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Genome editing for the reproduction and remedy of human diseases in mice

Abstract

With the recent progress in genome-editing technologies, such as the CRISPR/Cas9 system, genetically modified animals carrying nucleotide substitutions or large chromosomal rearrangements can be produced rapidly and at low cost. Such genome-editing techniques have been applied in the generation of animal models, especially mice, for reproducing human disease mutations, such as single-nucleotide polymorphisms (SNPs) or large chromosomal rearrangements identified by genome-wide screening analyses. While application methods are under development for various complex mutations involving genome editing for mimicking human disease-causing mutations in mice, functional studies of mouse models carrying replicated human mutations are gradually being published. In this review, we discuss the recent progress in application methods of the CRISPR/Cas9 system, focusing on the production of mouse models of diseases.

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References

  1. 1.

    Capecchi MR. Altering the genome by homologous recombination. Science. 1989;244:1288–92.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Kim YG, Cha J, Chandrasegaran S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc Natl Acad Sci USA. 1996;93:1156–60.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Christian M, Cermak T, Doyle EL, Schmidt C, Zhang F, Hummel A, et al. Targeting DNA double-strand breaks with TAL effector nucleases. Genetics. 2010;186:757–61.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Cong L, Ran FA, Cox D, Lin S, Barretto R. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339:819–23.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, et al. RNA-guided human genome engineering via Cas9. Science. 2013;339:823–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337:816–21.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Shen B, Zhang J, Wu H, Wang J, Ma K, Li Z, et al. Generation of gene-modified mice via Cas9/RNA-mediated gene targeting. Cell Res. 2013;23:720–3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Wang H, Yang H, Shivalila CS, Dawlaty MM, Cheng AW, Zhang F, Jaenisch R. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell. 2013;153:910–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Inui M, Miyado M, Igarashi M, Tamano M, Kubo A, Yamashita S, et al. Rapid generation of mouse models with defined point mutations by the CRISPR/Cas9 system. Sci Rep. 2014;4:823.

    Google Scholar 

  10. 10.

    Aida T, Chiyo K, Usami T, Ishikubo H, Imahashi R, Wada Y, et al. Cloning-free CRISPR/Cas system facilitates functional cassette knock-in in mice. Genome Biol. 2015;16:507.

    Article  Google Scholar 

  11. 11.

    Chu VT, Weber T, Wefers B, Wurst W, Sander S. Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells. Nature. 2015;33:543–8.

    CAS  Google Scholar 

  12. 12.

    Stracker TH, Carson CT, Weitzman MD. Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature. 2002;418:348–52.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Xie A, Kwok A, Scully R. Role of mammalian Mre11 in classical and alternative nonhomologous end joining. Nat Struct Mol Biol. 2009;16:814–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Maruyama T, Dougan SK, Truttmann MC, Bilate AM, Ingram JR, Ploegh HL. Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining. Nat Biotechnol. 2015;33:538–42.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Srivastava M, Nambiar M, Sharma S, Karki SS, Goldsmith G, Hegde M, et al. An inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression. Cell. 2012;151:1474–87.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Song J, Yang D, Xu J, Zhu T, Chen YE, Zhang J. RS-1 enhances CRISPR/Cas9- and TALEN-mediated knock-in efficiency. Nat Commun. 2016;7:10548.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Jayathilaka K, Sheridan SD, Bold TD, Bochenska K, Logan HL, Weichselbaum RR, et al. A chemical compound that stimulates the human homologous recombination protein RAD51. Proc Natl Acad Sci USA. 2008;105:15848–53.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Singh P, Schimenti JC. The genetics of human infertility by functional interrogation of SNPs in mice. Proc Natl Acad Sci USA. 2015;112:10431–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Lee VS, Halabi CM, Hoffman EP, Carmichael N, Leshchiner I, Lian CG, et al. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc Natl Acad Sci USA. 2016;113:8759–64.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Miyado M, Inui M, Igarashi M, Katoh-Fukui Y, Takasawa K, Hakoda A, et al. The p.R92W variant of NR5A1/Nr5a1 induces testicular development of 46,XX gonads in humans, but not in mice: phenotypic comparison of human patients and mutation-induced mice. Biol Sex Differ. 2016;7:56.

    Article  Google Scholar 

  21. 21.

    Igarashi M, Takasawa K, Hakoda A, Kanno J, Takada S, Miyado M, et al. Identical NR5A1 missense mutations in two unrelated 46,XX individuals with testicular tissues. Hum Mutat. 2016;38:39–42.

    Article  PubMed  Google Scholar 

  22. 22.

    Bulfield G, Siller WG, Wight PA, Moore KJ. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci USA. 1984;81:1189–92.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Sicinski P, Geng Y, Ryder-Cook A, Barnard E, Darlison M, Barnard P. The molecular basis of muscular dystrophy in the mdx mouse: a point mutation. Science. 1989;244:1578–80.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Long C, McAnally JR, Shelton JM, Mireault AA, Bassel-Duby R, Olson EN. Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science. 2014;345:1184–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Grompe M, al-Dhalimy M, Finegold M, Ou CN, Burlingame T, Kennaway NG, Soriano P. Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. Genes Dev. 1993;7:2298–307.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Aponte JL, Sega GA, Hauser LJ, Dhar MS, Withrow CM, Carpenter DA, et al. Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1. Proc Natl Acad Sci USA. 2001;98:641–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Yin H, Song C-Q, Dorkin JR, Zhu LJ, Li Y, Wu Q, et al. Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat Biotechnol. 2016;34:328–33.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Xie C, Zhang Y-P, Song L, Luo J, Qi W, Hu J, et al. Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome. Cell Res. 2016;26:1099–111.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Wu W, Lu Z, Li F, Wang W, Qian N, Duan J, et al. Efficient in vivo gene editing using ribonucleoproteins in skin stem cells of recessive dystrophic epidermolysis bullosa mouse model. Proc Natl Acad Sci USA. 2017;114:1660–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Wang L, Shao Y, Guan Y, Li L, Wu L, Chen F, et al. Large genomic fragment deletion and functional gene cassette knock-in via Cas9 protein mediated genome editing in one-cell rodent embryos. Sci Rep. 2015;5:17517.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Hara S, Kato T, Goto Y, Kubota S, Tamano M, Terao M, Takada S. Microinjection-based generation of mutant mice with a double mutation and a 0.5 Mb deletion in their genome by the CRISPR/Cas9 system. J Reprod Dev. 2016;62:531–6.

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Kato T, Hara S, Goto Y, Ogawa Y, Okayasu H, Kubota S, et al. Creation of mutant mice with megabase-sized deletions containing custom-designed breakpoints by means of the CRISPR/Cas9 system. Sci Rep. 2017;7:1156.

    Article  Google Scholar 

  33. 33.

    Boroviak K, Doe B, Banerjee R, Yang F, Bradley A. Chromosome engineering in zygotes with CRISPR/Cas9. Genesis. 2016;54:78–85.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Birling M-C, Schaeffer L, Andr P, Lindner L, Mar chal D, Ayadi A, et al. Efficient and rapid generation of large genomic variants in rats and mice using CRISMERE. Sci Rep. 2017;7:43331.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Kraft K, Geuer S, Will AJ, Chan WL, Paliou C, Borschiwer M, et al. Deletions, inversions, duplications: engineering of structural variants using CRISPR/Cas in mice. Cell Rep. 2015;10:833–9.

    CAS  Article  Google Scholar 

  36. 36.

    Yoshimi K, Kunihiro Y, Kaneko T, Nagahora H, Voigt B, Mashimo T. ssODN-mediated knock-in with CRISPR-Cas for large genomic regions in zygotes. Nat Commun. 2016;7:10431.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by JSPS KAKENHI Grant Number 17K07429 (to S.T.). We thank Editage (www.editage.jp) for English-language editing.

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Correspondence to Shuji Takada.

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Hara, S., Takada, S. Genome editing for the reproduction and remedy of human diseases in mice. J Hum Genet 63, 107–113 (2018). https://doi.org/10.1038/s10038-017-0360-4

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