%0 Journal Article
%A Chen, Zhongbo
%A Zhang, David
%A Reynolds, Regina H
%A Gustavsson, Emil K
%A García-Ruiz, Sonia
%A D'Sa, Karishma
%A Fairbrother-Browne, Aine
%A Vandrovcova, Jana
%A International Parkinson’s Disease Genomics Consortium (IPDGC)
%A Hardy, John
%A Houlden, Henry
%A Gagliano Taliun, Sarah A
%A Botía, Juan
%A Ryten, Mina
%T Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage.
%D 2021
%U https://hdl.handle.net/10668/26219
%X 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.
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