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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1425.)
© 2000 American Heart Association, Inc.

Brief Reviews

Viewpoint: Are Studies in Genetically Altered Mice Out of Control?

Curt D. Sigmund

From the Departments of Internal Medicine and Physiology & Biophysics, The University of Iowa College of Medicine, Iowa City.

Correspondence to Curt D. Sigmund, PhD, Chair, Molecular Biology Interdisciplinary Program, Director, Transgenic and Gene Targeting Facility, Department of Internal Medicine and Physiology & Biophysics, 2191 Medical Laboratory, The University of Iowa College of Medicine, Iowa City, IA 52242. E-mail curt-sigmund{at}uiowa.edu

	Abstract

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Abstract—Because the use of transgenic and gene-targeted models has increased in popularity, the number of reports describing unpredictable phenotypic effects caused by variation in the genetic background used to generate or propagate these models has steadily increased. There are now many examples in which animals containing the same exact genetic manipulation exhibit profoundly different phenotypes when present on diverse genetic backgrounds, demonstrating that genes unrelated, per se, to the ones being targeted can play a significant role in the observed phenotype. Herein, I will discuss (1) the source of genetic variability in mutant mouse models, (2) the appropriateness of using inbred mice as controls, and (3) strategies to help minimize genetic variation between experimental and control mice.

Key Words: transgenic mice • knockout mice • genetics • epigenetic

	Introduction

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It is well documented that many physiological parameters in mammals are genetically determined. Therefore, it should not come as a surprise that many of the phenotypes examined in transgenic and knockout models are influenced by the genetic background in which they are studied. Genetic background is the collection of all genes present in an organism that influences a trait or traits. These genes may be part of the same biochemical or signaling pathway or of an opposing pathway or may appear unrelated to the gene being studied. Although all mouse strains contain the same collection of genes, it is allelic variation (sequence differences) and the interactions between allelic variants that influence a particular phenotype. These "epigenetic" effects can dramatically alter the observed phenotype and therefore can influence or alter the conclusions drawn from experiments.

Studies performed over the past few years have clearly illustrated that phenotypes caused by specific genetic modifications are strongly influenced by genes unlinked to the target locus. For example, whereas deletion of the p53 tumor suppressor gene causes a dramatic increase in the frequency of tumor formation in those mice compared with wild-type mice, the types of tumors formed, their numbers per animal, and age of tumor onset vary in different genetic backgrounds.^{1 2 3} Other phenotypes observed in transgenic and gene-targeted animals influenced by genetic background include ethanol tolerance, sepsis, immunity, locomotor activity, behavior, organ structure, development, and cardiovascular physiology (Table). As examples of the latter, the incidence of stroke in mice deficient in tissue plasminogen activator and susceptibility to atherosclerosis in apoE-deficient mice differ when the knockout loci are present on C57BL/6, 129/Sv, or FVB/N backgrounds.^{8 13}

View this table: [in this window] [in a new window]   Table 1. Phenotypes Exhibiting Genetic Background Effects in Knockout and Transgenic Mice

On a positive note, phenotypic differences caused by allelic variation outside the target locus can provide a molecular genetic tool to identify and clone "modifier genes," which influence a phenotype.¹⁷ However, as stated above, these differences can cause significant problems when interpreting and comparing the results of transgenic and knockout studies between laboratories.

	The Problem

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At the heart of the problem is genetic heterogeneity among strains used to generate transgenic and knockout mice. It is generally acknowledged that it is easier and more efficient to generate transgenic mice by using hybrid strains derived from 2 different genetic backgrounds. Presumably, this is because hybrid strains exhibit superior reproductive performance, are easier to superovulate, and have higher quality embryos for microinjection, a phenomenon referred to as "hybrid vigor."^{18 19} Because of this, many transgenic laboratories use embryos derived from F₂ crosses of C57BL/6xSJL (B6SJL) or C57BL/6xDBA/2 (B6D2), among other combinations. When hybrid strains are used, each transgenic founder is genetically different from every other founder. This leaves the investigator with a choice of either continuing to breed their transgenic mice with hybrid strains to propagate the lines or, in cases in which genetic background issues are recognized and likely to be important, to generate congenic strains (defined below) by successive backcross breeding to 1 inbred strain, typically C57BL/6. Less frequently used are transgenic mice generated directly on inbred strains. The inbred FVB/N strain is used by some laboratories because it exhibits excellent reproductive performance, it has large litters, and the 1-cell fertilized embryos have prominent and easily injectable pronuclei.¹⁹ One limitation is that it is genetically distinct from the C57BL/6 strain, which is used by many investigators.

A second issue specifically related to transgenic mice (but not gene-targeted mice) is the position effect. Because of the random nature of the transgene insertion event after pronuclear injection, each resultant founder contains the transgene at a different site in the genome. These position effects can profoundly influence transgene expression and, therefore, the observed phenotype.^{20 21} This occurs because transcriptional regulatory elements present at or near the site of insertion (controlling the expression of a nearby gene or gene cluster) could impart new instructions on the transgene. Consequently, it is essential that several independent lines of mice, derived from founders with different insertion sites, are examined before a conclusion relating a phenotype to a specific pattern of transgene expression is made.

When performing gene targeting in embryonic stem (ES) cells, position effects are essentially eliminated but not the effects caused by genetic variability. As in the transgenic experiments, this results from the generation of hybrid strains. Most commonly used ES cell lines are derived from strain 129, and a number of 129 substrains are in existence (129/Sv, 129/SvEv, and 129/Ola), further complicating the scenario. As mentioned above, hybrid vigor has been reported for the viability of ES cell lines.²² Although many (but not all) ES cell lines are themselves inbred, most investigators report that the 129 strain exhibits poorer reproductive performance than other inbred strains and also exhibits other abnormalities, including development of teratocarcinoma. This has prompted most investigators to breed their chimeras to C57BL/6, thus generating a hybrid mouse that is heterozygous (+/-) at the target locus and an F₁ between C57BL/6x129 at all other loci. The F₁ mice are all genetically identical because they inherit 1 chromosomal complement each from the 129 and C57BL/6 strains. However, when they are intercrossed to generate a mouse homozygous (-/-) for the target locus, the resultant offspring become an F₂ of the parent strains. Therefore, whether wild-type, heterozygous, or homozygous for the target locus, the offspring have a random mix of 129 or C57BL/6 chromosomal DNA throughout the genome. The maintenance of a strain homozygous at the target locus by continuous inbreeding of these F₂ mice can eventually select for phenotypic changes because loci causing deleterious effects are lost, and those providing a survival advantage are retained. Consequently, maintenance of the targeted locus in this manner is not recommended. Therefore, investigators are again left with the option to retain the mixed genetic background of the strains or to generate congenic strains.

Further complicating this problem has been the marked increase in the generation of double-knockout strains and the combinatorial use of knockout and transgenic rescue. In the latter, transgenes expressed either systemically or tissue-specifically are transferred into a knockout mouse to rescue some altered phenotype (often lethality).²³ Moreover, the development of inducible transgenes and methods using the cre-loxP recombinase system to generate cell-specific knockouts will necessitate the introduction of multiple transgenes into a single genetic background. Clearly, it will become important to avoid the creation of a mixed genetic background so complex as to preclude any reasonable use of controls and prevent replication by other investigators.

	Effective Experimental Strategies

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Clearly, when transgenic and gene-targeting experiments are designed, the ideal situation would have control mice that are genetically identical to the experimental mice. The use of isogenic strains differing only in the presence or absence of the target locus would be the "gold standard." However, this can only be achieved if inbred mice are used for the generation of experimental models. Therefore, whenever possible, inbred strains should be used as the choice of controls becomes obvious. As discussed above, when this is not a practical or feasible option, the next best alternative is to develop a program of continuous inbreeding to a common strain, thus generating congenic mice. A congenic strain is one that is genetically identical to a control strain except for a single region of 1 chromosome (Figure 1). In the context of this discussion, this refers either to the target locus or the inserted transgene. The generation of congenic strains also provides an opportunity to place the target locus on a number of different genetic backgrounds and thus directly test for strain-specific modifier loci.

View larger version (28K): [in this window] [in a new window]   Figure 1. Generation of a congenic strain. A schematic representation of the chromosomal content in the generation of a congenic strain is shown. The 129 chromosomes are red, and the C57BL/6 chromosomes are blue. A targeted modification induced in ES cells is shown as a solid block box. Only 3 chromosomes are shown for simplicity. The top left illustrates a heterozygous knockout after germ-line transmission through a chimera. This mouse is heterozygous at the target locus, with an F1 between 129 and C57BL/6 at all loci. To generate the congenic strain, the F1 is successively backcrossed to a C57BL/6 mouse (all blue), and the targeted locus is selected in all offspring. The 129 genome is progressively diluted in each backcross because of the random assortment of chromosomes and homologous recombination. After 6 generations of backcross breeding, the resultant offspring are >99% C57BL/6 except for the region surrounding the targeted modification, which remains derived from the 129 strain.

Although the generation of congenic mice is simple, requiring only accurate record keeping, it can be time-consuming and expensive, especially when multiple lines must be developed. Six generations of backcross breeding (2 years) is required before the genetic backgrounds are statistically >99% homogeneous, and the return on additional generations of backcross breeding markedly diminishes thereafter. For example, it requires 4 additional generations to increase genetic homogeneity from 99.2% to 99.95%. The use of a speed-congenic approach or a combination of in vitro fertilization and prepubertal superovulation can be used to decrease the time needed to generate congenic strains.^{24 25} The speed-congenic approach makes use of the well-developed genetic map of the mouse, thus affording an opportunity to screen the DNA of each offspring generated along the route toward congenic production to select for mice containing markers from the appropriate genetic background at the target locus and elsewhere.^{26 27} Those mice that are "further" along in congenic development than expected, on the basis of random segregation alone, can be selected by this process for further breeding.

After a C57BL/6 congenic knockout strain is derived, either nontransgenic littermates or age-matched inbred C57BL/6 mice should serve as reasonable controls. However, it is important for the researcher to appreciate that even this scenario has weaknesses. Indeed, 1 limitation of using littermate or wild-type mice as controls for congenic transgenic (or knockout) strains is that some parental genomic DNA upstream and downstream from the target locus (129 DNA in the case of ES cell–derived gene targeting) remains. By use of the same example as described above, this occurs because as the targeted modification (made in 129 genomic DNA) is introgressed into the C57BL/6 strain, the targeted locus and therefore 129 DNA in the vicinity of (or linked to) the locus will be selected in each backcross generation (Figure 2A). The location of the breakpoint between C57BL/6 and 129 genomic DNA upstream and downstream from the target locus will depend on where the recombination between the 2 genomes occurred. Therefore, nontransgenic littermates and wild-type C57BL6 mice will lack the targeted locus and also the closely linked 129 genomic DNA (Figure 2B). In some cases, this DNA may contain closely linked modifier genes. This may be especially critical when examining large gene families, which may have members closely clustered in the genome.

View larger version (20K): [in this window] [in a new window]   Figure 2. Comparison between experimental and control strains. A schematic diagram of the chromosomal content between experimental (A) and control strains (B and C) is shown. The experimental mouse is homozygous for the targeted disruption (solid black box) and is a C57BL/6 (blue) congenic strain. A small amount of 129 genomic DNA (red) upstream and downstream from the target locus remains. A C57BL/6 inbred mouse (B) is blue at all loci, and although it lacks the targeted modification, it also lacks the 129 DNA linked to the disruption. The ideal control (C) would be a C57BL/6 congenic strain with a similar extent of 129 DNA as shown in panel A.

Therefore, the optimal control would be a congenic control strain containing a similar amount of foreign genomic information around the target locus but lacking the targeted modification itself (Figure 2C). Absolutely identical congenic strains cannot be generated. However, similarities between control and experimental strains can be maximized by taking advantage of the dense genetic map of the mouse and the thousands of polymorphic microsatellite markers distributed throughout the mouse genome.²⁸ For example, control mice can be selected that contain C57BL/6-specific markers throughout the genome except in the region of the target locus, where 129-specific markers would be selected. These mice can then be propagated to generate a control congenic strain that is similar to the experimental mouse but lacks the targeted ES cell–induced modification.

Of course, we must recognize that from a practical standpoint, circumstances will often dictate assessing the phenotype of a knockout mouse long before a congenic strain can be generated. If these mice were derived from 129 ES cells and the chimera was bred to C57BL/6, it is predictable that each mouse, while containing the same targeted modification of the genome, will be genetically different at all other loci because of random segregation and recombination in the F₂ generation. In this case, it would be inappropriate to use either inbred C57BL/6 or 129 mice solely as controls. Instead, wild-type or heterozygous littermates from the same breedings should be included as well. The use of littermates would help minimize environmental variability in such experiments. Moreover, larger numbers of mice should be examined to ensure that the range of phenotypes possible due to epigenetic interactions with the genetic background is observed. Although not genetically identical, when examined as a population, the experimental and control groups could be considered "genetically similar." Once the phenotypes are assessed, it would be prudent to generate congenic strains and reexamine the phenotype in the resultant animals.

	Guidelines

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Until such time as a standardized mouse strain exists that facilitates easy generation of transgenic and knockout mice, the debate over the proper use of experimental and control mice will continue. There are no easy solutions to this problem. As illustrated above, in the absence of inbred strains, there is no optimal set of experimental and control conditions that normalizes the epigenetic effects of unlinked loci. Therefore, it becomes the responsibility of the investigator to use common sense and design the best possible control experiments that fit the individual situation, to assess whether the phenotype observed in their model is due specifically to the targeted modification or is affected by other loci, and to inform the scientific community if phenotypic alterations become evident. The geneticists at the Banbury Conference on Genetic Background in Mice²⁹ in 1996 established 3 general guiding principals for the use of transgenic and gene targeted mice in neuroscience. These principals should be applicable to all disciplines, and the reader is referred to that article for a detailed discussion of options for designing such experiments.²⁹ Their guidelines state the following: (1) Published reports must include a detailed description of the genetic background of the mice studied that is sufficient enough to allow replication of the study. (2) The genetic background chosen for the studies should not be so complex as to preclude replication. (3) Use of common or standardized genetic background would facilitate comparison of experimental results among laboratories.

Minimally, these guidelines provide a common-sense approach that provides the reader with sufficient information to understand and potentially replicate reported results and also provide a framework to identify the causes of phenotypic variation observed in different laboratories. It makes common sense to recommend that these guidelines be adopted by all researchers using genetically modified mice as models of cardiovascular disease until such time as standardized strains are used universally.

	Footnotes

 
Guest Editor for this article was Elizabeth Nabel, National Institutes of Health, Bethesda, Md.

Received January 6, 2000; accepted February 28, 2000.

	References

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