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

Sep 23, 2026

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Genome-wide distributions of Alu elements shape a wide range of structural variants (SVs) through Alu/Alu-mediated genomic rearrangement (AAMR). This study quantifies how often AAMR occurs in human genomes and how it contributes to pathogenic SVs. A disease-focused dataset compiles 407 published pathogenic AAMR-SV alleles across 115 Mendelian genes, compared with controls from 100 healthy individuals. Results show AAMR often forms sub-100 kb CNVs, including single-exon dropout and intragenic multi-exonic changes, with many predicted events validating as non-coding CNVs.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

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Abstract

Background

Methods

Results

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Duan etal. Genome Medicine (2026) 18:36 [https://doi.org/10.1186/s13073-026-01602-4](https://doi.org/10.1186/s13073-026-01602-4) Genome Medicine RESEARCH Open Access Widespread distribution of Alu/Alu-mediated genomic rearrangement predisposing to abroad range of Mendelian disease and cancer in human populations Ruizhi Vince Duan1,5*†, Haowei Du 1†, Shruti Pande 1, Ahmed K. Saad 1, Meryem M. Atik 1, Minal Jamsandekar1, Karen J. Coveler 1, Zain Dardas1, Shalini N. Jhangiani2, Jennifer E. Posey 1, Richard A. Gibbs2 and James R. Lupski 1,2,3,4* Abstract Background Genome-wide distributions ofAlu elements contribute to a broad range of structural variants (SVs) through Alu/Alu-mediated genomic rearrangement (AAMR) . Yet, the prevalence and characteristics ofAAMR 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. Keywords Alu element, Structural variant, Alu/Alu-mediated genomic rearrangement, Genome integrity, Genome instability, Mendelian disease †Ruizhi Vince Duan and Haowei Du contributed equally to this work. *Correspondence: Ruizhi Vince Duan [duanr@wustl.edu](duanr@wustl.edu)[ ](duanr@wustl.edu)James R. Lupski[jlupski@bcm.edu](jlupski@bcm.edu) 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 2Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA 3Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA 4Texas Children’s Hospital, Houston, TX, USA 5Present address: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-nc-nd/4.0/.) Duan et al. Genome Medicine

FAQs

What is the focus of the study on Alu/Alu-mediated rearrangements (AAMR)?

The study examines the genome-wide distribution of AAMR in humans and evaluates its prevalence and role in generating pathogenic structural variants.

How were the disease-focused and control datasets constructed?

The disease-focused dataset was built from literature, collecting 407 pathogenic AAMR-SV alleles across 115 known Mendelian genes. The control dataset was derived from short-read genome sequencing of 100 healthy individuals.

What CNV patterns are associated with AAMR and what do validations show?

AAMR favors CNVs under 100 kb, including single-exon dropout and intragenic multi-exonic copy number variation. Orthogonal validations indicate many predicted AAMR events contribute mostly to non-coding CNVs.

Sep 23, 2026

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