This chapter presents a history of the efforts to achieve standardization of genetic nomenclature for mice and gives the 1964 rules for naming genes. The confusing terminology of the earlier years has gradually given way to increasing orderliness and uniformity; we recognize, however, that complete uniformity may not always be possible.
Several decades ago, Professor H. de Haan ( 1932) wrote: "It is high time to bring unity into genetic nomenclature....In my opinion it is due to the International Congress of Genetics to appoint a Committee for Genetic Nomenclature. A permanent committee which keeps drawing the attention to the international rules to be drafted by it could do much to promote unity in the nomenclature."
Five years earlier, at the Fifth International Congress of Genetics, A.S. Serebrovsky ( 1928) had presented an entirely new system of denoting hereditary factors analogous to a decimal bibliographic system. Casual inspection of this system indicates the motivation for de Hahn's plaint.
Earlier still, in 1919, the American Society of Naturalists appointed a Committee on Genetic Form and Nomenclature with C.C. Little as chairman and Sewall Wright, G.H. Shull, O.E. White, and A.H. Sturtevant as members. The scheme drawn up by this group was adopted and published ( Little, 1921). The hope of the chairman, expressed in his covering letter, that this publication would stimulate discussion of modifications was apparently largely ignored, and scant attention was paid to this succinct report.
It was indeed, as de Haan had suggested, left to future Genetics Congresses, both to appoint committees and to serve as meeting places for them. At the Sixth Congress in Ithaca, N.Y., in 1932, C.C. Little announced that several suggestions had been received that the Congress appoint a standing committee to consider matters of genetical nomenclature. There was no discussion and no action was taken. However, at a later plenary session of the same Congress, the resolutions committee moved that the problem of standardizing genetic symbolism and nomenclature be reconsidered. The motion was carried ( Jones, 1932).
As a result of a circular letter sent in the spring of 1939 from The Jackson Laboratory to biologists interested in mouse genetics, a committee was chosen consisting of L.C. Dunn, G.D. Snell, and F.A.E. Crew to prepare recommendations for symbols for mouse genes. Hans Grüneberg later replaced Crew. During the Seventh Congress in Edinburgh, an open meeting on rodent gene symbolism, chaired by A.L. Hagedoorn, considered a set of nomenclature rules drawn up by the committee ( Punnett, 1941). Recommendations from this meeting were incorporated into rules concerning only gene symbols, published in the Journal of Heredity ( Dunn et al., 1940).
In 1949, after consultation with the genetics group at The Jackson Laboratory and correspondence with other geneticists, G.D. Snell drew up a list of suggested rules of nomenclature for inbred strains of mice ( Mouse News Letter, 1950). This list, with minor variations, was sent by Snell and T.C. Carter to geneticists in 1951, asking for a vote on two alternative systems of notation. That giving maximum uniformity was adopted. Workers were also asked to select abbreviations of their own names for use in designating substrains.
This Committee on Standardized Nomenclature of Inbred Strains of Mice, as the informal working group came to be known, was responsible for issuing the first standardized nomenclature list in Cancer Research in 1952 ( Committee, 1952), following the format devised by Snell ( 1941) and Law ( 1948). This paper contained the recommended rules for strain names, a list of known inbred strains with their histories and characteristics, and a list of users of mice with abbreviations for their names or institutions.
As time went on, more substrains of existing strains were developed by spontaneous mutations, manipulation, or merely physical separation. New mutations and linkages were discovered, strains became more widely distributed, and the list of workers grew enormously. It became apparent that a reappraisal of the rules of nomenclature was in order.
Following the suggestion of Hans Grüneberg, the old nomenclature committee was reactivated, reconstituted, and renamed. During the 10th International Congress of Genetics in Montreal in 1958, the group met, was named the Committee on Standardized Genetic Nomenclature for Mice and discussed both strain and gene symbols. This body supersedes and represents a merger of the Mouse Genetics Nomenclature Committee (genes) and the Committee on Standardized Nomenclature for Inbred Strains of Mice (strains) ( Staats, 1963).
This body was responsible for issuing the second ( Committee, 1960) and third ( Staats, 1964) alphabetic listing of inbred strains in Cancer Research and the first major revision of the gene nomenclature rules ( Committee, 1963). The latter was made necessary by the detection of many presumed recurrences of old mutations, reversions to wild type, long series of alleles at single loci, translocations, and by the increased use of mice generally. In 1965, the members of the Committee were: Margaret C. Green, Hans Gruneberg, Paula Hertwing, W.E. Heston, Mary F. Lyon, N.N. Medvedev, George D. Snell, and Joan Staats.
The rules for symbols to designate inbred strains of mice as recommended by the Committee on Standardized Genetic Nomenclature are as follows (from Staats, 1964, with permission of Cancer Research):
1. Definition of inbred strain. A strain shall be regarded as inbred when it has been mated brother x sister (hereafter called b x s) for twenty or more consecutive generations. Parent x offspring matings may be substituted for b x s matings, provided that in the case of consecutive parent x offspring matings the mating in each case is to the younger of the two parents.
2. Symbols for inbred strains. Inbred strains shall be designed by a capital letter or letters in Roman type. It is urged that anyone naming a new stock consult [ Staats, 1964, Appendix 2 or the latest issue of Inbred Strains of Mice (see references)] to avoid duplication. Brief symbols are preferred.
An exception is allowed in the case of stocks already widely used and known by a designation which does not conform.
3. Definition of substrain. The definition of substrain presents some of the same problems as the definition of species. In practice, the determination of whether two related strains should be treated as substrains, and whether, in published articles, substrain symbols should be added to the strain symbol, must rest with the investigators using them. The following rules, however, may be of help.
Any strains separated after 8 to 19 generations of b x s inbreeding and maintained thereafter in the same laboratory without intercrossing for a further 12 or more generations shall be regarded as substrains. It shall be considered that substrains have been constituted (a) if pairs from a parent strain (or substrain) are transferred to another investigator, or (b) if detectable genetic differences become established.
4. Designation of substrains.
A substrain shall be known by the name of the parent strain followed by a slant line and an appropriate substrain symbol. Substrain symbols may be of two types.
a. Abbreviated name as substrain symbol. The symbol for substrains should usually consist of an abbreviation for the name of the person or laboratory maintaining it. The initial letter of this symbol should be set in Roman capitals; all other letters should be in lower case. Abbreviations should be brief, should as far as possible be standardized, and should be checked with published lists [ Staats, 1964, Appendix 3, and the latest issue of Inbred Strains of Mice] to avoid duplication. Examples: A/He (Heston substrain of strain A), A/Icrc (Indian Cancer Research Centre substrain of strain A).
When a new substrain is created by transfer, the old symbol may be retained and a new one added. Example: YBR/He, on transfer from Heston to Wilson, becomes YBR/HeWi. The accumulation of substrain symbols in this fashion provides a history of the strain. If the substrain symbols are not accumulated, the history of transfers should be recorded in Inbred Strains of Mice.
b. Numbers or lower-case letters. numbers or lower-case letters may be used as substrain symbols in certain circumstances. The position of these relative to other parts, if any, of the substrain symbol should be suggestive of a historical or time sequence. Thus, two substrain branches, separated in and maintained by one laboratory, may be designated by terminal numbers, with or without a preceding slant line. Example: two sublines of A/HeCrgl, separated and maintained by Crgl, become A/HeCrgl/1 (or A/Crgl/1) and A/HeCrgl/2 (or A/Crgl/2). Lower-case letters immediately following the strain symbol, with a slant line only intervening, may be employed when two substrains are separated from a common strain prior to complete inbreeding. Example: C57BR/a and C57BR/cd. (These were separated after nine generations of b x s.) The use of numbers or lower-case letters immediately after the slant line, to designate lines separated after twenty or more generations b x s, is ordinarily not recommended, but may occasionally be justified for sublines widely recognized as different. Example: DBA/1 and DBA/2. Appropriate checks to avoid duplication should be made before this type of symbol is adopted.
5. Coisogenic stocks. Coisogenic stocks produced by the occurrence of a single major mutation within an inbred strain, or by the introduction of a gene into an inbred background by a series of crosses, shall be designated by the strain symbol and, where appropriate (see rule 7), substrain symbol, followed by a hyphen and the gene symbol (in italics in printed articles). Example: DBA/Ha-D. Where the mutant or introduced gene is maintained in the heterozygous condition, this may be indicated by including a + in the symbol. Examples: A/Fa-+C. C3H/N-+ Wj.
When a coisogenic strain is produced by inbreeding with forced heterozygosis, indication of the segregating locus is strictly optional. Examples: 129 or 129- cchc (129 is customary); SEAC- d+/+ se or SEAC/Gn.
In the case of coisogenic stocks produced by repeated crosses of a dominant gene into a standard inbred strain, it may be desirable to indicate the number of backcross generations. Strains shall be regarded as coisogenic when at least seven such crosses have been made. Example: C57BL/6-+ Wv (N8). The first hybrid or F1 generation should be counted as generation 1, the first backcross generation as generation 2, etc.
6. Substrains developed through foster nursing, ova transfer, or ovary transplant. Substrains developed by foster nursing shall be indicated by appending an "f" to the strain symbol. Example: C3Hf. The strain used to foster parent may be indicated if desired by the addition of its symbol or an abbreviation for the same. Example: C3HfC57BL or C3HfB (C3H fostered on C57BL). In like manner, strains developed through egg transfer or ovary transplant shall be indicated by adding an "e" or "o," respectively. Example: AeB (A ova transferred to C57BL). Where the symbol for fostering or transfer might be confused with an adjoining substrain symbol, it may be used in a subscript position. Example: A/HefB (Heston substrain of A fostered on C57BL).
7. Compound substrain symbols for stocks of complex origin. When a stock has been produced by manipulation of a standard inbred strain, as, for example, by fostering or by introduction of a foreign gene, compound substrain symbols may be necessary. In general, the elements of such a compound symbol should be arranged in an order indicating a historical or time sequence. Specifically, different positions should be interpreted as follows:
a. Substrain symbol that immediately follows strain symbol. Examples: BALB/cf, DBA/2eB, C3H/Ha- p. In this position the substrain symbol (c, 2, or Ha in examples given) designated the substrain which was fostered or otherwise manipulated, or in which a mutation occurred.
b. Substrain symbols following symbol for manipulative process or introduced gene. Substrain symbols in this position refer either to the person performing the fostering or other manipulation, or to the person or laboratory currently maintaining the strain, or to both. The symbol or symbols may or may not be immediately preceded by a slant line. Examples: DBA/2eB/De or DBA/2eBDe (strain derived from ova of DBA/2 transferred by Deringer to C57BL, maintained by Deringer); C3H/HefHa (C3H/He fostered by Heston, currently maintained by Hauschka); CBA/Ca- se/Gn (Carter's substrain of CBA with mutation to se, maintained by Green). Since a single symbol in this position (e.g., the De in DBA/2eBDe) may refer either to the person producing or the person maintaining the strain, the intended meaning should be clearly recorded.
8. Indication of inbreeding. Where it is desired to indicate the number of generations of b x s inbreeding, this shall be done by appending, in parentheses, an F followed by the number of inbred generations. Example: A(F87). If because of incomplete information, the number given represents only part of the total inbreeding, this should be indicated by preceding it with a question mark an plus sign. Example: YBL(F?+10).
9. Priority in strain symbols. If two inbred strains are reassigned the same symbol, the symbol to be retained shall be determined by priority in publication. For this purpose, listing in Mouse News Letter or Inbred Strains of Mice shall be regarded as publication.
Abbreviations for symbols of some older strains are useful for forming hybrid designations and in other places where brevity is desired. However, such abbreviations should be used only after giving the full symbols. The following abbreviations for standard inbred strains are used in this book.
Example: AKD2F1 for (AKR x DBA/2)F1.
The rules for symbols to designate genes in mice as recommended by the Committee on Standardized Genetic Nomenclature for Mice ( 1963) are as follows (reprinted with permission from The Journal of Heredity):
1. The names of genes, as distinguished from the symbols, shall be written with a lower case initial letter, regardless of whether the mutant is dominant or recessive, except at the beginning of a sentence or other place in which capitalization would normally be used, or when the word is a proper noun. Examples: albinism, rex, Jay's dominant spotting.
2. The symbols for genes should typically be abbreviations of the name, e.g. d for dilution, dw for dwarf, ac for absence of corpus callosum. For convenience in alphabetical listings, the initial letters of names and symbols should be the same. Certain exceptions are indicated in subsequent rules.
3. Recessive mutations shall be indicated by the use of a small initial letter for the symbol of the dominant gene, e.g., a for nonagouti.
4. Dominant mutations (mutations with consistent heterozygous expression) shall be indicated by the use of a capital initial letter for the symbol of the mutant gene, e.g., Re for rex.
5. The locus symbol shall be the symbol of the first named mutant gene or allelic pair, except that any superscript indicative of a specific allele shall be omitted. Examples: d for the dilution locus, Re for the rex locus, H-2 for the histocompatibility locus.
6. The wild type may be designated by:
a. The locus symbol with a small initial letter and a plus superscript, e.g., t+, re+.
b. A + sign only, when the context leaves no doubt as to the locus represented.
c. The same symbol as the mutant gene but with a capital initial letter for recessive mutants, a small initial letter for dominant mutants. Examples: D for the wild type allele of d; re for the wild type allele of Re.
Alternatives (a) and (b) are recommended, except for teaching purposes or when there is doubt as to which allele is wild type, e.g., biochemical polymorphisms, the agouti locus.
7. Mutants of similar phenotype but different location (mimics) shall be indicated either by entirely different names and symbols (e.g., ln for leaden and d for dilution) or by the same name and symbol with the addition of a hyphen and a distinguishing number. Examples: H-1, H-2, H-3, etc. for different histocompatibility loci; wa-1 (waved-1) and wa-2 (waved-2). The preferred system is to give mimics distinctive names.
8. Multiple alleles determining visible or other clearly characterized distinctions shall be represented by the locus symbol with an added superscript, typically a small letter or letters suggestive of the name. The initial letter of the symbol shall be capitalized according as the allele behaves as a dominant or a recessive. Examples: cch (chinchilla allele of c or albino), Ay (the yellow allele of A or agouti), H-2k (the k allele of histocompatibility-2).
9. Variants which are members of a series (e.g., recurrences, reversions to wild type, translocations, some series of multiple alleles) should usually be separated one from another by the use of a series symbol. For this purpose an Arabic numeral corresponding to the serial number of the variant in any given laboratory, plus an abbreviation indicative of the name of the laboratory or the discoverer, shall be used. Where the laboratory or discoverer has already been assigned an abbreviation for the designation of inbred substrains, this shall be the abbreviation used. Where there is no preassigned abbreviation, any appropriate abbreviation may be used, except that it should not duplicate an existing symbol in the standard list of abbreviations ( Staats, 1964). In every case the first letter of the abbreviations should be capitalized. Example: 7Rl (the seventh recurrence of any particular type of variant found by Russell). To avoid the confusion of the numeral one and the letter l, any first-discovered variant may be left unnumbered. The second variant is then numbered 2.
10. Indistinguishable alleles of independent origin (supposed recurrences) shall be designated by the existing gene symbol with the series symbol (rule 9) appended as a superscript. If the gene symbol already has a superscript, this shall be separated from the appended superscript by a hyphen. Examples: c4Rl (the fourth recurrence of c found by Russell); at-7J (the seventh recurrence of at found at The Jackson Laboratory).
11. Reversions to wild type shall be designated by the symbol for the wild-type allele (rule 6a) with the series symbol (rule 9) appended as a superscript. Examples: d+J, d+2J (the first and second reversions from d to d+ found at The Jackson Laboratory).
12. Translocations, when initially discovered, shall be designated by a T followed by the series symbol (rule 9). Example: T138Ca (the 138th translocation found by Carter). When the linkage groups involved in the translocation have been identified, these shall be indicated by adding the appropriate numbers. These shall be inserted between the T and the series symbol, shall be Arabic rather than Roman numerals (except that the symbol for the X chromosome shall be either X or 20, and that the Y chromosome shall be indicated by Y), shall be enclosed in parentheses, and shall be separated by a semicolon. Example: after it is found that T138Ca involves linkage groups II and IX, the symbol becomes T(2;9)138Ca. If one of the linkage groups involved in the translocation has been identified but the other has not, the unknown linkage group shall be indicated by a question mark. Example: T(11;?)7Ca.
In general, the translocation symbol should be reserved for reciprocal translocations. If a translocation is shown to be something other than reciprocal, e.g., a transposition, some other appropriate initial letter or letters should be used.
13. In published articles in which symbols are used, the symbols should be set in italics.
The authors of this edition of the Biology of the Laboratory Mouse have adhered to the following conventions wherever possible.
Genotypes are designated with alleles separated by "/," nonalleles by a space. In heterozygotes with the type allele (+) at a given locus, the mutant allele is written first. Genotypes of males carrying sex-linked alleles are designated as shown in the examples using Ta. Examples: a/ a, a/+, H-2d/ H-2k, and in males only, Ta/Y or Ta.
Linked genes are written in sets with spaces between nonalleles. The sets are written on one line separated by a "/" or are written on two lines like a fraction. Examples:
|fr c p|
|fr c p/ + c +|
|+ c +|
Matings are denoted by a multiplication or times sign "x." Example: a/ a x a/+.
Hybrids between two inbred strains are designated as follows: (C57BL/6 x DBA/2)F1 or, for greater brevity, B6D2F1 (see Strain Abbreviations, this chapter). In every instance the female is listed first.
Since 1940, concerted efforts have been made to promote uniformity in genetic nomenclature for mice. The Committee on Standardized Genetic Nomenclature for Mice has published rules for designating both inbred strains and mutant genes. The rules are given in this chapter.
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 Nomenclature for Inbred Strains of Mice. 1952. Standardized nomenclature for inbred strains of mice. Cancer Res. 12: 602-613.
Committee on Standardized Nomenclature for Inbred Strains of Mice. 1960. Standardized nomenclature for inbred strains of mice, second listing. Cancer Res. 20: 145-169.
De Haan, H. 1932. The symbolizing of hereditary factors. Genetics 15: 1-21.
Dunn, L.C., H. Grüneberg, and G.D. Snell. 1940. Report of the Committee on Mouse Genetic Nomenclature. J. Hered. 31: 505-506.
Inbred Strains of Mice. An informal biennial mimeographed document distributed by The Jackson Laboratory and edited by Joan Staats. It carries lists of inbred strains of mice, arranged alphabetically by the cooperating laboratories.
Jones, D.F. [ed.] 1932. Proc. VI Int. Cong. Genet. (Ithaca, 1932) p. 16, 19. Vol I. Brooklyn Botanic Garden, New York.
Law, L.W. 1948. Mouse genetic news, No. 2. J. Hered. 39: 300-308.
Little, C.C. 1921. Report of the Committee on Genetic Form and Nomenclature. Amer. Natur. 55: 175-178.
Mouse News Letter, No. 2. 1950. p. 8-9. An informal semiannual mimeographed document distributed by the Laboratory Animals Centre, Carshalton, Surrey. It carries information on mutant genes, research stocks of mice, and research news, and is edited by Mary F. Lyon.
Punnett, R.C. 1941. p. 37. Proc. VII Int. Cing. Genet. (Edinburgh, 1939), Cambridge Univ. Press, London.
Serebrovsky, A.S. 1928. Versuch einer allgemeinen Nomenclatur des Genes. Proc. V Int. Cong. Genet. (Berlin, 1927) Z. Indukt. Abstamm. Vererb., Suppl. 2: 1320.
Snell, G.D. [ed.] 1941. Mouse genetic news, No. 1. Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Maine. 18 p. (Mimeo.)
Staats, J. 1963. International rules of nomenclature for mice, p. 517-521. In W.J. Burdette [ed.] Methodology in Mammalian Genetics. Holden-Day, San Francisco.
Staats, J. 1964.
Standardized nomenclature for inbred strains, Third listing. (Prepared for the Committee on Standardized Genetic Nomenclature for Mice.)
Cancer Res. 24: 147-168.
See also PubMed.