Widespread structural variations at human chromosome ends
- 1National University of Singapore
Abstract
The highly repetitive regions of the human genome were long underrepresented from reference assemblies, limiting study of their biological function. Long-read sequencing and improved assembly algorithms have since resolved many of these regions, from centromeres to ribosomal DNA arrays, revealing structural variation increasingly linked to human disease. However, the subtelomeres, the repeat-rich regions adjacent to the telomeres at each chromosome end, have remained poorly characterized. Here we present a collection of complete subtelomeric sequences spanning all non-acrocentric chromosome arms, derived from 860 haploid assemblies across six ancestry groups. We find that while subtelomeres are mosaics of blocks shared between chromosome arms, individual arms diverge extensively, such that most non-acrocentric autosomal arms (54%, 21 of 39) carry multiple haplotypes differing by up to 100-200 kb. These blocks are broadly conserved across the great apes. In humans, their diversity is associated with chromosome arm rather than ancestry, suggesting that cross-arm paralogy block duplications predate human population divergence, although some haplotypes show ancestry-specific enrichment. Remarkably, these divergent haplotypes differ in gene content, driving gene copy-number variation between individuals among olfactory receptors and other genes. This study also revealed rare subtelomeric recombination. We further show that our subtelomere data set enables the accurate measurement of telomere length at individual chromosome ends from long-read data. Together, these assemblies reveal an unappreciated scale of variation at human chromosome ends and provide a resource for studying the roles of this variation in disease, telomere biology and genome evolution across diverse populations.
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BibTeX
@misc{tan2026widespread,
title = {{Widespread structural variations at human chromosome ends}},
author = {K.-T. Tan and R. J. X. Ong and B. B. R. Kee and R. K. H. Yap and A. J. T. Ng and G. K. Rajapaksha and M. Garrity-Janger and Q. Lin and J. R. Chong and C. T. Kyi and Human Pangenome Reference Consortium and M. Meyerson and H. Li},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.748401},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.748401v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Widespread structural variations at human chromosome ends
AU - K.-T. Tan
AU - R. J. X. Ong
AU - B. B. R. Kee
AU - R. K. H. Yap
AU - A. J. T. Ng
AU - G. K. Rajapaksha
AU - M. Garrity-Janger
AU - Q. Lin
AU - J. R. Chong
AU - C. T. Kyi
AU - Human Pangenome Reference Consortium
AU - M. Meyerson
AU - H. Li
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.748401
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.748401v1
AB - The highly repetitive regions of the human genome were long underrepresented from reference assemblies, limiting study of their biological function. Long-read sequencing and improved assembly algorithms have since resolved many of these regions, from centromeres to ribosomal DNA arrays, revealing structural variation increasingly linked to human disease. However, the subtelomeres, the repeat-rich regions adjacent to the telomeres at each chromosome end, have remained poorly characterized. Here we present a collection of complete subtelomeric sequences spanning all non-acrocentric chromosome arms, derived from 860 haploid assemblies across six ancestry groups. We find that while subtelomeres are mosaics of blocks shared between chromosome arms, individual arms diverge extensively, such that most non-acrocentric autosomal arms (54%, 21 of 39) carry multiple haplotypes differing by up to 100-200 kb. These blocks are broadly conserved across the great apes. In humans, their diversity is associated with chromosome arm rather than ancestry, suggesting that cross-arm paralogy block duplications predate human population divergence, although some haplotypes show ancestry-specific enrichment. Remarkably, these divergent haplotypes differ in gene content, driving gene copy-number variation between individuals among olfactory receptors and other genes. This study also revealed rare subtelomeric recombination. We further show that our subtelomere data set enables the accurate measurement of telomere length at individual chromosome ends from long-read data. Together, these assemblies reveal an unappreciated scale of variation at human chromosome ends and provide a resource for studying the roles of this variation in disease, telomere biology and genome evolution across diverse populations.
ER -