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Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
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Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
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Journal Article
Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
2021
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 45/43
/ 45/91
/ Alzheimer Disease - genetics
/ Alzheimer Disease - pathology
/ Apolipoproteins E - genetics
/ Brain
/ Chromosomes, Human, Pair 19 - genetics
/ Conserved Sequence - genetics
/ Genes
/ Genomics
/ Humanities and Social Sciences
/ Humans
/ Linkage Disequilibrium - genetics
/ Molecular Sequence Annotation
/ Neurodegenerative Diseases - genetics
/ Polymorphism, Single Nucleotide - genetics
/ RNA, Long Noncoding - metabolism
/ Science
