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

Human Genomics

Xi Long¹  Hong Xue² 

[1] Division of Life Science and Applied Genomics Centre, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China;HKUST Shenzhen Research Institute, 9 Yuexing First Road, Nanshan, Shenzhen, China;Division of Life Science and Applied Genomics Centre, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China;HKUST Shenzhen Research Institute, 9 Yuexing First Road, Nanshan, Shenzhen, China;Centre for Cancer Genomics, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China;

关键词: Frequency independent;    Genetic diversity;    Missing heritability;    Retrotransposon;    Recombination-selection co-saturation;    Replication timing;   

DOI  :  10.1186/s40246-021-00318-3

来源: Springer

【 摘 要 】

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 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.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.

【 授权许可】

CC BY