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Genomically humanized mice: technologies and promises

Nature Reviews Genetics volume 13, pages 14–20 (2012)Cite this article

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Abstract

Mouse models have become an invaluable tool for understanding human health and disease owing to our ability to manipulate the mouse genome exquisitely. Recent progress in genomic analysis has led to an increase in the number and type of disease-causing mutations detected and has also highlighted the importance of non-coding regions. As a result, there is increasing interest in creating 'genomically' humanized mouse models, in which entire human genomic loci are transferred into the mouse genome. The technical challenges towards achieving this aim are large but are starting to be tackled with success.

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Figure 1: Methods of humanized mouse synthesis.

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Acknowledgements

A.D., R.B.-S., V.J.L.T., A.J.H.S. and E.M.C.F. were funded by the UK Medical Research Council, and V.L.J.T. and E.M.C.F. also received funding from the Wellcome Trust and the AnEUploidy consortium, a European Union FP6 Integrated Project. We thank M. Pepys, G. Taylor and S. Wood for information about serum amyloid P (SAP) and J.-F. Bureau, P. D'Eustachio, D. Hughes, R. Kumar, M. Landrum, J. Milner and H. Noyes for information about human-specific genes. We apologize if important papers have been omitted owing to space constraints.

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Authors and Affiliations

  1. Rosie K. A. Bunton-Stasyshyn and Elizabeth M. C. Fisher are at the Department of Neurodegenerative Disease, Anny Devoy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.,

    Anny Devoy, Rosie K. A. Bunton-Stasyshyn & Elizabeth M. C. Fisher

  2. Victor L. J. Tybulewicz is at the MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.,

    Victor L. J. Tybulewicz

  3. Andrew J. H. Smith is at the Institute for Stem Cell Research, MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh bioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, UK.,

    Andrew J. H. Smith

  4. Andrew J. H. Smith is also at the MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.,

    Andrew J. H. Smith

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Correspondence to Elizabeth M. C. Fisher.

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FURTHER INFORMATION

Victor L. J. Tybulewicz's homepage

Andrew J. H. Smith's homepage

Elizabeth M. C. Fisher's homepage

ENCylopedia Of DNA Elements

International Knockout Mouse Consortium

Knockout Mouse Project (KOMP)

Glossary

Conditional mutations

Mutated sequences that are expressed under experimental control. For example, in a conditional knockout, deletion of a crucial exon that is flanked by recombination sites can be induced by expressing a recombinase that is under the control of a tissue-specific promoter.

Gene targeting

A method of exchanging genetic information from a donor vector into a recipient genome by exploiting a DNA repair mechanism that recognizes homology between the donor DNA and the recipient locus. It results in the replacement of the original genomic sequence with the donor sequence.

Genome-wide association studies

(GWASs). Whole-genome scans that are designed to test the statistical association between finely spaced polymorphic genetic markers and traits under study. Large numbers of phenotypically well-classified DNA samples are required to have sufficient statistical power to detect such associations.

Inducible mutations

A class of conditional mutation that is expressed by using a ligand-inducible recombinase. Inducible mutations allow recombinase-driven changes to be induced at a particular time point by delivering the ligand into the animal by injection, diet or using viral vectors.

Knock-in mice

Mice carrying a targeted replacement or insertion. This could be generated by an exchange of nucleotide sequence to change the encoded protein sequence or by an insertion to create a tagged protein.

Knockout mice

Mice in which the functional protein-coding capacity of a particular gene has been disrupted. This could be generated by a targeted deletion, gene trap, or targeted conditional knockout.

Knockout Mouse Project

(KOMP). A programme funded by the US National Institutes of Health (NIH) contributing to the International Mouse Knockout Consortium (IKMC) to generate a null mutation in every mouse gene. Other contributors are the Texas Institute for Genomic Medicine (TIGM), the North American Conditional Mouse Mutagenesis Program (NorCOMM) and the European Conditional Mouse Mutagenesis Programme (EUCOMM).

Microcell-mediated chromosome transfer

(MMCT). A method for transferring entire chromosomes or chromosome fragments from a donor cell line into a recipient cell line.

Minigene

A gene construct that contains fewer exons and introns than its original full gene counterpart. Minigenes have been used to investigate regulatory sequences but may also be used because of their more convenient size.

Pronuclear injection

A process by which DNA is added to the genome, generally to create transgenic mice. Linearized DNA is injected into one of the two pronuclei of the fertilized egg, where it is stably incorporated into the genome. The eggs are then developed to term in a pseudopregnant female mouse.

Recombineering

Derived from 'recombination-mediated genetic engineering', this process uses recombination functions encoded by λ-phages to mediate in vivo recombination using short stretches of homologous sequence (30–50 nucleotides long) that can be readily appended to the termini of any desired DNA fragment.

Transchromosomic mouse strains

A mouse strain into which either an entire chromosome or a chromosome fragment from another species has been transferred. This chromosome or chromosome fragment may be freely segregating or inserted into an existing mouse chromosome.

Xenogeneic transplantation

The transplantation of tissues or cells derived from one species into another. For example, the introduction of human stem cells into an immune-deficient mouse strain.

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Devoy, A., Bunton-Stasyshyn, R., Tybulewicz, V. et al. Genomically humanized mice: technologies and promises. Nat Rev Genet 13, 14–20 (2012). https://doi.org/10.1038/nrg3116

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