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.
Highlights
Knowledge of genomic features specific to the human lineage may provide insights into brainrelated diseases
This contrasts with the pattern using constraint metrics alone where the most constrained genomic regions are highly enriched for coding exons[11]
We demonstrated the utility of this approach by showing: the genomic regions we identified are enriched for SNP heritability for intelligence test performance and brain-related disorders; the genes we identified are enriched for neurologically relevant gene ontology terms and genes causing neurogenetic disorders and the existence of an intron-3 retaining transcript of APOE, the usage of which is correlated with Alzheimer’s disease pathology and APOE-ε4 status
Summary
Knowledge of genomic features specific to the human lineage may provide insights into brainrelated diseases. Parkinson’s disease does not naturally occur in nonhuman primates, whose motor deficits do not respond to levodopa administration and a Lewy body pathological burden is not present[5,7] This has led to the hypothesis that the same evolutionary changes driving encephalisation which have steered the development of characteristic human features may predispose to disorders that affect the brain[2,5,6]. Ward and Kellis successfully applied this approach to demonstrate that a range of transcribed and regulatory non-conserved elements showed evidence of lineage-specific purifying selection[14] This analysis was limited by the availability of WGS data and metrics on human genetic variation were derived from the 1000 Genomes pilot data, which sequenced with only two to six times coverage[15]. The recent sequencing of the genomes of 10,545 human individuals at a coverage of 30–40 times identified
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