Copy number variation (CNV) refers to genomic deletions or duplications of tens of thousands to millions of nucleotides. CNV is both a normal feature of genetic variation and a major contributor to genetic disease, e.g., neurological disease and cancer. The mechanisms by which CNVs arise and the cellular pathways that suppress CNV formation are largely unknown. We are currently collaborating with the Glover and Wilson groups in the Department of Human Genetics at the University of Michigan. Our collaborators have established that agents that perturb normal replication and create conditions of replication stress, e.g., aphidicolin, are potent inducers of nonrecurrent CNVs in cultured human cells (Arlt et al., 2009; Arlt et al., 2012; Wilson et al., 2015) . The Glover and Wilson labs have also established that active large transcription units (<1 Mb) drive extreme locus- and cell-type-specific genomic instability under replication stress resulting in CNV formation (Wilson et al., 2015) . We have compared the genome-wide distributions of replication stress-induced CNV hotspots to FANCD2 ChIP-seq peak regions and have established that there is considerable overlap. Furthermore, in preliminary experiments using both aCGH and SNP arrays, we have determined that the FANCA and FANCD2 proteins may play an important role in the suppression of de novo CNV. We are currently awaiting results of additional RNA-seq and ChIP-seq experiments with hTERT-immortalized mutant and complemented FA-D2 patient cells to select specific actively transcribed large transcription units for CNV analysis using customized genotyping arrays.