Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-22262-5
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Funding
- Leonard Wolfson Foundation
- United Kingdom Medical Research Council (MRC) through Tenure Track Clinician Scientist Fellowship [MR/N008324/1]
- UK Dementia Research Institute from DRI Limited - UK Medical Research Council
- Alzheimer's Society
- Alzheimer's Research UK
- Medical Research Council [MR/N026004/1]
- Wellcome Trust [202903/Z/16/Z]
- Dolby Family Fund
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Science and Technology Agency, Seneca Foundation, CARM, Spain [00007/COVI/20]
- MRC [UKDRI-1009] Funding Source: UKRI
- Wellcome Trust [202903/Z/16/Z] Funding Source: Wellcome Trust
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Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases, with certain regions playing a potential role in both brain development and neurological disease.
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. Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.
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