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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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  • Media type: E-Article
  • Title: Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
  • Contributor: 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; [...]
  • Published: Springer Science and Business Media LLC, 2021
  • Published in: Nature Communications, 12 (2021) 1
  • Language: English
  • DOI: 10.1038/s41467-021-22262-5
  • ISSN: 2041-1723
  • Origination:
  • Footnote:
  • Description: 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.
  • Access State: Open Access