Copy Number Changes of CNV Regions in Intersubspecific Crosses of the House Mouse

Copy number variation (CNV) contributes significantly to natural genetic variation within and between populations. However, the mutational mechanisms leading to CNV, as well as the processes that control the size of CNV regions, are so far not well understood. Here, we have analyzed a gene family that forms CNV regions on the X and the Y chromosomes in Mus musculus. These CNV regions show copy number differences in two subspecies, M. musculus domesticus and M. musculus musculus. Assessment of copy numbers at these loci for individuals caught in a natural hybrid zone showed copy number increases and a large variance among individuals. Crosses of natural hybrid animals among each other produced even more extreme variants with major differences in copy number in the offspring from the same parents. To assess the inheritance pattern of the loci further, we have produced F1 and backcross hybrid animals from these subspecies. We found that copy number expansions can already be traced in F1 offspring and they became stronger in the backcross individuals. Specific analysis of hybrid male offspring indicated that neither meiotic recombination nor interchromosomal exchange was required for creating these changes because the X and Y chromosomes have no homologues in males. This suggests that intrachromosomal exchanges can drive CNV and that this can occur at an elevated frequency in interspecific crosses, even within an individual. Accordingly, we find copy number mosaicism in individuals, that is, DNA from different tissues of the same individual can have different copy numbers for the loci studied. A preliminary survey of autosomal loci suggests that these can also be subject to change in hybrids. Hence, we conclude that the effects we see are not only restricted to some specific loci but may also be caused by a general induction of replication-coupled repair processes.