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Chen, Zhongbo;
Zhang, David;
Reynolds, Regina H.;
Gustavsson, Emil K.;
García-Ruiz, Sonia;
D’Sa, Karishma;
Fairbrother-Browne, Aine;
Vandrovcova, Jana;
Noyce, Alastair J.;
Kaiyrzhanov, Rauan;
Middlehurst, Ben;
Kia, Demis A.;
Tan, Manuela;
Morris, Huw R.;
Plun-Favreau, Helene;
Holmans, Peter;
Trabzuni, Daniah;
Bras, Jose;
Quinn, John;
Mok, Kin Y.;
Kinghorn, Kerri J.;
Billingsley, Kimberley;
Wood, Nicholas W.;
Lewis, Patrick;
[...]
Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
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- Medientyp: E-Artikel
- Titel: Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
- Beteiligte: Chen, Zhongbo; Zhang, David; Reynolds, Regina H.; Gustavsson, Emil K.; García-Ruiz, Sonia; D’Sa, Karishma; Fairbrother-Browne, Aine; Vandrovcova, Jana; Noyce, Alastair J.; Kaiyrzhanov, Rauan; Middlehurst, Ben; Kia, Demis A.; Tan, Manuela; Morris, Huw R.; Plun-Favreau, Helene; Holmans, Peter; Trabzuni, Daniah; Bras, Jose; Quinn, John; Mok, Kin Y.; Kinghorn, Kerri J.; Billingsley, Kimberley; Wood, Nicholas W.; Lewis, Patrick; [...]
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Erschienen:
Springer Science and Business Media LLC, 2021
- Erschienen in: Nature Communications, 12 (2021) 1
- Sprache: Englisch
- DOI: 10.1038/s41467-021-22262-5
- ISSN: 2041-1723
- Entstehung:
- Anmerkungen:
- Beschreibung: AbstractKnowledge 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.
- Zugangsstatus: Freier Zugang