Introduction
Schizophrenia, a psychiatric disorder mostly characterized by hallucinations, has a high amount of genetic heritability at about 60-90% (Banerjee, Polushina, Bettella, Giddaluru, Steen, et al., 2018). Despite key characteristics of schizophrenia including increased mortality and decreased fertility, the prevalence of schizophrenia still persists (Banerjee, Polushina, Bettella, Giddaluru, Steen, et al., 2018).
Researchers have suggested multiple reasons for the persistence of schizophrenia through its decreased fertility levels of individuals with the disease and increase mortality due to the disease. One theory suggests that evolution indirectly selects schizophrenia instead of eradicating it due to the cosegregation creativity and intellectual skill associated with the disease and the advantages it provides to the families of these individuals suffering from schizophrenia (Power, et al., 2013). In 1995 and 1997, TJ Crow poised a theory that language and psychosis originate from the same region within the brain, he noted that this may be reason for the persistence of schizophrenia through generations and generations of the human population.
Through the Genome-Wide Association Studies (GWAS), thousands of genetic variants have been found to have an association with schizophrenia, however the mechniasm of these variants is poorly understood (Banerjee, Polushina, Bettella, Giddaluru, Steen, et al., 2018). Through the field of genomics, Human accelerated Regions (HARS) and Neanderthal selective sweep (NSS) has allowed scientists to use these genetics tags in order to evaluate genomic regions that are more associated with schizophrenia (Banerjee, Polushina, Bettella, Giddaluru, Steen, et al., 2018). Negative NSS regions found in genomics characterized by nucleotide changes have been used to find mutations in modern day humans (Banerjee, Polushina, Bettella, Giddaluru, Steen, et al., 2018). In multiple studies, including Srinivasan et al. in 2015 who was able to use the techniques of negative NSS in genomics, found that regions that have an increased concentration of negative NSS are associated with the schizophrenia disease.
Researchers evaluated genomic sequencing and mapped genome methylation levels from two extinct hominids; the Neanderthal and the Denisovan and then compared them to the modern day human and found that there was 2000 different methylated regions or DMRs among the three groups (Gokhman, et., 2014). DMRs are so important because they allow for insight into evolutionary epigenomic data and help to identify evolutionary changes that may be due to the everchanging environment (Banerjee, Polushina, Bettella, Giddaluru, Steen, et al., 2018).
In the present study by Banerjee, Polushina, Bettella, Giddaluru, Steen, et al., in 2018, a thorough investigation on evolutionary different methylated regions (DMRs) and their impact on schizophrenia was completed. An investigation of human traits in comparison to to the enrichment of other human traits was also completed. Researchers did a thorough analysis on twelve different phenotypes in order to investigate their possible role in regions that are association with epigenetic changes.
Methodology
DMR data was found from Gokhman et al., 2014 where they compared genomic sequences from fossilized limb samples of Neanderthals and Denisovan. Gokhman et al., 2014 used methylated cytosine to thymine C-T ratio and compared this among all three groups of human specific, Denisovan specific, and Neanderthal specific. Human accelerated regions were obtained from public data and Neanderthal selective sweep was obtained from a list of markers used by Srinivasan et al., in 2015.
Results
GWAS information of statistical analysis was done of 12 traits including schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, rheumatoid arthritis, high density lipoprotein, triglycerides, total cholesterol, systolic and diastolic blood pressure, body mass index, and height. A list of single nucleotide polymorphisms or SNPs within each different methylated region was done for each of the tweleve traits. Researchers used a quantile-quantile plot (QQ) adopted from schork et al., to test the DMR SNP enrichment. There was enrichment observed for both SNPs in linkage disequilibrium markers in DMRs.
Another genomic annotation they used was the Major histocompatibility complex (MHC) region that is notable for having several markers of schizophrenia. This showed there was no difference in enrichment when included MHC or excluded MHC. They then used QQ plots to examine the association of Neanderthal and Denisovan DMR enrichment association with schizophrenia. They found that no enrichment was observed in the Neanderthals and Denisovan DMRs. They then compared enrichment in human DMRs with NSS markers and HARs markers and found that enrichment is a comparable analysis to NSS markers and that enrichment was observed in a higher concentration then HARs.
They analyzed statistical significant of DMR enrichment in schizophrenia through the use of the genomics technology INRICH pathway analysis tool. They confirmed DMR enrichment and enrichment of NSS markers and their association in schizophrenia.
They analyzed DMR SNPs enrichment association with schizophrenia through a pathway analysis throught the use of Ingenuity Pathway Analysis (IPA) and found an association with CREB signaling pathways ways and synaptic long term potentiation pathways in association with enrichment of DMR in schizophrenia and NSS markers. This suggests the interaction of the environmental changes on gene variation as modulated by methylated variations (Banerjee, Polushina, Bettella, Giddaluru, Steen, et al., 2018).
Discussion
The results found SNPs in certain areas of the human genome that have certain changes on the DNA level in DNA methylation and that are enriched have certain associations with schizophrenia (Banerjee, Polushina, Bettella, Giddaluru, Steen, et al., 2018). A comparison of the evolutionary enrichments of schizophrenia variants was completed by looking at DMRs, NSS markers, and HARS. Researchers also compared Neanderthals, Denisovan, and human specific DNRs and found that Neanderthals and Denisovans have no enrichment in association of schizophrenia which suggests that the human lineage has regions of altered methylation levels that may cause higher risk variants for schizophrenia. There was no evidence of enrichment of DMRs in association with bipolar disorder in comparison with schizophrenia.
Through the use of multiple genomic techniques, the authors suggest that human genomic regions who have altered DNA methylation have an enrichment in markers for schizophrenia (Banerjee, Polushina, Bettella, Giddaluru, Steen, et al., 2018). They also conclude and add to the literature that changes in DNA methylation are the greatest threat for the modern human as this impacts the nervous system and downstream epigenetic changes in generations to come. Researchers suggest that it is important to research the evolution before the homo lineage in order to see if this methylation marker was a sign for schizophrenia for example in primates.