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

BACKGROUND: Genetic 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. METHODS: Herein, 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. RESULTS: The study has identified 44,379 hotspots with high genetic-variant densities, and 1135 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 tumor suppressor genes and oncogenes (p < 10(−10)), and enriched with somatic tumor 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. CONCLUSIONS: In 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40246-021-00318-3.