Human-lineage-specific genomic elements: relevance to neurodegenerative disease and APOE transcript usage

Zhongbo Chen, David Zhang, Regina H. Reynolds, Emil K. Gustavsson, Sonia García Ruiz, Karishma D’Sa, Aine Fairbrother-Browne, Jana Vandrovcova, International Parkinson’s Disease Genomics Consortium (IPDGC), John Hardy, Henry Houlden, Sarah A. Gagliano Taliun, Juan Botía, Mina Ryten

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Received Date: 28th April 20

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 (

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature