Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
Por:
Chen, ZB, Zhang, D, Reynolds, RH, Gustavsson, EK, Garcia-Ruiz, S, D'Sa, K, Fairbrother-Browne, A, Vandrovcova, J, Hardy, J, Houlden, H, Taliun, SAG, Botia, J, Ryten, M, Clarimón J., Dols-Icardo O., Kulisevsky J., Pagonabarraga J., Int Parkinson's Dis Genomics Conso
Publicada:
6 abr 2021
Resumen:
Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer's disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease. Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.
Filiaciones:
Chen, ZB:
Univ Coll London UCL, Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England
UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England
UCL, Great Ormond St Inst Child Hlth, Dept Genet & Genom Med, London, England
Zhang, D:
Univ Coll London UCL, Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England
UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England
UCL, Great Ormond St Inst Child Hlth, Dept Genet & Genom Med, London, England
Reynolds, RH:
Univ Coll London UCL, Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England
UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England
UCL, Great Ormond St Inst Child Hlth, Dept Genet & Genom Med, London, England
Gustavsson, EK:
Univ Coll London UCL, Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England
UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England
UCL, Great Ormond St Inst Child Hlth, Dept Genet & Genom Med, London, England
Garcia-Ruiz, S:
Univ Coll London UCL, Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England
UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England
UCL, Great Ormond St Inst Child Hlth, Dept Genet & Genom Med, London, England
D'Sa, K:
Univ Coll London UCL, Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England
UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England
UCL, Great Ormond St Inst Child Hlth, Dept Genet & Genom Med, London, England
Fairbrother-Browne, A:
Univ Coll London UCL, Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England
UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England
UCL, Great Ormond St Inst Child Hlth, Dept Genet & Genom Med, London, England
Vandrovcova, J:
Univ Coll London UCL, Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England
Hardy, J:
Univ Coll London UCL, Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England
UCL, Queen Sq Inst Neurol, Reta Lila Weston Inst, London, England
UCL, Queen Sq Inst Neurol, UK Dementia Res Inst, London, England
NIHR Univ Coll London Hosp, Biomed Res Ctr, London, England
Hong Kong Univ Sci & Technol, Inst Adv Study, Hong Kong, Peoples R China
Houlden, H:
UCL, Queen Sq Inst Neurol, Dept Neuromuscular Dis, London, England
Taliun, SAG:
Univ Montreal, Dept Med, Montreal, PQ, Canada
Univ Montreal, Dept Neurosci, Montreal, PQ, Canada
Montreal Heart Inst, Montreal, PQ, Canada
Botia, J:
Univ Coll London UCL, Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England
Univ Murcia, Dept Ingn Informac & Comunicac, Murcia, Spain
Ryten, M:
Univ Coll London UCL, Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London, England
UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London, England
UCL, Great Ormond St Inst Child Hlth, Dept Genet & Genom Med, London, England
Clarimón J.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Dols-Icardo O.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Kulisevsky J.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Pagonabarraga J.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Green Submitted, Green Published, gold, Green Accepted
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