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Biobank-scale genotyping of Robertsonian translocations reveals hidden structural variation on the human acrocentric chromosomes

Rhie, A.; Kim, J.; Rodriguez-Algarra, F.; Solar, S.; Koren, S.; Antipov, D.; Wilczewski, C. M.; Maxwell, G. L.; Gerton, J.; Paschall, J.; Potapova, T.; Wolfsberg, T. G.; Singh, S.; del Castillo del Rio, S. O.; Human Pangenome Reference Consortium, ; Turner, C.; Rakyan, V. K.; Phillippy, A. M.

2026-03-10 genomics
10.64898/2026.03.08.710242 bioRxiv
Show abstract

Balanced Robertsonian translocation (ROB) is the most common chromosomal rearrangement, with an estimated occurrence of 1:800 in newborns. Carriers are at increased risk of cancer and often diagnosed after facing recurrent miscarriages, infertility, or aneuploid offspring. Genotyping carriers with DNA sequencing has been challenging due to incomplete sequences of the fusion site in the human reference. Only recently, the acrocentric short arms were successfully characterized, including the most common ROB fusion site. A ROB results in loss of two rDNA arrays and its adjacent distal sequences, including the highly conserved distal junction (DJ). Here, we present a novel method to type ROB carriers directly from short reads. Applying to cohorts of healthy newborns (n=4,172) and the UK Biobank (n=490,416), we find candidate ROBs at a consistent frequency (0.11-0.12%). We report uncharacterized structural variations of one DJ loss (2.8-3.4%) or gain (8.4-9.3%) found in near telomere-to-telomere genomes of the HPRC.

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