Advances in modeling chromosomal aberrations to recapitulate genomic rearrangements.

Abstract

Chromosomal aberrations, including aneuploidies and structural rearrangements, are key drivers of cancer and numerous genetic disorders. Experimental modeling of these alterations is essential for understanding their role in disease initiation and progression. Historically, chromosome engineering relied on methods that lacked precision and could generate off-target genomic damage. Recent advances in genome editing have enabled the precise generation of defined chromosomal abnormalities in human cells. This review summarizes current approaches for modeling numerical and structural chromosomal aberrations, including CRISPR-based chromosome elimination, KaryoCreate, prime editing, programmable recombinases, and RNA-guided bridge recombinases. We also discuss strategies for generating complex chromosomal rearrangements, their applications in studying genome instability, and their limitations. Together, these technologies provide powerful tools to investigate the earliest genomic events underlying cancer and genetic diseases.