Large transcription units unify copy number variants and common fragile sites arising under replication stress.
Copy number variants (CNVs) resulting from genomic deletions and duplications and common fragile sites (CFSs) seen as breaks on metaphase chromosomes are distinct forms of structural chromosome instability precipitated by replication inhibition. Although they share a common induction mechanism, it is not known how CNVs and CFSs are related or why some genomic loci are much more prone to their occurrence. Here we compare large sets of de novo CNVs and CFSs in several experimental cell systems to each other and to overlapping genomic features. We first show that CNV hotpots and CFSs occurred at the same human loci within a given cultured cell line. Bru-seq nascent RNA sequencing further demonstrated that although genomic regions with low CNV frequencies were enriched in transcribed genes, the CNV hotpots that matched CFSs specifically corresponded to the largest active transcription units in both human and mouse cells. Consistently, active transcription units >1 Mb were robust cell-type-specific predictors of induced CNV hotspots and CFS loci. Unlike most transcribed genes, these very large transcription units replicated late and organized deletion and duplication CNVs into their transcribed and flanking regions, respectively, supporting a role for transcription in replication-dependent lesion formation. These results indicate that active large transcription units drive extreme locus- and cell-type-specific genomic instability under replication stress, resulting in both CNVs and CFSs as different manifestations of perturbed replication dynamics.
Department of Pathology, Department of Human Genetics, wilsonte@umich.edu.
Thomas E
http://orcid.org/0000-0002-8345-4985
TE
Wilson
Department of Human Genetics.
Martin F
http://orcid.org/0000-0002-4716-8295
MF
Arlt
Department of Human Genetics.
So Hae
SH
Park
Department of Human Genetics.
Sountharia
S
Rajendran
Department of Radiation Oncology and Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 48109, USA.
Michelle
M
Paulsen
Department of Radiation Oncology and Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 48109, USA.
Mats
M
Ljungman
Department of Pathology, Department of Human Genetics.
Thomas W
TW
Glover
D000818:Animals; D002460:Cell Line; D019457:Chromosome Breakage; D043283:Chromosome Fragile Sites; D002874:Chromosome Mapping; D056915:DNA Copy Number Variations; D004261:DNA Replication; D056426:Genetic Loci; D042822:Genomic Instability; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D009928:Organ Specificity; D015203:Reproducibility of Results; D014158:Transcription, Genetic