[Guidelines for Nomenclature 3]
Guidelines for Nomenclature of Genes, Genetic Markers, Alleles, and Mutations in Mouse and Rat
6 Definitions
The following definitions should aid the user in understanding what is being named, and in understanding the principles underlying these guidelines.
6.1 Gene
A gene is a functional unit, usually encoding a protein or RNA, whose inheritance can be followed experimentally. Inheritance is usually assayed in genetic crosses, but identification of the gene in cytogenetic or physical maps are other means of mapping the locus of a gene. The existence of a gene can also be inferred in the absence of any genetic or physical map information, such as from a cDNA sequence.
6.2 Pseudogene
A sequence that closely resembles a known functional gene, at another locus within a genome, that is non-functional as a consequence of (usually several) mutations that prevent either its transcription or translation (or both). In general, pseudogenes result from either reverse transcription of a transcript of their "normal" paralog (in which case the pseudogene typically lacks introns and includes a poly(A) tail; often called processed pseudogenes) or from recombination (in which case the pseudogene is typically a tandem duplication of its "normal" paralog).
6.3 Locus
A locus is a point in the genome, identified by a marker, which can be mapped by some means. It does not necessarily correspond to a gene; it could, for example, be an anonymous non-coding DNA segment or a cytogenetic feature. A single gene may have several loci within it (each defined by different markers) and these markers may be separated in genetic or physical mapping experiments. In such cases, it is useful to define these different loci, but normally the gene name should be used to designate the gene itself, as this usually will convey the most information.
6.4 Marker
A marker is the means by which a gene or a locus is identified. The marker is dependent on an assay, which could, for example, be identification of a mutant phenotype or presence of an enzyme activity, protein band, or DNA fragment. The assay must show genetic variation of the marker to map the locus on a genetic map but not to place it on a physical map.
6.5 Allele
The two copies of an autosomal gene or locus on the maternal and paternal chromosomes are alleles. If the two alleles are identical, the animal is homozygous at that locus. When genetically inherited variants of a gene or locus are detectable by any means, the different alleles enable genetic mapping. A single chromosome can only carry a single allele and, except in cases of duplication, deletion or trisomy, an animal carries two autosomal alleles. In particular, a transgene inserted randomly in the genome is not an allele of the endogenous locus; the condition is termed hemizygous if the transgene is present only in one of the two parental chromosome sets. By contrast, a gene modified by targeting at the endogenous locus is an allele and should be named as such.
6.6 Allelic Variant
Allelic variants are differences between alleles, detectable by any assay. For example, differences in anonymous DNA sequences can be detected as simple sequence length polymorphism (SSLP) or single nucleotide polymorphisms (SNPs). Other types of variants include differences in protein molecular weight or charge, differences in enzyme activity, or differences in single-stranded conformation (SSCP). Many allelic variants, in particular DNA variants, do not confer any external phenotype on the animal. These variants are often termed “polymorphisms” although, strictly speaking, that term applies only to variants with a frequency of more than 1% in the population.
6.7 Splice Variant or Alternative Splice
Alternative splicing of a gene results in different, normally occurring forms of mRNA defined by which exons (or parts of exons) are used. Thus one or more alternative protein products can be produced by a single allele of a gene. Among different alleles, alternative splice forms may or may not differ, depending on whether the sequence difference between the alleles affects the normal splicing mechanism and results in differences in the exon (or partial exon) usage. For example, allele A may produce mRNAs of splice form 1, 2, and 3; while allele B may produce mRNAs of splice form 1, 2, and 4; and Allele C may produce mRNAs of splice form 1, 2, and 3. In this case, each of the alleles A, B, and C by definition must differ in their DNA sequence. However, the difference between allele B versus alleles A and C must include a sequence difference that affects the splicing pattern of the gene.
6.8 Mutation
A mutation is a particular class of variant allele that usually confers a phenotypically identifiable difference to a reference "wild type" phenotype. However, in some cases, such as when homologous recombination is used to target a gene, a readily identified phenotype may not result even though the gene may be rendered non-functional. In such cases, the targeted genes are nevertheless referred to as mutant alleles.
6.9 Dominant and Recessive
Dominant and recessive refer to the nature of inheritance of phenotypes, not to genes, alleles, or mutations. A recessive phenotype is one that is only detected when both alleles have a particular variant or mutation. A dominant phenotype is detectable when only one variant allele is present. If both alleles can be simultaneously detected by an assay, then they are codominant. For example, an assay that detects variation of DNA or protein will almost invariably detect codominant inheritance, as both alleles are detected. If a mutation produces a phenotype in the heterozygote that is intermediate between the homozygous normal and mutant, the phenotype is referred to as semidominant. A single mutation may confer both a dominant and a recessive phenotype. For example, the mouse patch (Ph) mutation has a heterozygous (dominant) pigmentation phenotype but also a homozygous (recessive) lethal phenotype. As the terms are applied to phenotypes not to genes or alleles, then in the case where a gene has multiple mutant alleles, each can confer a phenotype that is dominant to some, but recessive to other, phenotypes due to other alleles.
Penetrance is a quantitative measure of how often the phenotype occurs in a population; and expressivity is a measure of how strongly a phenotype is expressed in an individual. Particularly in segregating crosses, or where there is a threshold effect on phenotypic manifestation, these measures provide additional ways to describe how particular allelic combinations result in a phenotype.
6.10 Genotype
Genotype is the description of the genetic composition of the animals, usually in terms of particular alleles at particular loci. It may refer to single genes or loci or to many. Genotype can only be determined by assaying phenotype, including test mating to reveal carriers of recessive mutations. Strictly speaking, even direct determination of DNA variants is assaying phenotype not genotype as it is dependent on a particular assay, although it is so close to genotype that it serves as a surrogate.
6.11 Phenotype
Phenotype is the result of interaction between genotype and the environment and can be determined by any assay.
6.12 Quantitative Trait Loci (QTLs)
Quantitative Trait Loci (QTL) are polymorphic loci that contain alleles, which differentially affect the expression of continuously distributed phenotypic traits. Usually these are markers described by statistical association to quantitative variation in the particular phenotypic traits that are controlled by the cumulative action of alleles at multiple loci.
6.13 Haplotype
A haplotype is the association of genetically linked alleles, as found in a gamete. They may be a combination of any type of markers, and may extend over large, genetically separable distances, or be within a short distance such as within a gene and not normally separated.
6.14 Homolog
Genes are homologous if they recognizably have evolved from a common ancestor. Note that genes are either homologous or not; there are no degrees of homology! For example, all globin genes, and myoglobin, are homologs, even though some are more closely related to each other than others. When a measure of relatedness between sequences is required, percent identity or similarity should be used.
6.15 Ortholog
Genes in different species are orthologs if they have evolved from a single common ancestral gene. For example, the beta globin genes of mouse, rat and human are orthologs. Note that several genes in the mouse or rat may have a single ortholog in another species and vice versa.
6.16 Paralog
Paralogous genes are genes within the same species that have arisen from a common ancestor by duplication and subsequent divergence. For example, the mouse alpha globin and beta globin genes are paralogs.
7 References
- Bestor TH. Transposons reanimated in mice. 2005. Cell 122:322-325.
Committee on Rat Nomenclature, Cochairmen Gill T.J. III, Nomura T. 1992. Definition, nomenclature, and conservation of rat strains. ILAR News 34:S1-S56.
Committee on Standardized Genetic Nomenclature for Mice. 1963. A revision of the standardized genetic nomenclature for mice. J. Hered. 54:159-162.
Committee on Standardized Genetic Nomenclature for Mice. 1973. Guidelines for nomenclature of genetically determined biochemical variants in the house mouse, Mus musculus. Biochem. Genet. 9:369-374.
Committee on Standardized Genetic Nomenclature for Mice, Chair: Lyon, M.F. 1981. Rules and guidelines for gene nomenclature. In: Genetic Variants and Strains of the Laboratory Mouse, Green, M.C. (ed.), First Edition, Gustav Fischer Verlag, Stuttgart, pp. 1-7.
Committee on Standardized Genetic Nomenclature for Mice, Chair: Lyon, M.F. 1989. Rules and guidelines for gene nomenclature. In: Genetic Variants and Strains of the Laboratory Mouse, Lyon, M.F., A.G. Searle (eds.), Second Edition, Oxford University Press, Oxford, pp. 1-11.
Committee on Standardized Genetic Nomenclature for Mice, Chairperson: Davisson, M.T. 1996. Rules and guidelines for gene nomenclature. In: Genetic Variants and Strains of the Laboratory Mouse, Lyon, M.F., Rastan, S., Brown, S.D.M. (eds.), Third Edition, Volume 1, Oxford University Press, Oxford, pp. 1-16.
Ding S, Wu X, Li G, Han M, Zhuang Y, Xu. T. 2005. Efficient transposition of the piggyBac (PB) transposon in mammalian cells and mice. Cell 122:473-483.
Dunn, L.C., H. Gruneberg, G.D. Snell. 1940. Report of the committee on mouse genetics nomenclature. J. Hered. 31:505-506.
Dupuy AJ, Akagi K, Largaespada DA, Copeland NG, Jenkins NA. 2005. Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 436:221-226.
Eppig, JT. 2006. Mouse Strain and Genetic Nomenclature: an Abbreviated Guide. In: Fox J, Barthold S, Davvison M, Newcomer C, Quimby F, Smith A (eds) The Mouse in Biomedical Research, Volume 1, Second Edition. Academic Press. pp.79-98.
International Committee on Standardized Genetic Nomenclature for Mice, Chairperson: Davisson, M.T. 1994. Rules and guidelines for genetic nomenclature in mice. Mouse Genome 92 vii-xxxii.
Levan G., H.J. Hedrich, E.F. Remmers, T. Serikawa, M.C. Yoshida. 1995. Standardized rat genetic nomenclature. Mamm. Genome 6:447-448.