Widespread Distribution of Alu/Alu-Mediated Genomic Rearrangement Predisposing to a Broad Range of Mendelian Disease and Cancer in Human Populations

Authors

• 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

Language

English

Publication Date

4-1-2026

Journal

Genome Medicine

DOI

10.1186/s13073-026-01602-4

PMID

41923117

PMCID

PMC13041450

PubMedCentral® Posted Date

4-1-2026

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Humans, Alu Elements, Neoplasms, DNA Copy Number Variations, Genome, Human, Genetic Predisposition to Disease, Gene Rearrangement, Genetic Diseases, Inborn, Alu element, Structural variant, Alu/Alu-mediated genomic rearrangement, Genome integrity, Genome instability, Mendelian disease

Published Open-Access

yes

Recommended Citation

Duan, Ruizhi Vince; Du, Haowei; Pande, Shruti; et al., "Widespread Distribution of Alu/Alu-Mediated Genomic Rearrangement Predisposing to a Broad Range of Mendelian Disease and Cancer in Human Populations" (2026). Faculty, Staff and Students Publications. 7128.
https://digitalcommons.library.tmc.edu/baylor_docs/7128