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bioRxiv · 10.1101/2020.10.16.342188

Genetic-variant hotspots and hotspot clusters in the human genome facilitating adaptation while increasing instability

Long, X.·Xue, H.
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Abstract

BackgroundGenetic variants, underlining phenotypic diversity, are known to distribute unevenly in the human genome. A comprehensive understanding of the distributions of different genetic variants is important for insights into genetic functions and disorders. MethodsHerein, a sliding-window scan of regional densities of eight kinds of germline genetic variants, including single-nucleotide-polymorphisms (SNPs) and four size-classes of copy-number-variations (CNVs) in the human genome has been performed. ResultsThe study has identified 44,379 hotspots with high genetic-variant densities, and 1,135 hotspot clusters comprising more than one type of hotspots, accounting for 3.1% and 0.2% of the genome respectively. The hotspots and clusters are found to co-localize with different functional genomic features, as exemplified by the associations of hotspots of middle-size CNVs with histone-modification sites, work with balancing and positive selections to meet the need for diversity in immune proteins, and facilitate the development of sensory-perception and neuroactive ligand-receptor interaction pathways in the function-sparse late-replicating genomic sequences. Genetic variants of different lengths co-localize with retrotransposons of different ages on a long-with-young and short-with-all basis. Hotspots and clusters are highly associated with tumour suppressor genes and oncogenes (p < 10-10), and enriched with somatic tumour CNVs and the trait- and disease-associated SNPs identified by genome-wise association studies, exceeding tenfold enrichment in clusters comprising SNPs and extra-long CNVs. ConclusionsIn conclusion, the genetic-variant hotspots and clusters represent two-edged swords that spearhead both positive and negative genomic changes. Their strong associations with complex traits and diseases also open up a potential Common Disease-Hotspot Variant approach to the missing heritability problem.

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Long, X., Xue, H.. 2020-10-16. Genetic-variant hotspots and hotspot clusters in the human genome facilitating adaptation while increasing instability. https://doi.org/10.1101/2020.10.16.342188

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