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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.
Fuente: Nature Communications 12, 2076 (2021)
Editorial: Nature Publishing Group
Fecha de publicación: 06/04/2021
Nº de páginas: 13
Tipo de publicación: Artículo de Revista
Url de la publicación: https://doi.org/10.1038/s41467-021-22262-5
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REYNOLDS, REGINA H.
GUSTAVSSON, EMIL K.
GAGLIANO TALIUN, SARAH A.
JON INFANTE CEBERIO