A genome-wide study reveals an association between CNVs and gene activity in haematopoietic stem cells
Geneticists recently began to appreciate how much individuals vary in their numbers of copies of certain long DNA sequences. However, little is known about how these copy number variations translate into physical traits. A group led by Timothy Graubert at Washington University in St. Louis, Missouri, now reveals that copy number variation polymorphism could account for close to 30% of variability in gene expression in mouse haematopoietic stem cells1.
Hoping to uncover genetic reasons that make some people more susceptible to leukaemia, Graubert's team investigated several classes of genetic variants, including copy number variants (CNVs), in haematopoietic stem cells. Using a technique called comparative genomic hybridization, they created a genome-wide map of CNVs of unprecedented resolution for 20 inbred mouse strains, identifying and characterizing CNVs even smaller than 5kb. They subjected these genotypes to expression quantitative trait locus mapping, a procedure that allowed them to associate differences in gene expression with CNVs in diverse tissues. They found that in blood stem cells, 28% of gene expression differences were statistically associated with CNVs.
Perhaps most surprisingly, 92% of the 672 differentially expressed genes associated to a CNV were not located within the identified CNV. “We expected most differences to be due to gene dosage effects, but it was the opposite,” explains Graubert. In other words, most expression differences cannot be explained by simple variation in copy numbers. Instead CNVs likely affect gene expression indirectly, via local modifications of chromatin structure or alterations in neighbouring sequences that might bind transcriptional regulators.
Graubert cautions that effects should be confirmed. “These are associations; by no means did we prove causality.” Still, he doubts that the findings apply only to haematopoietic stem cells. “I would be surprised if stem cell lines did not show gene expression differences associated with CNVs as well.” This could apply both to CNVs present in the original embryos or tissue samples as well as those that stem cells can acquire in culture.
Michael Teitell, who investigates CNVs in stem cell lines at University of California, Los Angeles, agrees. In fact, he says, much of the reported variation in cell lines' differentiation capacity might eventually be linked to CNVs. Graubert's study, he stresses, demonstrates that even relatively small CNVs could have effects that should not be overlooked. “These small CNVs escape detection with lower-resolution methodologies, and this study reinforces the need to use higher-resolution methods for CNV detection.”
The next step, as Graubert writes in his paper, is to “reach beyond” statistics and learn how CNVs affect gene expression. “We now need to prioritize specific candidates, confirm our findings by independent means and investigate the underlying mechanisms.” Teitell agrees that Graubert's study is just a beginning: “Like most interesting work, it generates many more important questions than it addresses.”
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References
Cahan, P. et al. The impact of copy number variation on local gene expression in mouse hematopoietic stem and progenitor cells. Nature Genet. advance online publication, 10.1038/ng.350 (8 March 2009).
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Coll, M. Noncoding DNA copy number variation links to gene expression in stem cells. Nat Rep Stem Cells (2009). https://doi.org/10.1038/stemcells.2009.49
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DOI: https://doi.org/10.1038/stemcells.2009.49