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



Chen, Zhongbo ORCID: 0000-0001-6668-7202, Zhang, David, Reynolds, Regina H ORCID: 0000-0001-6470-7919, Gustavsson, Emil K ORCID: 0000-0003-0541-7537, García-Ruiz, Sonia, D'Sa, Karishma, Fairbrother-Browne, Aine ORCID: 0000-0002-7196-1410, Vandrovcova, Jana, International Parkinson’s Disease Genomics Consortium (IPDGC), Hardy, John ORCID: 0000-0002-3122-0423
et al (show 4 more authors) (2021) Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage. Nature communications, 12 (1). 2076-.

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Abstract

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
Uncontrolled Keywords: International Parkinson’s Disease Genomics Consortium (IPDGC), Brain, Chromosomes, Human, Pair 19, Humans, Alzheimer Disease, Neurodegenerative Diseases, Apolipoproteins E, DNA, Intergenic, RNA, Messenger, Regression Analysis, Phylogeny, Conserved Sequence, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Genome, Human, Introns, Molecular Sequence Annotation, RNA, Long Noncoding, Gene Ontology
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 25 Oct 2021 10:24
Last Modified: 18 Jan 2023 21:25
DOI: 10.1038/s41467-021-22262-5
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3141599