of disease or infection resistance, a theory that has found basis in diseases such as

Studies in kynurenine pathway activation reveal that M. tuberculosis infection of the pathway causes niacin receptors in the pathway to indicate high levels of niacin, a precursor to NAD that makes de novo synthesis of NAD from tryptophan unnecessary. This change creates the illusion that NAD levels are adequate and that tryptophan conversion is unnecessary.^[16] Coevolution with M. tuberculosis has resulted in an attempt to overcome this illusion in a variety of manners, including the up-regulation of niacin receptors and up-regulation of de novo synthesis of NAD from tryptophan via the kynurenine pathway.^[16]

An enzyme implicated in the initiation of the kynurenine pathway, tryptophan 2,3-dioxygenase (TDO2) is found to activate during niacin-deficient conditions and is also found to be in increased levels in schizophrenic brains.

The self-domestication hypothesis suggests that schizophrenia results from hypofunction of the neural crest development, triggered by the selection for domesticated "tameness", and emphasize the domestic characteristics that make up the clinical phenotype of schizophrenia. Deficits related to language production and processing are prevalent in both positive and negative symptoms of schizophrenia.[24] In addition, schizophrenic patients often demonstrate more marked domesticated traits at the morphological, physiological, and behavioral levels; including craniofacial abnormalities, desensitized cortical response to stress, and disorganized speech.^[24]

A study published in 2017 targeted various candidate genes (FOXD3,