Mutation characterization and protocols

Spontaneous mutation characterization

Mice with newly identified spontaneous mutations undergo genetic, genomic and phenotypic characterization to evaluate and develop their value as resources for ongoing biomedical research. Each new mutant strain is characterized:

• Genetically, by determining its mode of inheritance, its chromosomal location and its complementation status with any known colocalizing mutations that produce similar phenotypes.
• Genomically, by regional array capture-, whole exome capture- or whole genome high-throughput DNA sequence analysis, transcriptome analysis and/or array comparative genome hybridization.
• Phenotypically, by observing its fertility, growth, viability, life span and behavior, and by defining its anatomical, histopathological and physiological abnormalities

Novel phenotypic mutations

New spontaneous mutations are genetically mapped, tested for complementation with other colocalizing candidate genes (mapping to the same chromosomal region), and subjected to regional array-capture, whole exome-capture, or whole genome high-throughput DNA sequence analysis. If a new spontaneous mutation results in the first phenotypic allele within a given gene, it is designated as a novel phenotypic mutation.

Novel phenotypic mutations often provide the first experimental insights into gene function, uncovering roles for genes that may never have been anticipated based on primary sequence alone. Moreover, novel phenotypic mutations in mouse frequently provide the first known animal models of human genetic disorders.

Allelic series

If a newly arising spontaneous mutation occurs in the same gene in which other mutations have previously been described, the mutant allele is considered the second or subsequent allele of an allelic series. Allelic series are valuable for confirming that candidate mutations are causative of observed phenotypes. Allelic series also provide a means to assess the effect of a particular mutation type or location on the phenotype.  Differing mutations in a single pleiotropic gene can provide domain-specific insight into gene function and may even result in models for distinct human diseases.