Pangenome alignment reveals global diversity and evolution of human centromeric regions
- 1University of California, Santa Cruz
Abstract
Centromeres play essential roles in chromosome segregation and genome stability, yet they remain among the least characterized regions of the human genome. Despite advances in long-read sequencing and complete genome assembly, the extreme repetitiveness and structural complexity of these regions still challenge population-scale analysis, obscuring their mutational dynamics. The Human Pangenome Reference Consortium has now accurately assembled over 6,000 centromeres, providing an opportunity to catalog global centromere variation. However, centromeric regions have been systematically excluded from pangenome alignments due to the technical challenge of aligning their highly repetitive tandem arrays and extreme structural variability. Here we introduce Centrolign, a graph-based multiple sequence alignment tool that combines a uniqueness-driven objective function with partial-order partial-order alignment to accurately align alpha satellite higher-order repeats. By prioritizing rare matches within tandem arrays and leveraging extended centromere-spanning haplotypes formed by suppressed recombination, Centrolign produces progressive multiple sequence alignments that preserve ancestral repeat organization. Applied across human centromeres, these alignments reveal the phylogenetic structure of similar satellite array haplotypes and enable precise estimation of variation rates, structural variant frequencies, and spatial patterns of mutation within satellite arrays. Integrating Centrolign graphs with repeat annotation tools and pangenome mapping algorithms allows accurate variant calling and genotyping from long reads without prior assembly. Moreover, we show that centromere haplotypes can be accurately subtyped with k-mers alone. Together, these advances establish a robust framework for incorporating centromeres into broader pangenomes, and population genomics in general, advancing our understanding of human genome evolution and diversity.
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BibTeX
@misc{eizenga2026pangenome,
title = {{Pangenome alignment reveals global diversity and evolution of human centromeric regions}},
author = {J. Eizenga and M. Mastoras and J. K. Lucas and J. Menendez and F. Okamoto and G. Hickey and P. Hebbar and S. A. Langley and H. Loucks and F. Ryabov and Y. Zybina and M. Asri and J. M. Franklin and N. Altemose and Human Pangenome Reference Consortium and I. A. Alexandrov and C. H. Langley and B. Paten and K. H. Miga},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.749043},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749043v1},
note = {Public domain},
}
RIS
TY - UNPB
TI - Pangenome alignment reveals global diversity and evolution of human centromeric regions
AU - J. Eizenga
AU - M. Mastoras
AU - J. K. Lucas
AU - J. Menendez
AU - F. Okamoto
AU - G. Hickey
AU - P. Hebbar
AU - S. A. Langley
AU - H. Loucks
AU - F. Ryabov
AU - Y. Zybina
AU - M. Asri
AU - J. M. Franklin
AU - N. Altemose
AU - Human Pangenome Reference Consortium
AU - I. A. Alexandrov
AU - C. H. Langley
AU - B. Paten
AU - K. H. Miga
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.749043
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.749043v1
AB - Centromeres play essential roles in chromosome segregation and genome stability, yet they remain among the least characterized regions of the human genome. Despite advances in long-read sequencing and complete genome assembly, the extreme repetitiveness and structural complexity of these regions still challenge population-scale analysis, obscuring their mutational dynamics. The Human Pangenome Reference Consortium has now accurately assembled over 6,000 centromeres, providing an opportunity to catalog global centromere variation. However, centromeric regions have been systematically excluded from pangenome alignments due to the technical challenge of aligning their highly repetitive tandem arrays and extreme structural variability. Here we introduce Centrolign, a graph-based multiple sequence alignment tool that combines a uniqueness-driven objective function with partial-order partial-order alignment to accurately align alpha satellite higher-order repeats. By prioritizing rare matches within tandem arrays and leveraging extended centromere-spanning haplotypes formed by suppressed recombination, Centrolign produces progressive multiple sequence alignments that preserve ancestral repeat organization. Applied across human centromeres, these alignments reveal the phylogenetic structure of similar satellite array haplotypes and enable precise estimation of variation rates, structural variant frequencies, and spatial patterns of mutation within satellite arrays. Integrating Centrolign graphs with repeat annotation tools and pangenome mapping algorithms allows accurate variant calling and genotyping from long reads without prior assembly. Moreover, we show that centromere haplotypes can be accurately subtyped with k-mers alone. Together, these advances establish a robust framework for incorporating centromeres into broader pangenomes, and population genomics in general, advancing our understanding of human genome evolution and diversity.
ER -