Inferring ecDNA Evolution from Allele Frequency Spectra
- 1University of California, San Diego
Abstract
Extrachromosomal DNA (ecDNA) can arise early in the development of aggressive tumors or later upon progression, but the impact of chronology on patient outcome is not known. Currently, it is not possible to determine when an ecDNA arose in the course of tumor development and progression, based on genome sequencing data. Here, we develop an analytic method, ecEvol, to infer ecDNA emergence time, selection strength, mutation rate, and clonal dominance from allele frequency spectra in bulk whole-genome sequencing. EcEvol outperforms other methods and predicts parameters with high accuracy across a wide range of parameter values. Applying ecEvol to primary, treatment-naive tumors, we find that ecDNA typically emerges early and undergoes strong positive selection, albeit with substantial variation across cancer types. EcDNAs carrying known oncogenes emerge earlier and reach greater clonal dominance than ecDNAs lacking known oncogenes. In advanced and predominantly treated tumors, ecDNA emerges substantially later than in matched primary tumors, consistent with the generation and selection of new ecDNA during tumor progression and therapy. Longitudinal samples further support continued expansion of ecDNA-bearing lineages. Finally, earlier ecDNA emergence is associated with poorer overall survival. These results provide insight into the chronology of ecDNA formation from a single tumor biopsy taken at any point during the course of the disease, revealing that allele-frequency spectra encode the evolutionary history of ecDNA and provide a quantitative framework for reconstructing its emergence and expansion.
Related
- Inferring the age of a fixed beneficial allele.
- PoLoCo: A reproducible pooled low-coverage workflow for draft genome assembly and allele frequency analysis from ethanol-preserved small non-model invertebrates
- LoGicAl: local ancestry and genotype calling uncertainty-aware ancestry-specific allele frequency estimation from admixed samples
- How deterministic trajectories and their fluctuations underlie allele-frequency statistics in the strong-selection regime
- A rank-conditioned α-stable perturbation for differential evolution: Separating perturbation frequency and tail heaviness
BibTeX
@misc{dameracharla2026inferring,
title = {{Inferring ecDNA Evolution from Allele Frequency Spectra}},
author = {B. Dameracharla and G. Prasad and J. Luebeck and S. Amin and J. Kirkland and O. S. Chapman and L. Chavez and R. Verhaak and W. Huang and P. S. Mischel and B. Werner and V. Bafna},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.09.758054},
url = {https://www.biorxiv.org/content/10.64898/2026.10.09.758054v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Inferring ecDNA Evolution from Allele Frequency Spectra
AU - B. Dameracharla
AU - G. Prasad
AU - J. Luebeck
AU - S. Amin
AU - J. Kirkland
AU - O. S. Chapman
AU - L. Chavez
AU - R. Verhaak
AU - W. Huang
AU - P. S. Mischel
AU - B. Werner
AU - V. Bafna
PY - 2026
DA - 2026/10/09
PB - bioRxiv
DO - 10.64898/2026.10.09.758054
UR - https://www.biorxiv.org/content/10.64898/2026.10.09.758054v1
AB - Extrachromosomal DNA (ecDNA) can arise early in the development of aggressive tumors or later upon progression, but the impact of chronology on patient outcome is not known. Currently, it is not possible to determine when an ecDNA arose in the course of tumor development and progression, based on genome sequencing data. Here, we develop an analytic method, ecEvol, to infer ecDNA emergence time, selection strength, mutation rate, and clonal dominance from allele frequency spectra in bulk whole-genome sequencing. EcEvol outperforms other methods and predicts parameters with high accuracy across a wide range of parameter values. Applying ecEvol to primary, treatment-naive tumors, we find that ecDNA typically emerges early and undergoes strong positive selection, albeit with substantial variation across cancer types. EcDNAs carrying known oncogenes emerge earlier and reach greater clonal dominance than ecDNAs lacking known oncogenes. In advanced and predominantly treated tumors, ecDNA emerges substantially later than in matched primary tumors, consistent with the generation and selection of new ecDNA during tumor progression and therapy. Longitudinal samples further support continued expansion of ecDNA-bearing lineages. Finally, earlier ecDNA emergence is associated with poorer overall survival. These results provide insight into the chronology of ecDNA formation from a single tumor biopsy taken at any point during the course of the disease, revealing that allele-frequency spectra encode the evolutionary history of ecDNA and provide a quantitative framework for reconstructing its emergence and expansion.
ER -