Cell-cycle dependent DNA repair and replication unifies patterns of chromosome instability

Area of Science:

• Genomics
• Computational Biology
• Cancer Research

Background:

• Chromosomal instability (CIN) is a hallmark of human tumors, causing structural and numerical aberrations.
• Somatic structural variants (SVs) are linked to copy number alterations but are often studied separately.
• Quantitative models for SV generation are lacking.

Purpose of the Study:

• To develop a computational cell-cycle model for SV generation.
• To quantitatively link mechanisms like breakage-fusion-bridge cycles and chromothripsis to SV patterns.
• To infer SV generation parameters from whole-genome sequencing data.

Main Methods:

• Developed a computational cell-cycle model for SVs originating from double-strand breaks.
• Integrated end-joining repair and replication processes into the model.
• Employed Bayesian inference for parameter estimation using whole-genome sequencing data.

Main Results:

• The model quantitatively describes the relationship between breakage-fusion-bridge cycles, chromothripsis, seismic amplification, and extrachromosomal circular DNA.
• It provides a unified framework for disparate genomic patterns arising from CIN.
• The model serves as a null mutational model for SVs.

Conclusions:

• This quantitative framework offers deeper insights into genome rearrangement and tumor evolution.
• It unifies previously disparate observations of CIN-driven genomic alterations.
• The model facilitates a more comprehensive understanding of SV generation in cancer.