Although extensive genome-wide association studies (GWAS) have been conducted, only a small proportion of the genetic components of complex diseases and traits have been elucidated. This missing heritability suggests the need for a more comprehensive understanding of the genetic variants. Herein, a sliding-window scan of the human genome was conducted for regional densities of germline genetic variants, including single-nucleotide-polymorphisms (SNPs) and four size-classes of copy-number-variations (CNVs). The study has identified 45,513 hotspots containing high genetic-variant densities, and 1,246 hotspot clusters comprising more than one type of hotspots, accounting for 3.1% and 0.21% of the genome respectively. They co-localize idiosyncratically with different functional geno...[ Read more ]

Although extensive genome-wide association studies (GWAS) have been conducted, only a small proportion of the genetic components of complex diseases and traits have been elucidated. This missing heritability suggests the need for a more comprehensive understanding of the genetic variants. Herein, a sliding-window scan of the human genome was conducted for regional densities of germline genetic variants, including single-nucleotide-polymorphisms (SNPs) and four size-classes of copy-number-variations (CNVs). The study has identified 45,513 hotspots containing high genetic-variant densities, and 1,246 hotspot clusters comprising more than one type of hotspots, accounting for 3.1% and 0.21% of the genome respectively. They co-localize idiosyncratically with different functional genomic features, as exemplified by the prominent associations of hotspots of small-to-middle size CNVs with histone-modification sites. Hotspots are found to work in conjunction with positive selection to fulfil the requisite diversity in immune proteins. They also accommodate the development of fast evolving pathways such as the sensory-perception and neuroactive ligand-receptor interaction pathways in the function-sparse late-replicating genomic sequences. Genetic variants of different lengths are found co-localized with retrotransposons of different ages on a ‘long-with-young’ and ‘short-with-all’ basis. The densities of tumor CNVs and GWAS-identified SNPs are both increased to 29-fold in hotspots of extra-long CNVs and clusters comprising SNPs and extra-long CNVs respectively. In conclusion, the genetic-variant hotspots and clusters represent two-edged swords that spearhead both positive and negative genomic changes, which result in their strong associations with complex traits and diseases, thereby enabling a potential ‘Common Disease-Hotspot Variant’ approach to the missing heritability problem.