LINE1 insertions as a genomic risk factor for schizophrenia: Preliminary evidence from an affected family

Abstract

Recent studies show that human-specific LINE1s (L1HS) play a key role in the development of the central nervous system (CNS) and its disorders, and that their transpositions within the human genome are more common than previously thought. Many polymorphic L1HS, that is, present or absent across individuals, are not annotated in the current release of the genome and are customarily termed "non-reference L1s." We developed an analytical workflow to identify L1 polymorphic insertions with next-generation sequencing (NGS) using data from a family in which SZ segregates. Our workflow exploits two independent algorithms to detect nonreference L1 insertions, performs local de novo alignment of the regions harboring predicted L1 insertions and resolves the L1 subfamily designation from the de novo assembled sequence. We found 110 non-reference L1 polymorphic loci exhibiting Mendelian inheritance, the vast majority of which are already reported in dbRIP and/or euL1db, thus, confirming their status as non-reference L1 polymorphic insertions. Four previously undetected L1 polymorphic loci were confirmed by PCR amplification and direct sequencing of the insert. A large fraction of our non-reference L1s is located within the open reading frame of protein-coding genes that belong to pathways already implicated in the pathogenesis of schizophrenia. The finding of these polymorphic variants among SZ offsprings is intriguing and suggestive of putative pathogenic role. Our data show the utility of NGS to uncover L1 polymorphic insertions, a neglected type of genetic variants with the potential to influence the risk to develop schizophrenia like SNVs and CNVs. Ó2016WileyPeriodicals, Inc.

Novel Bioinformatics Approach Identifies Transcriptional Profiles of Lineage-Specific Transposable Elements at Distinct Loci in the Human Dorsolateral Prefrontal Cortex

“…Our findings are consistent with the hypothesis previously introduced by others that altered expression of TEs in human DLPFC may affect the expression of protein-coding genes leading to malfunction of genetic regulatory networks during development as well as during the clinical manifestation of Schizophrenia and other brain disorders in humans ( Chen et al. 2016 ; Guffanti et al. 2016 ; Mills et al.…”

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 [ …”

Inverse changes in L1 retrotransposons between blood and brain in major depressive disorder

“…L1 retrotransposition, as one of the DNA damaging agents, can lead to various types of genomic instability1718. There is growing evidence that genomic instability can be caused by environmental stress19.…”