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 Vandrovcová, Alastair J. Noyce, Rauan Kaiyrzhanov, Ben Middlehurst, Demis A. Kia, Manuela Tan, Huw R. Morris, Hélène Plun‐Favreau, Peter Holmans, Daniah Trabzuni, José Brás, John P. Quinn, Kin Y. Mok, Kerri J. Kinghorn, Kimberley J. Billingsley, Nicholas Wood, Patrick A. Lewis, Sebastian R. Schreglmann, Rita Guerreiro, Ruth C. Lovering, Lea R’Bibo, Claudia Manzoni, Mie Rizig, Sebastian Guelfi, Valentina Escott‐Price, Viorica Chelban, Thomas Foltynie, Nigel Williams, Alexis Brice, Fabrice Danjou, Suzanne Lesage, Jean‐Christophe Corvol, María Martínez, Claudia Schulte, Kathrin Brockmann, Javier Simón‐Sánchez, Peter Heutink, Patrizia Rizzu, Manu Sharma, Thomas Gasser, Aude Nicolas, Mark Cookson, Sara Bandrés‐Ciga, Cornelis Blauwendraat, David W. Craig, Faraz Faghri, J. Raphael Gibbs, Dena G. Hernandez, Kendall Van Keuren‐Jensen, Joshua Shulman, Hampton L. Leonard, Mike A. Nalls, Laurie Robak, Steven Lubbe, Steven Finkbeiner, Niccolò E. Mencacci, Codrin Lungu, Andrew Singleton, Sonja W. Scholz, Xylena Reed, Roy N. Alcalay, Ziv Gan‐Or, Guy A. Rouleau, Lynne Krohn, Jacobus J. van Hilten, Johan Marinus, Astrid Adarmes‐Gómez, Miquel Aguilar, Ignacio Álvarez, Victoria Álvarez, Francisco Javier Barrero, Jesús Alberto Bergareche Yarza, Inmaculada Bernal‐Bernal, Marta Blazquez, Marta Bonilla‐Toribio, Juan A. Botía, María Teresa Boungiorno, Dolores Buiza‐Rueda, Anna Maria Novella Càmara, Fátima Carrillo, Mario Carrión‐Claro, Debora Cerdan, Jordi Clarimón, Yaroslau Compta, Mónica Díez-Fairén, Oriol Dols‐Icardo, Jacinto Duarte, Raquel Durán, Francisco Escamilla‐Sevilla, Mario Ezquerra, Cici Feliz, Manel Fernández, Rubén Fernández‐Santiago
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.