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Background <p>Genome-wide distributions of <i>Alu</i> elements contribute to a broad range of structural variants (SVs) through <i>Alu/Alu</i>-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.</p> Methods <p>We established a disease-focused, AAMR-SV dataset and a control dataset to comprehensively delineate the genomic landscape of <i>Alu</i> 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.</p> Results <p>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.</p> Conclusions <p>Our study provides a comprehensive survey of <i>Alu</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月1日

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  • Ruizhi Vince Duan,
  • Haowei Du,
  • Shruti Pande,
  • Ahmed K. Saad,
  • Meryem M. Atik,
  • Minal Jamsandekar,
  • Karen J. Coveler,
  • Zain Dardas,
  • Shalini N. Jhangiani,
  • Jennifer E. Posey,
  • Richard A. Gibbs,
  • James R. Lupski

摘要

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.