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.

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

“…In the post‐mortem brains of patients with schizophrenia, mapping of LINE1 insertion sites by whole‐genome sequencing showed increased insertions into synapse‐related genes or genes implicated in schizophrenia . Increased copy number of LINE1 in the post‐mortem brains of schizophrenic patients was replicated in another study . These findings suggest that somatic retro‐transposition of LINE1 plays a pathophysiological role in schizophrenia and possibly in BD as well.…”

“…86 Increased copy number of LINE1 in the post-mortem brains of schizophrenic patients was replicated in another study. 87 These findings suggest that somatic retrotransposition of LINE1 plays a pathophysiological role in schizophrenia and possibly in BD as well.…”

Retrotransposon-induced mosaicism in the neural genome

“…Here, we consider association as a study having shown that a retrotransposon insertion, or insertions, may cause a disease, or the study having reported elevation of retrotransposon copy number or mRNA level in the brain tissue of affected individuals when compared with healthy individuals. retrotransposon neurological disease insertions activity (mRNA levels, CNV, biomarkers) HERV multiple sclerosis [ 166 – 168 ] 3q13.31 microdeletion syndrome [ 169 ] amyotrophic lateral sclerosis [ 170 , 171 ] multiple sclerosis [ 166 – 168 , 172 ] schizophrenia [ 173 – 176 ] bipolar disorder [ 173 , 175 , 177 ] HIV-associated dementia [ 178 ] major depression [ 177 ] autism [ 179 ] ADHD [ 180 ] L1 pyruvate dehydrogenase complex deficiency [ 110 ] Fukuyama-type congenital muscular dystrophy [ 181 ] neurofibromatosis type I [ 182 ] ataxia with oculomotor apraxia 2 [ 183 ] glioblastoma [ 184 , 185 ] schizophrenia [ 176 ] ataxia telangiectasia [ 54 ] Coffin Lowry syndrome [ 186 ] major depression [ 187 , 188 ] schizophrenia [ 187 – 189 ] Rett syndrome [ …”

Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia

“…PZMs however, may ensure that neuronal genomes in an individual are not singular, homogeneous, or static, but instead establish mosaic, heterogeneous and dynamic populations of neural genomes, with new neurons arising throughout life (42). Among other processes, neurons are known to undergo de novo long interspersed nuclear element (LINE-1/L1) retrotransposition (44), as has been reported in adult neurons (45,46) and during embryonic development (43,47,48). Interestingly, the number of retrotranspositions has been reported as significantly higher in brain than non-brain tissue samples (49).…”