RT Journal Article
T1 Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage.
A1 Chen, Zhongbo
A1 Zhang, David
A1 Reynolds, Regina H
A1 Gustavsson, Emil K
A1 García-Ruiz, Sonia
A1 D'Sa, Karishma
A1 Fairbrother-Browne, Aine
A1 Vandrovcova, Jana
A1 International Parkinson’s Disease Genomics Consortium (IPDGC), 
A1 Hardy, John
A1 Houlden, Henry
A1 Gagliano Taliun, Sarah A
A1 Botía, Juan
A1 Ryten, Mina
AB 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.
YR 2021
FD 2021-04-06
LK https://hdl.handle.net/10668/26219
UL https://hdl.handle.net/10668/26219
LA en
DS RISalud
RD Apr 7, 2025