Unravelling ring chromosome structures and formation mechanisms by short-read and long-read genomic sequencing

作者：Mei Ling Chong, Bruna Burssed, Chen Zhao, Jiadi Wen, Evelyn Ng, B Szewczyk, Guilin Wang, Khi Pin Chua, Thomas Liehr, Ying Zou, Jaclyn B. Murry, Frenny Sheth, Peining Li, Maria Isabel Melaragno · 发表于：Genetics in Medicine Open · 年份：2025 · DOI：10.1016/j.gimo.2025.103475 · 被引用次数：1 · 研究领域：Genomic variations and chromosomal abnormalities、Telomeres, Telomerase, and Senescence、Chromosomal and Genetic Variations

Purpose: Ring chromosomes (RCs) are rare cytogenetic abnormalities involving copy-number variants and chromosome instability. Identifying the breakage-fusion sequences of RCs at nucleotide-level resolution can elucidate the cytogenomic rearrangements and ring formation mechanisms. Methods: This study used short-read genomic sequencing (srGS) and long-read genomic sequencing (lrGS) alongside the telomere-to-telomere reference genome to characterize the breakage-fusion events of 17 RC cases. Results: Complete RCs without loss of euchromatin by a fusion of subtelomeric or telomeric regions were noted in a RC14 and a RC20. Incomplete RCs with intrachromosomal copy-number variants were noted in 15 cases, including a RC3, a RC4, 4 RC13s, a RC14, 3 RC18s, a RC21, 3 RC22s, and an RCY. srGS defined breakage-fusion sequences in single-copy sequences, and lrGS mapped subtelomeric and pericentric repetitive sequences using the telomere-to-telomere reference genome. The breakage-fusion sequences revealed ring formation mechanisms by intrastrand nonhomology end joining in 5 RCs, microhomology-mediated end joining in 8 RCs, and microhomology-mediated break-induced replication in 4 RCs. Conclusion: This study demonstrated the analytic validity and diagnostic utility of srGS and lrGS in delineating the genomic rearrangements in RCs for better interpreting clinico-cytogenomic correlations and further analysis of RC behavior in cell cycles.