Fine-scale characterization of genomic structural variation in the human genome reveals adaptive and biomedically relevant hotspots

Genomic structural variants (SVs) are distributed nonrandomly across the human genome. These “hotspots” have been implicated in critical evolutionary innovations, as well as serious medical conditions. However, the evolutionary and biomedical features of these hotspots remain incompletely understood. In this study, we analyzed data from 2,504 genomes from the 1000 Genomes Project Consortium and constructed a refined map of 1,148 SV hotspots in human genomes. By studying the genomic architecture of these hotspots, we found that both nonallelic homologous recombination and non-homologous mechanisms act as mechanistic drivers of SV formation. We found that the majority of SV hotspots are within gene-poor regions and evolve under relaxed negative selection or neutrality. However, we found that a small subset of SV hotspots harbor genes that are enriched for anthropologically crucial functions, including blood oxygen transport, olfaction, synapse assembly, and antigen binding. We provide evidence that balancing selection may have maintained these SV hotspots, which include two independent hotspots on different chromosomes affecting alpha and beta hemoglobin gene clusters. Biomedically, we found that the SV hotspots coincide with breakpoints of clinically relevant, large de novo SVs, significantly more often than genome-wide expectations. As an example, we showed that the breakpoints of multiple large de novo SVs, which lead to idiopathic short stature, coincide with SV hotspots. As such, the mutational instability in SV hotpots likely enables chromosomal breaks that lead to pathogenic structural variation formations. Our study contributes to a better understanding of the mutational landscape of the genome and implicates both mechanistic and adaptive forces in the formation and maintenance of SV hotspots.