Article
Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
Author/s | Chen, Zhongbo
Zhang, David Reynolds, Regina H. Labrador-Espinosa, Miguel Á. Periñán Tocino, María Teresa Mir Rivera, Pablo ![]() ![]() ![]() ![]() ![]() ![]() ![]() Ryten, Mina |
Department | Universidad de Sevilla. Departamento de Medicina |
Publication Date | 2021-04-06 |
Deposit Date | 2022-11-03 |
Published in |
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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 ... 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. |
Citation | Chen, Z., Zhang, D., Reynolds, R.H., Labrador-Espinosa, M.Á., Periñán Tocino, M.T., Mir Rivera, P. y Ryten, M. (2021). Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage. Nature Communications, 12 (1), 2076. https://doi.org/10.1038/s41467-021-22262-5. |
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