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

Zhongbo Chen, David Zhang, Regina H. Reynolds, Emil K. Gustavsson, Sonia García-Ruiz, Karishma D’Sa, Aine Fairbrother-Browne, Jana Vandrovcova, John Hardy, Henry Houlden, Sarah A. Gagliano Taliun, Juan Botía and Mina Ryten ()
Additional contact information
Zhongbo Chen: University College London (UCL)
David Zhang: University College London (UCL)
Regina H. Reynolds: University College London (UCL)
Emil K. Gustavsson: University College London (UCL)
Sonia García-Ruiz: University College London (UCL)
Karishma D’Sa: University College London (UCL)
Aine Fairbrother-Browne: University College London (UCL)
Jana Vandrovcova: University College London (UCL)
John Hardy: University College London (UCL)
Henry Houlden: UCL
Sarah A. Gagliano Taliun: Université de Montréal
Juan Botía: University College London (UCL)
Mina Ryten: University College London (UCL)

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-22262-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22262-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-22262-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().