Human-lineage-specific genomic elements: relevance to neurodegenerative disease and APOE transcript usage
Regina H. Reynolds,
Emil K Gustavsson,
Sonia García Ruiz,
International Parkinson’s Disease Genomics Consortium (IPDGC),
Sarah A. Gagliano Taliun,
Posted 18 Apr 2020
bioRxiv DOI: 10.1101/2020.04.17.046441
Posted 18 Apr 2020
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 Statement The authors have declared no competing interest.
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