Genes
Spontaneous mutations, including sequence variants, copy number variants, small indels, and multigenic chromosomal aberrations constantly arise in colonies but at relatively low rates so they are often missed unless a careful screening program is in place to identify them. This is called genetic drift and can be a major problem for large production colonies. There is also the real potential problem of genetic contamination, where strains are inadvertently mixed. To minimize and control these problems, two approaches are used in large production colonies: the Genetic Stability Program (GSP) (Methods for maintaining genetic stability of inbred animal strains (https://www.jax.org/jax‐mice‐and‐services/find‐and‐order‐jax‐mice/why‐jax‐mice/patented‐genetic‐stability‐program) US 7592501 [22 September 2009]; SG 119769; CN 200480023858.4 [23 June 2010]; AU [11 November 2010]; US 8110721 [7 February 2012]; JP 5072359 [31 August 2012]; USA 8552254 [8 September 2013]) and a genetic quality control program [37]. GSP essentially resets the genetic drift back to an arbitrary start point every ~5 generations by the use of a large pool of inbred embryos to replace the Founder stock. Genetic quality control programs regularly screen breeders at the top and sample the bottom of the production chain for a variety of molecular markers (SNPs) and phenotypes [38]. Newer methods, built around SNPs, utilize MiniMUGA Genotyping Arrays [38]. Prior to polymerase chain reaction (PCR), a variety of diagnostic screens (enzyme assays) and tail skin grafts were used (https://resources.jax.org/misc/jax‐handbook‐genetically‐standardized‐mice).
Spontaneous mutations can be recessive, semi‐dominant, or dominant and can be true nulls, hypomorphic alleles, or gain‐of‐function mutations. Some result from retrovirus integration events, such as the hairless allele (Hrhr) discussed above [39]. Radiation and chemical mutagenesis are also used to create mutations in mice without targeting specific genes, although specific phenotypes may be the focus. Genetically engineered mice can be created by transgenesis, recombineering, or nuclease mediated approaches. While many engineered mutations are called knockouts, not all are true nulls so this term has to be used carefully.
Spontaneous Mutations in Mice
Spontaneous mutations have traditionally been named for the readily observable phenotype(s) they initially present. In the pre‐genomic era chromosomes were defined in large part by the linkage maps of phenotypic mutants. The gene(s) impacted by a spontaneous mutation are not initially known, and the symbol for such a heritable phenotypic marker is italicized and all lower case for recessive mutations, such as bg for beige, ob for obese, and d for dilute. The first letter of the symbol is in upper case for dominant or semi‐dominant mutations, such as Tr for trembler. When the impacted gene is identified, if the mutation is a molecular lesion in only one gene, then the original marker symbol becomes a superscript of that gene for the allele symbol, Lystbg, Lepob, Myo5ad, and Pmp22Tr, respectively. Although gene symbols may change over time as the function and ontology of the gene is better understood, other than becoming a superscript of the gene, the allele symbol remains the same as does the allele name. For example the commonly used nude mouse gene name has changed considerably over time (Table 3.11). For mice, the gene symbol has the first letter capitalized and subsequent letters in lower case, all in italics. Hyphens are avoided except to depict new alleles of the initial phenotypic mutation (Table 3.12). For example, while interleukin 10 is commonly written in journals as IL‐10, the correct gene symbol would be Il10 and protein symbol would be IL10. Human gene symbols are essentially the same as for mice except the human gene symbols are all in capital letters and italicized. Greek letters are not used at all, only Roman letters and Arabic numbers. For example, interferon gamma is Ifng. The protein coded for by this gene is listed in capital letters with no italics (IFNG) for both mouse and human proteins.
Non‐engineered Induced Mutations
The system for naming chemically or radiation‐induced mutations is similar to that for spontaneous mutations, except that while many are initially assigned phenotypic names and corresponding symbols, some are instead assigned program accession numbers. One example of this is nmf12, which was the 12th characterized ENU induced mutation in the neuroscience mutagenesis facility (nmf) at The Jackson Laboratory. Once the underlying mutation was found to be a H716R point substitution in the gene MER proto‐oncogene tyrosine kinase, the symbol changed to Mertknmf12 [40].
Table 3.11 Evolution of the nomenclature for nude.
| nu original mutation symbol D11Bhm185e, Hfh11, whn‐ early gene symbols Foxn1 (current gene symbol, forkhead box N1) Foxn1 nu current allele symbol for the nude allelic mutation |
Table 3.12 Nomenclature for spontaneous mouse mutations.
| C57BL/6J‐Lystbg‐J/J C57BL/6J‐Pax3Sp‐d/JC57BL/6J = Inbred strain carrying the mutationLyst = Lysosomal trafficking regulator (gene name, italics)bg‐J = Allele symbol for beige Jackson. Note the first letter in the allele (bg‐J) is lower case indicating it is recessive |
| C57BL/6J‐Pax3Sp‐d/JC57BL/6J = Inbred strain carrying the mutationPax3 = Paired box 3 (gene name, italics)Sp‐d = Allele symbol for delayed splotch. Note the first letter in the allele (Sp‐d) is upper case indicating dominant or semi‐dominant |
Radiation‐induced mutations have also often been assigned phenotypic names, such as disproportionate micromelia (Col2a1Dmm), but because radiation‐induced mutations often impact more than one gene, the mutation symbol is in those instances not superscripted to a single gene symbol. A.G. Searle reported several phenotypic mutants generated in neutron irradiation experiments, one of which caused severe ocular colobomas in heterozygotes and was therefore named coloboma, with the symbol Cm [41, 42]. When this mutation was determined to be a multigenic deletion encompassing 29 genes the symbol remained Cm but the name changed from coloboma to coloboma deletion region. The symbol and name could have been changed to follow chromosomal aberration nomenclature for deletions, but because of the long history of this mutation in the literature this was not done.
Chromosomal Aberration Nomenclature
Mutations that include more than one gene or alter chromosomal organization are often, but not always, assigned symbols and names that indicate this. The symbol begins with an indicator of the nature of the mutation followed by details about the chromosomal location of the mutation in parentheses followed by a line number and lab code of the laboratory that identified it. The most common types of chromosomal aberrations are multigenic deletions, but we include here a short list of examples of a few other important types:
Del(10)77H: Deletion in Chromosome 10 that was the 77th deletion identified at Harwell (http://www.informatics.jax.org/accession/MGI:5314347).
Del(5Letm1‐Htt)1Jcs: Deletion in Chromosome 5 from the gene Letm1 to the gene Htt that was the first made by Dr. John Schimenti (http://www.informatics.jax.org/accession/MGI:3798057).
