Different species, populations and individuals vary considerably in the copy number of discrete segments of their genomes. The manner and frequency with which these genetic differences arise over generational time is not well understood. Taking advantage of divergence among lineages sharing a recent common ancestry, we have conducted a genome-wide analysis of spontaneous copy number variation (CNV) in the laboratory mouse. We used high-resolution microarrays to identify 38 CNVs among 14 colonies of the C57BL/6 strain spanning ∼967 generations of inbreeding, and we examined these loci in 12 additional strains. It is clear from our results that many CNVs arise through a highly nonrandom process: 18 of 38 were the product of recurrent mutation, and rates of change varied roughly four orders of magnitude across different loci. Recurrent CNVs are found throughout the genome, affect 43 genes and fluctuate in copy number over mere hundreds of generations, observations that raise questions about their contribution to natural variation.
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We thank J.C. Mell, L. Stein, B. Stillman and J.D. Watson for comments on the manuscript; L. Bianco for technical assistance; C. Ward for the B6N substrain and for advice; H. Hedrich and M. Dorsch for supplying the B6HanZtm substrain; A. Lerro for the B6Icr substrain; all strain suppliers for crucial genealogical details; N. Navin, V. Grubor, B. Lakshmi, A. Leotta and J. Kendall for computational contributions; and X. She and E.E. Eichler for sharing unpublished data. This work was supported by grants to I.M.H. from the Cold Spring Harbor President's Council and the Burroughs Wellcome Fund and to M.W. from The Simons Foundation. M.W. is an American Cancer Society Research Professor.
Supplementary Note, Supplementary Methods, Supplementary Figures 1–5, Supplementary Table 1 (PDF 22008 kb)
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