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

Abstract

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 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. 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.

Copy number variation profile-based genomic subtyping of premenstrual dysphoric disorder in Chinese

“…in the prevention of PMDD occurrence. As well, more D-favoring CNVG features were located in G2-replicating sequences compared to genomic DNA sequences replicating in other cell-cycle phases within the D>C and D>V groups, which was particularly notable in view of the enrichment of G2 phase-replicating sequences in non-coding sequences (27, 29). In addition, the abundance of V-favoring 50-kb CNVL features in the V>C and V>D comparisons (Figure 4B and D) suggests that small-size CNVLs also played important roles in the development of V-type PMDD.…”

“…The genomics features apparently differed between D and V types included: (1) In terms of retrotransposons, D-favoring CNVG features enriched with more of the subfamily of evolutionarily very young short transposons SVAef, while V-favoring CNVG and D-favoring CNVL features enriched with the very young long transposon subfamily, L1vy. (2) With respect to genetic markers, P-favoring, especially D-favoring CNVL features were enriched with recombination events as well as genetic variation hotspots and clusters (27). GWAS reported markers were co-localized with D-favoring CNVGs in S1, V-favoring CNVLs in S4 and C-favoring CNVLs G1b.…”

“…When diagnostic CNVs were analyzed for their genomic feature enrichment with reference to replication phases, interesting observations were obtained (Figure 6; Table 3). It has been revealed that the late-replicating S4-G2 phases in the gene-distal zones are found to be depleted of functional genomic features (27). However, the present study observed associations of open chromatin signals, regulatory elements and epigenetic regulation sites with the diagnostic CNV features in these late-replicating sequences (Table 3), indicating that the diagnostic CNV features might represent pivotal genomic sites in the late-replicating sequences that sequence alterations may give raise to functional perturbations underlying PMDD and its two subtypes.…”

“…DNA sequences on 22 autosomes and chromosome X were subject to replication-time segmentation according to Long & Xue (27). Briefly speaking, experiment-assessed replication timing of all 1-kb sequence windows in the genomes of fifteen human cell lines were retrieved from the ‘UW Repli-seq track’ in the UCSC Table Browser (28), and the representative replication phase of each sequence window was identified as one of the six types of sequencing segments (viz.…”