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Transgenesis and Genome Manipulations

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Genetics of the Mouse

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Abstract

In the early 1980s, the expression of transgenic animals was proposed to define animals having foreign DNA sequences stably and deliberately inserted into their genome through human intermediaries. With time and the advent of new techniques, this concept has progressively evolved, and nowadays, it is probably more appropriate to consider that transgenic animals are animals whose genetic characteristics have been altered using one of the techniques of genetic engineering. Whatever the definition, transgenic animals belong to the category of genetically modified or genetically engineered organisms (GMOs).

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Notes

  1. 1.

    For this reason, the technique is sometimes designated “pronuclear transgenesis.”

  2. 2.

    The genetic elements regulating gene expression are sometimes numerous and not always located in the close vicinity of structural genes. This explains (at least in part) why cloned structural genes, when used as transgenes, are sometimes regulated differently from the same genes in their natural, native environment (see Chap. 5). This point is inherent to transgenesis by in ovo injection and must always be kept in mind.

  3. 3.

    In situ hybridization with labeled cDNAs is another way of analyzing the expression profile of a given gene.

  4. 4.

    The phage-transfected bacteria with mutations in the lacI gene form blue plaques, whereas bacteria with a non-mutated lacI form colorless plaques in tests with the Big Blue® strain. With the Muta™Mouse strain, the basic principle is similar but the color of the plaques depends upon the experimental conditions.

  5. 5.

    The first of the two alleles resulting from a transgenic insertion at the Formin locus (Fmn-Chr 5) has been known for a long time under the name of limb deformity (ld).

  6. 6.

    Well before the development of ES cells, another kind of cell, the embryonal carcinoma or EC cells, was used by oncologists and geneticists for investigating the genetics of cell–tissue differentiation. These cells were derived from spontaneous or experimentally induced testicular or ovarian teratocarcinomas (Stevens 1960). They were cultured in vitro, in the form of stable undifferentiated cell lines and then transplanted into mice of the same strain (syngeneic transplantation). Most of these cell lines, once engrafted, were able to differentiate into a variety of tissue (nervous tissue, bone, fat tissue, muscle, etc.), and some even proved able to participate in the formation of a chimeric organism (Papaioannou et al. 1975). They had, however, major drawbacks for the study of tissue differentiation: They were malignant and became rapidly aneuploid, and accordingly, they could not be used for the production of chimeric mice with germ line transmission.

  7. 7.

    Induced pluripotent stem cells (iPSCs) are pluripotent cells derived from adult somatic cells after forced re-expression of some specific genes that are normally inactive. Such cells have been established in many species including human and mice. These iPSCs have many characteristics in common with ES cells and are being used in many experiments (for example, in the area of regenerative medicine). However, they have no obvious advantages over the long-established ES cells for the production of transgenic mice, and accordingly, they will not be considered in this chapter.

  8. 8.

    The two strains C57BL/6N (ES cells) and C57BL/6J (genome sequence) are not completely identical, and recent estimates indicate a difference of ~1–2 % (SNPs) at the genome level (see Chap. 9).

  9. 9.

    Mutations at the mouse Hprt locus probably occurred spontaneously in the past but were not recorded due to the complete absence of symptoms in the affected mice. We will never know for sure.

  10. 10.

    The observation of differences (sometimes dramatic) in the symptomatology associated with a human syndrome and those observed in mice affected by mutations in the same orthologous gene is common. This, however, does not affect the value of the model.

  11. 11.

    For their discoveries of the principles for introducing specific gene modifications in mice by the use of embryonic stem cells Drs. Mario Capecchi, Martin Evans, and Oliver Smithies were awarded the Nobel Prize in Medicine or Physiology in 2007.

  12. 12.

    The definition of knock-in also applies to the targeted insertion (and substitution) of any coding sequence at a particular locus of an organism. In these conditions, and in most instances, the inserted coding sequence is controlled by the regulatory regions of the targeted gene.

  13. 13.

    The HPRT mini-gene is a selection cassette that is unique, since selection may be applied for its presence or absence.

  14. 14.

    Hprt - cells cannot grow in HAT medium because aminopterin blocks the endogenous synthesis of both purines and pyrimidines.

  15. 15.

    Mice of this type are not transgenic animals sensu stricto because they do not have any exogenous DNA sequences “stably inserted into their genome.” However, they are still GMOs.

  16. 16.

    In short, the main difference between a knock-out and a knock-in allele is that, in the case of a knock-in, the gene product is different from the normal allele but still has a function, even if the function in question is totally unrelated to the function of the original allele. In the case of a knock-out, the gene has simply been made inoperative.

  17. 17.

    According to the official nomenclature rules, the symbol for this mutation should be Polb tm1.1Rsky. This was the first targeted mutagenesis at this locus in Rajewsky’s laboratory.

  18. 18.

    This explains why, with such molecular tools, any kind of chromosomal rearrangement can be engineered in vitro. In the past, these chromosomal rearrangements were occasionally collected in the progenies of mice after irradiation in the post-meiotic stages (see Chap. 3).

  19. 19.

    Trapping cassettes have also been designed with a marker gene or a selectable gene coupled to a suitable promoter but lacking a downstream polyadenylation signal. In this case, the transcript was also a hybrid molecule, utilizing the 3′ sequences of the host gene to acquire a poly (A) tail.

  20. 20.

    With, however, some handling fees.

  21. 21.

    Some domestic species (the rat in particular), present phenotypes that have not yet been documented in the mouse; this is why it would be important that the genetic arsenal that has been developed for the mouse be replicated in these other species.

  22. 22.

    A specific ZFN binds with 3 bp at the DNA level. Since there is a great variety of such motifs, a judicious selection of 3–6 of them allows the targeting of a 9–18-bp DNA domain, which is highly specific. Libraries of ready-made ZFNs are also available which allow the targeting of virtually any sequence in the mouse genome.

  23. 23.

    This comment concerning the time necessary to produce a knockout mutation in the mouse genome by using the ZFN strategy, although reduced, must nevertheless be compared with the time necessary to purchase, when available, an ES cell line harboring the same ready-made knockout, when the latter is available in a repository such as KOMP (https://www.komp.org/).

  24. 24.

    CRISPR is an acronym for clusters of regularly interspaced short palindromic repeats.

  25. 25.

    To paraphrase the title of an interesting review on the subject one could say that, nowadays, geneticists have at their disposition “a mouse for all reasons” (International Mouse Knockout Consortium 2007).

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Authors and Affiliations

  1. Institut Pasteur, Paris, France

    Jean-Louis Guénet

  2. Division of Basic Science Research, Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA

    Fernando Benavides

  3. Mouse Functional Genetics Unit, Institut Pasteur, Paris, France

    Jean-Jacques Panthier & Xavier Montagutelli

  4. Ecole Nationale Vétérinaire d’Alfort, Maisons-Alfort, France

    Jean-Jacques Panthier

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  1. Jean-Louis Guénet
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  2. Fernando Benavides
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  3. Jean-Jacques Panthier
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  4. Xavier Montagutelli
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Correspondence to Jean-Louis Guénet .

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Guénet, JL., Benavides, F., Panthier, JJ., Montagutelli, X. (2015). Transgenesis and Genome Manipulations. In: Genetics of the Mouse. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-44287-6_8

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