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Analysis of LINE-1 Elements in DNA from Postmortem Brains of Individuals with Schizophrenia.

ABSTRACT: Whereas some rare genetic variants convey high risk for schizophrenia (SZ), common alleles conveying even moderate risk remain elusive. Long interspersed element-1s (L1) are mobile retrotransposons comprising ~17% of the human genome. L1 retrotransposition can cause somatic mosaicism during neurodevelopment by insertional mutagenesis. We hypothesized that, compared to controls, patients diagnosed with schizophrenia (PDS) may have increased numbers of deleterious L1 insertions, perhaps occurring de novo, in brain-expressed genes of dorsolateral prefrontal cortex (DLPFC) neurons. Neuronal and non-neuronal nuclei were separated by fluorescence-activated cell sorting from postmortem DLPFC of 36 PDS and 26 age-matched controls. Genomic sequences flanking the 3'-side of L1s were amplified from neuronal DNA, and neuronal L1 libraries were sequenced. Aligned sequences were analyzed for L1 insertions using custom bioinformatics programs. Ontology and pathway analyses were done on lists of genes putatively disrupted by L1s in PDS and controls. Cellular or population allele frequencies of L1s were assessed by droplet digital PCR or Taqman genotyping. We observed a statistically significant increase in the proportion of intragenic novel L1s in DLPFC of PDS. We found over-representation of L1 insertions within the gene ontologies 'cell projection' and 'postsynaptic membrane' in the gene lists derived from PDS samples, but not from controls. Cellular allele frequencies of examined L1 insertions indicated heterozygosity in genomes of DLPFC cells. An L1 within ERI1 exoribonuclease family member 3 (ERI3) was found to associate with SZ. These results extend prior work documenting increased L1 genetic burden in the brains of PDS and also identify unique genes that may provide new insight into the pathophysiology of schizophrenia.

SUBMITTER: Doyle GA

PROVIDER: S-EPMC5686486 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Analysis of LINE-1 Elements in DNA from Postmortem Brains of Individuals with Schizophrenia.

Doyle Glenn A GA Crist Richard C RC Karatas Emre T ET Hammond Matthew J MJ Ewing Adam D AD Ferraro Thomas N TN Hahn Chang-Gyu CG Berrettini Wade H WH

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20170606 13

Whereas some rare genetic variants convey high risk for schizophrenia (SZ), common alleles conveying even moderate risk remain elusive. Long interspersed element-1s (L1) are mobile retrotransposons comprising ~17% of the human genome. L1 retrotransposition can cause somatic mosaicism during neurodevelopment by insertional mutagenesis. We hypothesized that, compared to controls, patients diagnosed with schizophrenia (PDS) may have increased numbers of deleterious L1 insertions, perhaps occurring ...[more]

PMID: 28585566

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Project description:Schizophrenia (SCZ) is a psychiatric disorder that can include symptoms of disorganized speech and thoughts with uncertain underlying mechanisms possibly linked to over-activated microglia. In this study, we used brain samples from sixteen donors with SCZ and thirteen control donors to assess the differential activation of microglia by quantifying density and 3D reconstruction of microglia stained with ionized calcium-binding adaptor molecule-1 (Iba1). Our samples consisted of sections from the frontal, temporal, and cingulate cortical gray matter, subcortical white matter regions (SCWM), and included the anterior corpus callosum. In the first series of studies, we performed a density analysis followed by a spatial analysis to ascertain the microglial density, distribution, and soma size in SCZ brains. Second, we performed a series of morphological quantification techniques to investigate the arborization patterns of the microglia in SCZ. The results demonstrated an increase in microglia density in the cortical gray matter regions in SCZ cases, while in the SCWM, there was a significant increase in microglia density in the frontal and temporal, but not in the other brain regions of interest (ROIs). Spatial analysis using the "nearest neighbor" demonstrated that there was no effect in "clustering", but there were shorter distances between microglia seen in the SCZ cases. The morphological measures showed that there was a region-dependent increase in the microglia soma size in the SCZ cases while the Sholl analysis revealed a significant decrease in the microglia arborization in the SCZ cases across all the ROI's studied. An in-depth 3D reconstruction of microglia in Brodmann area 9 cortical region found that there was a significant association between age and reduced microglial arborization in the SCZ cases. This region-dependent age association can help determine whether longitudinal changes in microglial activation across age are brain region-dependent, which may point to potential therapeutic targets.

Dataset Information

Analysis of LINE-1 Elements in DNA from Postmortem Brains of Individuals with Schizophrenia.

Publications

Analysis of LINE-1 Elements in DNA from Postmortem Brains of Individuals with Schizophrenia.

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