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Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

Chen, Zhongbo, Zhang, David, Reynolds, Regina H., Gustavsson, Emil K., García-Ruiz, Sonia, D'Sa, Karishma, Fairbrother-Browne, Aine, Vandrovcova, Jana, Hardy, John, Houlden, Henry, Gagliano Taliun, Sarah A., Botía, Juan, Ryten, Mina, Holmans, Peter ORCID:, Escott-Price, Valentina ORCID: and Williams, Nigel ORCID: 2021. Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage. Nature Communications 12 (1) , 2076. 10.1038/s41467-021-22262-5

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 25 February 2022
Date of Acceptance: 3 March 2021
Last Modified: 06 May 2023 11:51

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