BuiltWithNOF
History of inbred strains

Inbred strains of mice, rats and guinea-pigs have been available for nearly a century. And yet many research workers do not fully understand their properties and value in research. This page reviews the history of their introduction into biomedical research.

Early Years
Inbreeding of  guinea-pigs, rats and mice
The Jackson Laboratory
Immunogenetics
Literature and communication
More Recent Developments
References

 

 

 

 

 


 

 

 

Early Years

    Mendel's laws

      The rediscovery of Mendel's 1866 paper in 1900 by De Vries, Correns and Tschermak conveniently marks the beginning of  modern genetics. This led to controversy  about the importance of Mendelian genetics in evolution. The "Mendelians", led by William Bateson, thought that the laws would prove to be universal while the "Biometricians", led by Karl Pearson were unable to reconcile Mendel's laws with the  inheritance of quantitative characteristics (Provine 1971). Inbred strains were unknown at this time in mammals, although they occur naturally in self-fertilising plants, but Mendel's laws showed immediately that "pure" (i.e. homozygous) lines breed true, an important attribute of inbred strains.

    Self-fertilised  beans

      In 1903 Johannsen, who worked  with self-fertilised beans published a paper on "Heredity in populations and pure lines"; the first  paper to demonstrate the properties of inbred strains.  He recognised that his material could be divided up into pure lines, i.e. it consisted of parallel sub-strains of  inbred strains. Selection was found to be effective in altering the mean,  but it arose from ". . . a step-wise progression in each generation of the  differing lines concerned". Similarly, when the material was considered as  a whole (i.e. including all the substrains), Galton's law of regression to the mean was found to be fully substantiated. However, when considering individual pure lines, he found that: "It has been demonstrated that in  all cases within the pure lines the retrogression mentioned above has been completed. Selection within pure lines has produced no new shift in the genotype." (Peters 1959). Selection within modern inbred strains of laboratory animals is similarly ineffective in changing their  characteristics (Ginsburg 1967).

    First  transplantable tumours

      Hints of the potential value of  inbred strains of mice in cancer research came between 1902 and 1908. Early attempts to transplant tumours led  to unpredictable results: in some cases the tumours survived, but in others they did not, and the reasons for this were not known (Klein 1975). However, a spontaneous alveolar carcinoma was successfully propagated through 19  generations using a single stock of "white mice" which had apparently become relatively inbred through being maintained as a closed population for many years (Jensen 1903). Transplantation of the tumour to other stocks of mice failed. Similarly, a tumour of Japanese waltzing mice was  successfully grown in other mice of the same stock (Loeb 1908). These  waltzing mice had been bred in the Far East for many centuries, where it was known that the waltzing characteristic was recessive; hence, the mice  were probably highly inbred.

    The genetic basis  of tumour rejection

      The work of Jensen and Loeb led to the recognition of the importance of  "race" as a factor governing susceptibility to transplantable tumours, and the suggestion that susceptibility to such tumours may be inherited. An  explanation of the genetic basis of tumour rejection was developed by Little in 1914. He showed that the pattern of susceptibility could be explained on the basis of acceptance being dependent on a number of  genes acting with a dominant mode of inheritance (Klein 1975). Eventually,  studies of the nature of these genes contributed substantially to the  development of a whole new branch of immunology, the study of the histocompatibility genes and the cell mediated immune response.

Inbreeding of mice, rats  and guinea-pigs

    Inbreeding of  guinea-pigs

      In 1906 an inbreeding experiment involving guinea-pigs was started by G. M. Rommel of the Animal Husbandry Division of the United States Department of Agriculture. Strain 2 and 13 guinea-pigs,  derived from these are still in use today. The  experiment was taken over in 1915 by Dr Sewall Wright. “Faced with the  task of analysing the accumulated data he (Wright) became seriously  interested in constructing a general mathematical theory of inbreeding”. (Provine  1971). By 1920 Wright had developed his method of path coefficients, which he then used to develop his mathematical theory of inbreeding. He introduced the inbreeding coefficient F as the correlation between uniting gametes in 1922, and most of the subsequent theory of  inbreeding has been developed from his work. The definition of the  inbreeding coefficient now most widely used is mathematically equivalent to that of Wright (Falconer 1981).

    Inbreeding of rats and mice

      The period before World War I also led to the initiation of inbreeding in  rats by Dr Helen King in about 1909 (King 1918) and in mice by Dr C. C. Little in 1909 (Staats 1966). The latter project led to the development of the DBA strain of mice, now widely distributed as the two major substrains DBA/1 and DBA/2, which were separated in 1929-1930. DBA mice were nearly lost in 1918, when the main stocks were wiped out by murine paratyphoid, and only three un-pedigreed mice remained alive (Strong 1942). Soon after  World War I, inbreeding in mice was started on a much larger scale by Dr L. C. Strong, leading in particular to the development of strains C3H and CBA, and by Dr C. C. Little, leading to the C57 family of strains (C57BL, C57BR and C57L). Many of the most popular strains of mice were developed during the next decade, and some are closely related. Evidence from the  uniformity of mitochondrian DNA suggests that most of the common inbred mouse strains were probably derived from a single breeding female about  150-200 years ago (Ferris et al 1982).

      A chart of the genealogy of mouse inbred strains is maintained on the Jackson  Laboratory web site.

      Many of the most widely used inbred  strains of rats were also developed during this period, several of them by Curtis and Dunning at the Columbia University Institute for Cancer Research (Curtis et al 1931). Strains dating back to this time include F344, M520 and Z61 (in 1920) and later ACI, ACH, A7322 and COP. Tryon's classic work on selection for maze-bright and dull rats led to the development of the TMB and TMD inbred strains, and later to the common use of inbred rats by experimental psychologists.

 The Jackson Laboratory

    Founding

      The founding of the Roscoe B. Jackson Memorial Laboratory (now The Jackson Laboratory) at Bar Harbor, Maine, in 1929 by Dr C. C. Little was an event  of great importance in the history of inbred strains. According to E. L.  Green, who succeeded Dr Little as Director in 1956: “The purpose of The  Jackson Laboratory is to increase man's knowledge of himself, of his development, growth and reproduction, of his physiological and  psychological behaviour, and of his inborn ailments, through research with  genetically controlled experimental animals” (Green 1966).
       

    Early work

      The earliest investigations were a reflection of the research  interests of Dr Little in the genetics of cancer and in radiation biology. “Underlying these two predominant types of study was a continuing effort to improve the “tools” (Green 1966). This meant the continuing development of inbred strains of mice each with its unique set of distinguishing characteristics, the discovery and propagation of new mutations, and the development of more and more basic knowledge of the early embryogenesis, histogenesis,  growth, pathogenesis, teratogenesis, ageing patterns, normal and abnormal physiology, and reproductive behaviours of the increased number of strains.  In the exact characterisation and analysis of the differences between the  inbred strains, and between mutant and non-mutant types within an inbred strain, lay the research ore to be mined.
      The staff of the Jackson Laboratory soon began to make a significant contribution to research. An early discovery published in 1933 was that  mammary tumours in mice arose as a result of an “agent” which was passed from mother to offspring through the milk. This could be eliminated if the  young were fostered onto a low mammary tumour strain, suggesting that  these tumours were caused by a vertically transmitted virus. The  Laboratory has continued to play a leading role in cancer research,  immunology, genetics and many other areas of research involving the mouse  as a model organism (see below).
       

    Training

      In addition to its role as a research institute, The Jackson Laboratory has played an important part in training research scientists.  Training programmes range from short courses on mammalian and medical genetics to programmes for high school students, and pre- and post-doctoral appointments. Established research workers have also been  encouraged to come to Bar Harbor to carry out short projects in  collaboration with staff scientists. As a result of these various training  programmes, many research scientists have come to realise the value of  using genetically defined stocks in their research programmes. This influence was also extended by the publication of The Biology of the Laboratory Mouse, edited by G. D. Snell, in 1941, with a second edition, edited by E. L. Green, in 1966.
       

    Supply of animals

      The Jackson Laboratory has always been a supplier of animals. “From its earliest days the Laboratory has followed a policy of making any research materials it can spare available to research workers elsewhere.” (Green 1966). The Laboratory now has the largest collection of mouse  genetic stocks in the world. Sales of animals make a substantial  contribution to the total budget. The work of the Laboratory was  interrupted in 1947 when it was destroyed by fire. However, most of the  stocks were eventually recovered from other investigators. A second fire in May 1989 led to the loss of a large breeding facility and several thousand mice, but no strains were lost. Breeding colonies of all  commercial strains are now always maintained on more than one site.
       

Immunogenetics

    The alloantigen  hypothesis

      In 1933 Haldane proposed the alloantigen hypothesis of tumour regression (Haldane 1933). The genetic theory of transplantation developed by Little and Tyzzer (Klein 1975) failed to  define the nature of the hypothetical susceptibility genes. By this time  it was generally believed that neoplastic cells differed from normal cells  and that there was an immune reaction directed against this difference.  However, this did not explain why tumours were not rejected when transplanted within an inbred strain. Haldane postulated that an immunity  was directed against alloantigens, rather than tumour-specific antigens.  He predicted that antigenic differences similar to blood group differences  exist in other tissues and that a tumour arising in a tissue preserves the  alloantigen characteristics of that tissue. He further speculated that the tumour alloantigens induce an immune response in a host lacking them. Transplantation within an inbred strain does not induce such a response because the donor of the tumour and the host share the same antigens.

      In 1936 Peter A. Gorer, working at the Lister Institute, London, discovered four blood group antigens in the mouse, which he designated I,  II, III and IV (Klein 1975). In 1937 he showed that one of these, antigen II, was associated with resistance to transplanted tumours. Gorer's work  demonstrated that the genes for susceptibility to tumour transplants were identical with the genes coding for alloantigens, and also conclusively  demonstrated the immunological basis of tumour rejection. The antigen II locus later became known as the H-2 locus or H-2 complex (now designated H2; hyphens were eliminated from gene symbols in 1994).

    Further work on  genetics of tumour rejection

      The next major step was the further analysis of the genetic basis of tumour rejection by G. D. Snell, at The Jackson  Laboratory, who recognised that the first step in the analysis was to separate and identify individual histocompatibility loci and alleles.  This was achieved by  backcrossing from a donor stock to an inbred strain with appropriate  selection, and the resultant lines were called initially coisogenic and  later congenic lines (Snell 1948). In any pair of congenic lines of this type, one of the lines resists tumour grafts from the other line, so they are also called congenic resistant lines. Such mouse and rat lines  are now widely used in immunological research. By using congenic lines has  it become possible to dissect out and study the various loci governing the  cell-mediated immune response, work for which George Snell was a co-recipient of the 1980 Nobel Prize in Physiology and Medicine. Moreover,  the use of congenic lines in immunology has demonstrated their potential  value in other fields. It has now become standard practice to study mutants and transgenes only when they are maintained as a congenic line  on an inbred strain genetic background.

Literature And communication

    Problems with  accumulating information

      By the beginning of World War II there were large numbers of inbred strains and mutants of mice, and genetic nomenclature and the flow of information between investigators in Europe and  the USA was beginning to be a problem. Accordingly, in 1939 a letter was  circulated by George Snell asking whether a Committee on Mouse Genetic  Nomenclature should be formed. This letter was favourably received, and a small committee consisting of Drs Crew (later replaced by Gruneberg), Dunn and Snell was formed. Proposals for a system of genetic nomenclature were  canvassed, and after much discussion and a ballot the resulting rules were  published in the Journal of Heredity in 1940. The accompanying gene list included a total of 31 genetic loci. The committee (with a new and enlarged membership) continues to ensure that nomenclature systems are adequate to  cope with genetic advances, and publishes new rules where appropriate. Rules for chromosome nomenclature were also formulated (Committee on Standardised Nomenclature of Mice 1972).

      More recently, the rules have  undergone a process of almost constant review as new types of genetic marker  such as gene and DNA probes have been developed. Gene symbols are also being changed as the biochemical processes underlying a mutation are elucidated,  and in an attempt to keep common nomenclature for the same genes in different species, including humans.

      Brief nomenclature rules for inbred strains are given elsewhere in this web site (see Nomenclature button), with more extensive rules both for inbred strains and genes given on the Jackson Laboratory web site.

    Early sources of information

      The first edition of Biology of the Laboratory Mouse, published in 1941(Snell 1941), and edited by Dr G. D. Snell, helped to consolidate  information available at that time. Chapters included early embryology,  histology, spontaneous neoplasma, gene and chromosome mutations, the  genetics of spontaneous tumour formation, the genetics of tumour transplantation, endocrine secretion and tumour formation, the milk  influence in tumour formation, inbred and hybrid animals and their value  in research, parasites, infectious diseases of mice and care and recording. Most of the references to inbred strains occurred in the  chapters on various aspects of cancer and are now largely out of date,  although the chapter on the value of inbred strains and hybrids by W. L.  Russell was one of the first written statements on the value of inbred strains in research and remains valid to this day. The second edition of Biology of the Laboratory Mouse, edited by E. L. Green, was published in  1966 (Green 1966), with individual chapters written by staff of The  Jackson Laboratory. This book covered all aspects of mouse biology and  again led to the consolidation of information available up to that time.

      The Genetics of the Mouse, by Hans Gruneberg, published in 1943, with  a second edition in 1952, (Gruneberg 1952) summarised the information to  date on genetic variation in the mouse. Although the book did not deal specifically with inbred strains, it gave many examples of the differences  between strains both in anatomical features and resistance to disease. Genetic variants and strains of the laboratory mouse, edited by Dr.  Margaret Green in 1989, with a second edition edited by Drs. Mary Lyon and A.G. Searle in 1989, and a 3rd. edition published in 1996, edited by Drs.  Mary Lyon Sohaila Rastan and SDM Brown (Lyon et al 1996) is essentially it  is a catologue of information on mouse genetics. However, there is so much  information and it is up-dated so frequently that it is now only  manageable on the Web. “Mouse Genetics” by Lee Silver (Silver 1995) is a true successor to Gruneberg’s book. It covers the history and origins of laboratory mice, the mouse genome, mutagenesis and transgenesis, genetic mapping and linkage analysis and other strategies for locating genes.
       

    Mouse News Letter

      In 1939 George Snell had also foreseen the need to improve communications between geneticists working with the mouse, and proposed that a Mouse Genetic News should be produced. The first edition was published in November 1941, but because of the war it could only be distributed in North America. It contained the rules on gene nomenclature,  lists of mutants and inbred strains, and lists of laboratories holding  mouse stocks. A second edition was published in the Journal of Heredity in 1948. Although this publication was useful, it was recognised by many that a regular news sheet was needed. Eventually, Mouse News Letter was  started, and the first edition was produced in July 1949, under the editorship of Drs L. C. Dunn and S. Gluecksohn-Schoenheimer, although the  editorship was immediately handed over to Dr T. C. Carter. By 1958 Mouse  News Letter (MNL) was being edited by Dr Mary Lyon, who stated its  functions as follows:
      1. “The reporting of new mutants, inbred strains and substrain symbols,  and the ancillary function of helping contributors in standardising  symbols and avoiding duplication.
      2. The locating of stocks of mutants and inbred strains.
      3. The prevention of loss of important stocks by enabling contributors to  advertise their intention to discontinue these stocks.
      4. The dissemination of general news of interest to mouse workers (those items at the front of MNL).
      5. The notification of research news.”
      According to Dr. Lyon “MNL is not a journal for the publication of scientific results. The research items are intended to indicate to readers what subjects are under investigation (Work in progress) and what  published results they may expect to find in other periodicals either now (Publications) or in the future (Research notes).'
       

      In 1990 Mouse News Letter changed its name to Mouse Genome, in order to  reflect the ever increasing emphasis on fundamental mouse genetics. It also began to accept short refereed reports in addition to the unrefereed Laboratory Reports, and increased publication to four times per year.  Finally, it was incorporated into a more formal journal Mammalian Genome.

      In 1954 a new dimension was added to Mouse News Letter with the  publication of the first bibliography listing of inbred strains by Joan Staats. This contained about 270 references to papers which had used  inbred or mutant mice, published during six months of 1953 and indicating which strains were used in each study. Some 46 per cent of the papers were  from the general area of cancer research, with less than 4 per cent being in the field of immunology. This bibliographical supplement continued until Joan Staats retired in 1984.

    First listing of inbred strains of mice

      The Committee on Standardised Nomenclature for Inbred Strains of Mice,  published its first report in 1952. It included rules for the  nomenclature of inbred strains, the first listing of more than 80 such strains and a list of those people or institutions which maintained them. Examination of the long lists of synonyms for some of these strains shows  that by this time nomenclature had almost got out of hand, and it took a  number of subsequent editions to get the listings into good order.
      The first listing of inbred strains of other species was published (Billingham and Silvers 1959), but lack of a committee on nomenclature or appropriate  News Letters for other species has resulted in continuing confusion,  although the lists of strains of rats was updated in 1990 before it was  eventually transferred to the Web (Greenhouse et al 1990).

More Recent Developments

    Recombinant inbred strains (1971)

      The development of the first set of recombinant inbred strains by D.W. Bailey (Bailey 1971) and their subsequent development on a large scale by B. A. Taylor (both of the Jackson Laboratory) provided research workers  with a powerful new tool for genetic analysis of differences between pairs  of inbred strains. Sets of RI strains are developed by crossing two  standard inbred strains, and then sib mating the offspring for 20 or more generations as a number of parallel “recombinant” strains in which genes from the two parental strains have become assorted into new combinations. Study of the “strain distribution pattern” or “SDP” will often indicate whether or not the observed character is due to the segregation of a single Mendelian locus. If so, there is a strong chance that the pattern  may coincide with the pattern observed for a marker locus, which implies  genetic linkage. Sets of RI strains can be sometimes be used to map  quantitative trait loci (QTLs), although large numbers of strains are needed to resolve more than two or three loci. For example, the AXB, BXA  set of RI strains has been used to show that there is a locus for lung  tumour susceptibility on chromosome 6 in mice(Malkinson et al 1985). RI  strains are particularly useful for analysing characters such a percent mortality which can not be studied in a single individual.

    Recombinant  congenic strains

      “Recombinant congenic strains” (RC) are produced by crossing two standard inbred strains, followed by a few (often 2-4) generations of  backcrossing to one of the parental strains, then sib mating (Demant and Hart 1986). These provide an interesting tool for identifying genes  associated with polygenic inheritance. The use of these strains is  discussed in more detail in chapter 10. More recently, the availability of genetic markers covering the full length of all of the chromosomes has made it possible to develop consomic or chromosome substitution strains in which a whole chromosome from one strain has been backcrossed into another strain(Nadeau et al 2000). A comparison of the background strain with the consomic strain provides a highly sensitive way of determining whether  there are any genes on the substituted chromosome which affect the  expression of a character of interest. Several sets of such strains are now in development.

    Freeze preservation of embryos

      The development of a practical technique for the freeze preservation of pre-implantation mouse embryos (Whittingham et al 1972) makes it more economic to preserve strains and congenic lines which are only  infrequently used, reduces genetic drift in inbred strains due to the accumulation of new mutations, makes the international exchange of genetic  stocks easier, and acts as an insurance against disease or other  catastrophe destroying the stocks held at one centre. Although this  technique has been available for over thirty years, and is used routinely in some laboratories, there is still considerable scope for its more widespread use. Many laboratories are producing genetically modified mice  leading to a proliferation of strains. Embryo freezing can be used as a cost effective way of maintaining stocks which are likely to be wanted in  the future, but are not under immediate investigation.

    Molecular  techniques

      Undoubtedly the most significant advance during the last two decades is the exploitation of molecular techniques in biomedical research. The discovery of “variable number of tandem repeas” or VNTR loci by Alec  Jeffreys and others (Jeffreys et al 1987) leading to DNA fingerprinting, and the development of genetic markers based on restriction fragment length polymorphisms were important developments. This was followed by the  discovery of microsatellite markers which can be detected with very small  samples of DNA using the polymerase chain reaction and synthetic  oligonucleotide primers (Dietrich et al 1992,Love et al 1990) and the more recent development of methods for detecting single nucleotide polymorphisms (SNPs) has transformed mammalian genetics.{Wiltshire, 2003  959 /id}. For the first time, it is now practical to map quantitative  trait loci (QTLs) controlling characters such as susceptibility to tumours  and behaviour, although the identification of the individual loci remains a difficult problem. This is discussed in greater detail in later  chapters.

    Transgenic strains

      Transgenic strains (Gordon et al 1980) which carry a foreign stretch of DNA as a result of microinjection into early embryos, have been used in  many ways including the study the role of non-coding regions in regulating gene expression, the effects of over-expression of a gene or expression in an abnormal site and the expression of abnormal genes such as oncogenes. Foreign proteins can be produced in, say, milk as a practical method of  manufacturing proteins of pharmaceutical importance. About 10% of such  strains result in “insertional mutagenesis” when the foreign DNA gets  incorporated into the host DNA in such a way that one of the host genes is inactivated. Most transgenic strains are produced using F1 hybrid embryos,  as these are more robust than inbred ones. As a result, many genes will segregate in later generations, so the transgenic strain is not inbred.  However, it is possible to use inbred embryos of some of the more robust strains. Strain FVB has proved to be of particular value as the male pronucleus, into which DNA is injected, is particularly large and easy to  see (Taketo et al 1991). The most widely used embryonal stem cell lines are based on strain 129, so in this case there is the potential to  maintain the transgenic strain on an inbred genetic background, although this strain has a poor breeding performance.

    Embryonic step cells, "knockout" and related technologies.

      ES cells are developed from pre-implantation embryos,  and retain the ability to differentiate into all tissue types (i.e. they are “totipotent”). Their development (Evans and Kaufman 1981) was of critical importance in the production of “knockout” mice in which a  specific gene is inactivated following homologous recombination with an inactivated gene (Thomas and Capecchi 1987,Travis 1992). The technique is  ideal for producing animal models of human diseases such as cystic fibrosis, and hereditary anaemias. It has also been used to study the function of several genes associated with the immune system and cancer,  often with surprising results. For example the p53 protein is thought to  be a key regulator of cell division, and it was predicted that if the gene for this protein was inactivated, the mice would die soon after birth. However, p53 knockout mice proved to be fully viable, though they do  develop a high incidence of tumours from about six months of age (Donehower  et al 1992). Many genes can be inactivated without any obvious change in  the phenotype. This may be because there are alternative pathways or  because the gene only has survival value in some circumstances, such as when encountering a pathogen.

      The sequencing of the human genome in 2001 (Lander et al 2001) the mouse in 2002 (Waterston et al 2002) and rat in 2004 will undoubtedly  speed up the rate of biological research. The challenge will now be to identify all the genes and their products, and inbred strains of mice are likely to play an important part in this research.
       

References

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 Billingham  RE, Silvers WK (1959), Inbred animals and tissue transplantation immunity,  Transplantation Bulletin 6: 399-40

 Committee (The) on Standardised Nomenclature for Inbred Strains of Mice (1952), Standardised nomenclature for inbred strains of mice, Cancer  Research 12: 602-613

 Committee on Standardised Nomenclature of Mice (1972), Standard karyotype of the mouse Mus musculus, Journal of Heredity 63: 69-72

 Curtis  MR, Bullock FD, Dunning WF (1931), A statistical study of the occurrence of spontaneous tumours in a large colony of rats, American Journal of Cancer  15: 67

 Demant  P, Hart AAM (1986), Recombinant congenic strains- a new tool for analyzing  genetic traits determined by more than one gene, Immunogenetics 24: 416-422

 Dietrich W, Katz H, Lincoln SE, Shin HS, Friedman J, Dracopoli NC, Lander E (1992), A genetic map of the mouse suitable for typing intraspecific  crosses, Genetics 131: 423-447

 Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery Jr CA, Butel JS, Bradley A  (1992), Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours, Nature 356: 215-221

 Evans MF, Kaufman MH (1981), Establishment in culture of pluripotential cells from mouse embryos, Nature 292: 154-156

 Falconer DS (1981), Introduction to quantitative genetics, Longman, London, New York

 Ferris  SD, Sage RD, Wilson AC (1982), Evidence from mt D.N.A. sequences that common  strains of inbred mice are descended from a single female, Nature 295:  163-165

 Ginsburg BE (1967), Genetic parameters in behavior research, in Behavior  genetic analysis, ed. Hirsch J, McGraw-Hill, New York p 135-153

 Gordon  JW, Scangos GA, Plotkin DJ, Barbosa JA, Ruddle FH (1980), Genetic transformation of mouse embryos by microinjection of purified DNA, Proceedings of the National Academy of Sciences 77: 7380-7384

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