Genomic characterization of mutant laboratory mouse strains by exome sequencing and annotation lift-over.
BACKGROUND
Exome sequencing has become a popular method to evaluate undirected mutagenesis experiments in mice. However, the most suitable mouse strain for the biological model may be relatively distant from the standard mouse reference genome. For pinpointing causative variants, a matching reference with gene annotations is essential, but not always readily available.


RESULTS
We present an approach that allows to use murine Ensembl annotations on alternative mouse strain assemblies. We resolved ENU-induced mutation screening for 8 phenotypic mutant lines generated on C3HeB/FeJ background aligning the sequences against the closely related, but not annotated reference of C3H/HeJ. Variants occurring in all strains were filtered out as specific for the C3HeB/FeJ strain but unrelated to mutagenesis. Variants occurring exclusively in all individuals of one mutant line and matching the inheritance model were selected as mutagenesis-related. These variants were annotated with gene and exon names lifted over from the standard murine reference mm9 to C3H/HeJ using megablast. For each mutant line, we could restrict the results to exonic variants in between 1 and 23 genes.


CONCLUSIONS
The presented method of exonic annotation lift-over proved to be a valuable tool in the search for mutagenesis-derived coding genomic variants and the assessment of genotype-phenotype relationships.
Centro Nacional de Análisis Genómico, Parc Científic de Barcelona - Torre I, Baldiri Reixac, 4, 08028, Barcelona, Spain. sderdak@pcb.ub.es.
Sophia
S
Derdak
Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Institute of Experimental Genetics and German Mouse Clinic, Ingolstädter Landstr.1, 85764, Neuherberg, Germany. sabrautzki@helmholtz-muenchen.de.|Member of German Center for Diabetes Research (DZD), Neuherberg, Germany. sabrautzki@helmholtz-muenchen.de.
Sibylle
S
Sabrautzki
Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Institute of Experimental Genetics and German Mouse Clinic, Ingolstädter Landstr.1, 85764, Neuherberg, Germany. hrabe@helmholtz-muenchen.de.|Member of German Center for Diabetes Research (DZD), Neuherberg, Germany. hrabe@helmholtz-muenchen.de.|Technische Universität München, Lehrstuhl für Experimentelle Genetik, 85350, Freising-Weihenstephan, Germany. hrabe@helmholtz-muenchen.de.
Martin Hrabě
MH
de Angelis
Centro Nacional de Análisis Genómico, Parc Científic de Barcelona - Torre I, Baldiri Reixac, 4, 08028, Barcelona, Spain. mgut@pcb.ub.es.
Marta
M
Gut
Centro Nacional de Análisis Genómico, Parc Científic de Barcelona - Torre I, Baldiri Reixac, 4, 08028, Barcelona, Spain. igut@pcb.ub.es.
Ivo G
IG
Gut
Centro Nacional de Análisis Genómico, Parc Científic de Barcelona - Torre I, Baldiri Reixac, 4, 08028, Barcelona, Spain. sbeltrana@pcb.ub.es.
Sergi
S
Beltran
D000818:Animals; D059472:Exome / Q000235:genetics*; D005260:Female; D023281:Genomics / Q000379:methods*; D007753:Laboratories; D008297:Male; D051379:Mice; D058977:Molecular Sequence Annotation; D009154:Mutation; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods*