Abstract
Submicroscopic (less than 2 Mb) segmental DNA copy number changes are a recently recognized source of genetic variability between individuals. The biological consequences of copy number variants (CNVs) are largely undefined. In some cases, CNVs that cause gene dosage effects have been implicated in phenotypic variation. CNVs have been detected in diverse species, including mice and humans. Published studies in mice have been limited by resolution and strain selection. We chose to study 21 well-characterized inbred mouse strains that are the focus of an international effort to measure, catalog, and disseminate phenotype data. We performed comparative genomic hybridization using long oligomer arrays to characterize CNVs in these strains. This technique increased the resolution of CNV detection by more than an order of magnitude over previous methodologies. The CNVs range in size from 21 to 2,002 kb. Clustering strains by CNV profile recapitulates aspects of the known ancestry of these strains. Most of the CNVs (77.5%) contain annotated genes, and many (47.5%) colocalize with previously mapped segmental duplications in the mouse genome. We demonstrate that this technique can identify copy number differences associated with known polymorphic traits. The phenotype of previously uncharacterized strains can be predicted based on their copy number at these loci. Annotation of CNVs in the mouse genome combined with sequence-based analysis provides an important resource that will help define the genetic basis of complex traits.
Highlights
Inbred mice are the model organisms of choice for studying the genetic basis of complex traits such as diabetes, heart disease, and cancer
The recent application of microarray technology to detect genetic variation in humans has led to the realization that copy number variant (CNV) are common
Rough estimates indicate that CNVs and small-scale variants may constitute similar proportions of total genomic DNA
Summary
Inbred mice are the model organisms of choice for studying the genetic basis of complex traits such as diabetes, heart disease, and cancer. Sequence-based studies have begun to define the genetic differences that exist between these strains at the nucleotide level. Variation in segmental DNA copy number has emerged as an additional dimension of genetic diversity that exists in the germline of rodents and primates. More than 3,800 human CNVs have been identified and cataloged (http://projects.tcag.ca/variation). These CNVs extend the spectrum of genetic changes that contribute to phenotypic differences in mammalian species. The CNV profiles of these strains recapitulate aspects of their known ancestry This high-resolution map of mouse CNVs in diverse strains will facilitate ongoing efforts to map phenotypes to genes
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