MEC pilot exome data
Functional Genomics in Mice by Exome Sequencing
Exome sequencing of 15 mouse mutants (ENU induced and spontaneous) and 4 inbred strains.
The mapping of mutations underlying monogenic phenotypes in the laboratory mouse has proven to be an extraordinarily powerful paradigm, yielding functional insights into thousands of genes, as well as mouse strains that are highly effective for modeling human disease.  Although massively parallel sequencing extraordinary potential to accelerate the gene discovery process in mice, the complete sequencing of mouse genomes remains burdensome and expensive for many laboratories. Targeted sequencing of genetically concordant intervals represents a more cost-effective approach, but requires substantial genetic mapping and custom capture reagents. In contrast, targeted sequencing of the “exome”, i.e. all coding sequences, potentially allows for the comprehensive, cost-effective identification of protein-altering mutations in mouse mutants with minimal mapping data and utilizing a standardized protocol. To this end, we developed reagents for in solution, hybridization based capture of the mouse exome, comprising 54 Mb of annotated coding sequence (C57BL/6J, NCBI37/mm9).  We describe the application of these reagents to sequence the exomes of 18 strains of mice, including 15 novel mutants and 3 controls, and identify strong candidate genes for the majority of these mutants including new models of orofacial clefting, urogenital dysmorphology, kyphosis and autoimmune hepatitis.  Moreover, these data provide novel functional associations for several poorly characterized genes including Lhfpl2 and Pfas.  Whole exome sequencing is a robust method for mutation discovery in the mouse genome, and will be useful for completing the genetic analysis of the thousands of established mouse mutants exhibiting clinically relevant phenotypes.