Mouse_Collateral_Damage

Following screening of new mouse mutants through the Mouse Genetics Project, we have found four lines with hearing impairment that seems to be unlinked to the targeted mutation. We do not know the nature of the mutations, but ES cells are known to be liable to have chromosomal damage. We wish to identify the mutations causing the deafness and would like to use array CGH to look for copy number variations, and also whole exome resequencing to look for point mutations. For one of the lines, we were able to isolate affected mice to establish a breeding colony and set up a backcross for linkage analysis, so we should be able to map the location to a broad chromosomal region over the coming months. However, for the remaining three lines,the affected individuals were either part of the MGP screen and so were culled two weeks after the hearing screen, or were detected in an aging study long after the animals were useful for breeding. For these three lines, the pedigree is consistent with autosomal recessive inheritance and we expect the mutant allele to be recoverable from current breeding stock if we can identify the mutation using archive DNA from the affected mice and screen current breeding-age mice for carrier status. Identifying the nature of the mutations in these four lines will give important information about the sort of collateral damage that might be expected in mice derived from ES cells, and so might be useful in indicating tailored screening for quality control before using the cells for generating mice. It will also identify four new mutations, and potentially four new genes, involved in deafness. We have been successful in identifying a separate mutation causing hearing impairment by whole exome resequencing, and we have experience in analysing mouse CGH, so we are well-placed to exploit the new data requested. The new mutations are all on a C57BL/6 genetic background so should be relatively straightforward to isolate.