Human-lineage-specific genomic elements: relevance to neurodegenerative disease andAPOEtranscript usage

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

Leveraging omic features with F3UTER enables identification of unannotated 3’UTRs for synaptic genes

“…Surprisingly, we noted that unannotated 3’UTRs were also enriched for RBP binding motifs compared to known 3’UTRs ( p < 2.2 × 10 −16 , es = 0.28, Wilcoxon Rank Sum Test, Figure 4d ) suggesting that these regions may be of particular functional significance. To investigate this further, we leveraged constrained, non-conserved (CNC) scores [27], a measure of human-lineage-specificity, to determine whether the unannotated 3’UTRs identified were of specific importance in humans. CNC score, a metric combining cross-species conservation and genetic constraint in humans, was used to identify and score genomic regions which are amongst the 12.5% most constrained within humans but yet are not conserved.…”

“…The CNC scores, as reported by Chen et al [27], were used to quantify the occurrence of CNCRs within unannotated 3’UTRs. We extracted the CNC score for each 10 bp window and averaged it across the query region to calculate a mean CNC score for each query region.…”

Identification of a specific APOE transcript and functional elements associated with Alzheimer’s disease

“…Interestingly, a splicing variant of APOE mRNA with intron-3 retention, a long non-coding RNA, was found to govern APOE gene expression in neurons 8 . Furthermore, this non-coding RNA of APOE is more abundant in AD with more severe tau and amyloid pathological burden 9 . In contrast, we still do not know the roles of each APOE protein-coding transcript in AD pathogenesis.…”