Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.17.046441v1?rss=1 Authors: Chen, Z., Zhang, D., Reynolds, R. H., Gustavsson, E. K., Garcia Ruiz, S., D'Sa, K., Fairbrother-Browne, A., Vandrovcova, J., Genomics Consortium (IPDGC), I. P. D., Hardy, J., Houlden, H., Gagliano Taliun, S. A., Botia, J. A., Ryten, M. 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/s to be more abundant in Alzheimer's disease with more severe tau and amyloid pathological burden. Thus, we demonstrate the importance of human-lineage-specific sequences in brain development and neurological disease. We release our annotation through vizER (https://snca.atica.um.es/browser/app/vizER). Copy rights belong to original authors. Visit the link for more info