PT  - JOURNAL ARTICLE
AU  - Zhongbo Chen
AU  - David Zhang
AU  - Regina H. Reynolds
AU  - Emil K. Gustavsson
AU  - Sonia García Ruiz
AU  - Karishma D’Sa
AU  - Aine Fairbrother-Browne
AU  - Jana Vandrovcova
AU  - International Parkinson’s Disease Genomics Consortium (IPDGC)
AU  - John Hardy
AU  - Henry Houlden
AU  - Sarah A. Gagliano Taliun
AU  - Juan Botía
AU  - Mina Ryten
TI  - Human-lineage-specific genomic elements: relevance to neurodegenerative disease and <em>APOE</em> transcript usage
AID  - 10.1101/2020.04.17.046441
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.17.046441
4099  - http://biorxiv.org/content/early/2020/05/26/2020.04.17.046441.short
4100  - http://biorxiv.org/content/early/2020/05/26/2020.04.17.046441.full
AB  - 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/s to be more abundant in Alzheimer’s disease with more severe tau and amyloid pathological burden. Thus, we demonstrate the importance of human-lineage-specific sequences in brain development and neurological disease. We release our annotation through vizER (https://snca.atica.um.es/browser/app/vizER).Competing Interest StatementThe authors have declared no competing interest.