Model for CFS and CNV formation at active large transcription units. (A) Replication fork failures, even double-fork failures, occurring in most genomic loci can be rescued by the firing of late “dormant” origins. (B) The Transcription-dependent Double-Fork Failure (TrDoFF) model for extreme locus instability under replication stress proposes two mutagenic properties of active large TUs: (1) that they promote simultaneous failure of two converging forks, e.g., through the formation of R-loops; and (2) that they create large late-replicating domains where pre-RC eviction by prolonged transcription into S-phase prevents late origin firing. CFS breaks and deletion CNVs arise in the resulting unreplicated DNA, within the span of the TU, while duplications arise on the flanks, likely by template switching (red arrows).