Beyond gene editing: the age of chromosome-scale genome engineering

Genome engineering is moving from local sequence modification to manipulation of megabase-scale regions and whole chromosomes. This shift reflects the growing recognition that many biological functions and disease states are shaped by chromosome-scale features, including gene dosage across multiple loci, long-range regulation, chromatin context, replication timing, competition for limiting epigenetic factors, and three-dimensional genome organization. Here, we review the toolkit for chromosome-scale manipulation in higher eukaryotes, focusing on chromosome transfer, targeted chromosome elimination, and their integration into chromosome transplantation workflows. We discuss how these approaches, together with advances in large DNA assembly, synthetic biology, and genome-wide validation, are making chromosome-scale genome engineering an increasingly tractable experimental framework for understanding, building, and repairing genomes, while outlining the analytical requirements and current technical barriers that limit routine implementation.