The impact of copy number variation on local gene expression in mouse hematopoietic stem and progenitor cells

Abstract

Timothy Graubert and colleagues report a high-resolution survey of copy number variation in mouse inbred strains and assess the impact of such variation on gene expression. They find that up to 26% of strain-dependent expression variation in hematopoietic stem/progenitor cells is associated with copy number variation. The extent to which differences in germline DNA copy number contribute to natural phenotypic variation is unknown. We analyzed the copy number content of the mouse genome to sub–10-kb resolution. We identified over 1,300 copy number variant regions (CNVRs), most of which are <10 kb in length, are found in more than one strain, and, in total, span 3.2% (85 Mb) of the genome. To assess the potential functional impact of copy number variation, we mapped expression profiles of purified hematopoietic stem and progenitor cells, adipose tissue and hypothalamus to CNVRs in cis. Of the more than 600 significant associations between CNVRs and expression profiles, most map to CNVRs outside of the transcribed regions of genes. In hematopoietic stem and progenitor cells, up to 28% of strain-dependent expression variation is associated with copy number variation, supporting the role of germline CNVs as key contributors to natural phenotypic variation in the laboratory mouse.