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

• Published in: Nature communications Vol. 12; no. 1; pp. 2076 - 13
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/43; 45/91; 631/208/457/649; 631/378/1689/1283; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Annotations; Apolipoprotein E; Apolipoproteins E - genetics; Brain; Brain - pathology; Chromosomes, Human, Pair 19 - genetics; Conserved Sequence - genetics; Depletion; DNA, Intergenic - genetics; Enrichment; Gene Ontology; Gene sequencing; Genes; Genetic diversity; Genome, Human; Genomics; Heritability; Humanities and Social Sciences; Humans; Introns - genetics; Linkage Disequilibrium - genetics; Molecular Sequence Annotation; multidisciplinary; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neurological diseases; Phenotype; Phenotypes; Phylogeny; Polymorphism, Single Nucleotide - genetics; Regression Analysis; RNA, Long Noncoding - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Single-nucleotide polymorphism; Tau protein; Transcription; Whole genome sequencing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22262-5

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. Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.