Widespread distribution of Alu/Alu-mediated genomic rearrangement predisposing to a broad range of Mendelian disease and cancer in human populations

Background: Genome-wide distributions of Alu elements contribute to a broad range of structural variants (SVs) through Alu/Alu-mediated genomic rearrangement (AAMR). Yet, the prevalence and characteristics of AAMR on the human genome and its scale in generating pathogenic SVs remain poorly understood. Methods: We established a disease-focused, AAMR-SV dataset and a control dataset to comprehensively delineate the genomic landscape of Alu mutagenesis. The disease-focused dataset included 407 published pathogenic AAMR-SV alleles in 115 known genes for Mendelian disorders or traits through a literature survey. A control dataset was collected from short-read genome sequencing analyses of 100 randomly selected, healthy individuals. Results: AAMR favors the formation of copy number variant (CNV) less than 100 kb, including single-exon dropout and intragenic multi-exonic copy number variation. Genome-wide deletion length distribution from analyses of 526,806 deletion calls from 100 genomes reveals a high prevalence of AAMR in healthy individuals. Orthogonal experimental validations of these predicted AAMR events indicated their contributions mostly to non-coding CNVs. Conclusions: Our study provides a comprehensive survey of Alu-related SV mutagenesis across global populations, analyzing their roles in reported pathogenic events and their prevalence among healthy individuals. It further documents AAMR-SVs responsible for a broad spectrum of Mendelian diseases and cancers.