Noto, F. K., Adjan-Steffey, V., Tong, M., Ravichandran, K., Zhang, W., Arey, A., et al. (2018). Sprague dawley Rag2-null rats created from engineered spermatogonial stem cells are immunodeficient and permissive to human xenografts. *Mol. Cancer Ther.* 17, 2481-2489. doi: 10.1158/1535-7163.MCT-18-0156

Noto, F. K., Sangodkar, J., Adedeji, B. T., Moody, S., McClain, C. B., Tong, M., et al. (2020). The SRG rat, a sprague-dawley Rag2/Il2rg double-knockout validated for human tumor oncology studies. *PLoS One* 15:e0240169. doi: 10.1371/journal.pone.0240169

Ohtsuka, M., Sato, M., Miura, H., Takabayashi, S., Matsuyama, M., Koyano, T., et al. (2018). i-GONAD: a robust method for in situ germline genome engineering using CRISPR nucleases. *Genome Biol.* 19:25. doi: 10.1186/s13059-018-1400-x

Okada, K., Itoh, H., Kamikubo, Y., Adachi, S., and Ikemoto, M. (2018). Establishment of S100A8 transgenic rats to understand innate property of S100A8 and its immunological role. *Inflammation* 41, 59-72. doi: 10.1007/s10753-017-0664-8

Okuyama, M., and Funahashi, H. (2012). Glycosaminoglycans improves early development of zona-free 8-cell rat embryos to blastocysts in a chemically defined medium, but not the pregnancy rate following transfer of the blastocysts. *J. Reprod. Dev.* 58, 295-301. doi: 10.1262/jrd.11-092h

Ong, G. L., and Mattes, M. J. (1989). Mouse strains with typical mammalian levels of complement activity. *J. Immunol. Methods* 125, 147-158. doi: 10.1016/0022-1759(89)90088-4

Osborn, M. J., Ma, B., Avis, S., Binnie, A., Dilley, J., Yang, X., et al. (2013). High-affinity IgG antibodies develop naturally in Ig-knockout rats carrying germline human IgH/Igk/Igλ, loci bearing the rat CH region. *J. Immunol.* 190, 1481-1490. doi: 10.4049/jimmunol.1203041

Ossart, J., Moreau, A., Autrusseau, E., Ménoret, S., Martin, J. C., Besnard, M., et al. (2018). Breakdown of immune tolerance in AIRE-deficient rats induces a severe autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy-like autoimmune disease. *J. Immunol.* 201, 874-887. doi: 10.4049/jimmunol.1701318

Ouisse, L.-H., Gautreau-Rolland, L., Devilder, M.-C., Osborn, M., Moyon, M., Visentin, J., et al. (2017). Antigen-specific single B cell sorting and expression-cloning from immunoglobulin humanized rats: a rapid and versatile method for the generation of high affinity and discriminative human monoclonal antibodies. *BMC Biotechnol.* 17:3. doi: 10.1186/s12896-016-0322-5

Ouisse, L.-H., Remy, S., Lafoux, A., Larcher, T., Tesson, L., Chenouard, V., et al. (2019). Immunophenotype of a Rat model of duchenne's disease and demonstration of improved muscle strength after anti-CD45RC antibody treatment. *Front. Immunol.* 10:2131. doi: 10.3389/fimmu.2019.02131

Palmer, N., and Kaldis, P. (2016). "Chapter One - regulation of the embryonic cell cycle during mammalian preimplantation development," in *Current Topics in Developmental Biology Mammalian Preimplantation Development*, ed. M. L. DePamphilis (Cambridge, MA: Academic Press), 1-53. doi: 10.1016/bs.ctdb.2016.05.001

Palmiter, R. D., Brinster, R. L., Hammer, R. E., Trumbauer, M. E., Rosenfeld, M. G., Birnberg, N. C., et al. (1982). Dramatic growth of mice that develop from eggs microinjected with metallothionein-growth hormone fusion genes. *Nature* 300, 611-615. doi: 10.1038/300611a0

Pandey, S., and Dvorakova, M. C. (2020). Future perspective of diabetic animal models. *Endocr. Metab. Immune Disord. Drug Targets* 20, 25-38. doi: 10.2174/1871530319666190626143832

Panzer, S. E., Wilson, N. A., Verhoven, B. M., Xiang, D., Rubinstein, C. D., Redfield, R. R., et al. (2018). Complete B cell deficiency reduces allograft inflammation and intragraft macrophages in a rat kidney transplant model. *Transplantation* 102, 396-405. doi: 10.1097/TP.00000000000002010

Patterson, K. C., Hawkins, V. E., Arps, K. M., Mulkey, D. K., and Olsen, M. L. (2016). MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats. *Hum. Mol. Genet.* 25, 3303-3320. doi: 10.1093/hmg/ddw179

Peng, H., Zheng, Y., Zhao, Z., Liu, T., and Li, J. (2018). Recognition of CRISPR/Cas9 off-target sites through ensemble learning of uneven mismatch distributions. *Bioinformatics* 34, i757-i765. doi: 10.1093/bioinformatics/bty558

Peng, W., Li, M., Li, H., Tang, K., Zhuang, J., Zhang, J., et al. (2017). Dysfunction of myosin light-chain 4 (MYL4) leads to heritable atrial cardiomyopathy with

electrical, contractile, and structural components: evidence from genetically-engineered rats. *J. Am. Heart Assoc.* 6:e007030. doi: 10.1161/JAHA.117.007030

Phadnis-Moghe, A. S., Chen, W., Li, J., Crawford, R. B., Bach, A., D'Ingillo, S., et al. (2016). Immunological characterization of the aryl hydrocarbon receptor (AHR) knockout rat in the presence and absence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). *Toxicology* 368-369, 172-182. doi: 10.1016/j.tox.2016.08.019

Philipeaux, J. (1856). Note sur l'extirpation des capsules surrénales chez les rats albinos (Mus ratus). *C. R. Acad. Sci.* 43, 904-906.

Pickar-Oliver, A., and Gersbach, C. A. (2019). The next generation of CRISPR-Cas technologies and applications. *Nat. Rev. Mol. Cell Biol.* 20, 490-507. doi: 10.1038/s41580-019-0131-5

Plaas, M., Seppa, K., Reimets, R., Jagomäe, T., Toots, M., Koppel, T., et al. (2017). Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration. *Sci. Rep.* 7:10220. doi: 10.1038/s41598-017-09392-x

Platt, J. L., and Cascalho, M. (2018). B Cells in transplantation of rat, mouse, and man. *Transplantation* 102, 357-358. doi: 10.1097/TP.00000000000002051

Ponce de León, V., Méillat, A.-M., Tesson, L., Anegón, I., and Hummler, E. (2014). Generation of TALEN-mediated GRdim knock-in rats by homologous recombination. *PLoS One* 9:e88146. doi: 10.1371/journal.pone.0088146

Pridans, C., Raper, A., Davis, G. M., Alves, J., Sauter, K. A., Lefevre, L., et al. (2018). Pleiotropic impacts of macrophage and microglial deficiency on development in rats with targeted mutation of the Csf1r locus. *J. Immunol.* 201, 2683-2699. doi: 10.4049/jimmunol.1701783

Qaisar, N., Lin, S., Ryan, G., Yang, C., Oikemus, S. R., Brodsky, M. H., et al. (2017). A critical role for the type I interferon receptor in virus-induced autoimmune diabetes in rats. *Diabetes* 66, 145-157. doi: 10.2337/db16-0462

Qin, W., Dion, S. L., Kutny, P. M., Zhang, Y., Cheng, A. W., Jillette, N. L., et al. (2015). Efficient CRISPR/Cas9-mediated genome editing in mice by zygote electroporation of nuclease. *Genetics* 200, 423-430. doi: 10.1534/genetics.115.176594

Quek, H., Luff, J., Cheung, K., Kozlov, S., Gatei, M., Lee, C. S., et al. (2017). Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage. *J. Leukoc. Biol.* 101, 927-947. doi: 10.1189/jlb.4VMA0716-316R

Ramírez-Solis, R., Liu, P., and Bradley, A. (1995). Chromosome engineering in mice. *Nature* 378, 720-724. doi: 10.1038/378720a0

Ran, F. A., Hsu, P. D., Lin, C.-Y., Gootenberg, J. S., Konermann, S., Trevino, A. E., et al. (2013). Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. *Cell* 154, 1380-1389. doi: 10.1016/j.cell.2013.08.021

Ranchoux, B., Antigny, F., Rucker-Martin, C., Hautefort, A., Péchoux, C., Bogaard, H. J., et al. (2015). Endothelial-to-mesenchymal transition in pulmonary hypertension. *Circulation* 131, 1006-1018. doi: 10.1161/CIRCULATIONAHA.114.008750

Ranjha, L., Howard, S. M., and Cejka, P. (2018). Main steps in DNA double-strand break repair: an introduction to homologous recombination and related processes. *Chromosoma* 127, 187-214. doi: 10.1007/s00412-017-0658-1

Rees, H. A., and Liu, D. R. (2018). Base editing: precision chemistry on the genome and transcriptome of living cells. *Nat. Rev. Genet.* 19, 770-788. doi: 10.1038/s41576-018-0059-1

Remy, S., Chenouard, V., Tesson, L., Usal, C., Ménoret, S., Brusselle, L., et al. (2017). Generation of gene-edited rats by delivery of CRISPR/Cas9 protein and donor DNA into intact zygotes using electroporation. *Sci. Rep.* 7:16554. doi: 10.1038/s41598-017-16328-y

Remy, S., Tesson, L., Menoret, S., Usal, C., De Cian, A., Thepenier, V., et al. (2014). Efficient gene targeting by homology-directed repair in rat zygotes using TALE nucleases. *Genome Res.* 24, 1371-1383. doi: 10.1101/gr.171538.113

Renaud, J.-B., Boix, C., Charpentier, M., De Cian, A., Cochennec, J., Duvernois-Berthet, E., et al. (2016). Improved Genome Editing Efficiency and Flexibility Using Modified Oligonucleotides with TALEN and CRISPR-Cas9 Nucleases. *Cell Rep.* 14, 2263-2272. doi: 10.1016/j.celrep.2016.02.018

Renaud, S. J., Scott, R. L., Chakraborty, D., Rumi, M. A. K., and Soares, M. J. (2017). Natural killer-cell deficiency alters placental development in rats. *Biol. Reprod.* 96, 145-158. doi: 10.1095/biolreprod.116.142752
Richardson, C. D., Ray, G. J., DeWitt, M. A., Curie, G. L., and Corn, J. E. (2016). Enhancing homology-directed genome editing by catalytically active and inactive CRISPR-Cas9 using asymmetric donor DNA. *Nat. Biotechnol.* 34, 339–344. doi: 10.1038/nbt.3481

Robertson, A. S., Majchrzak, M. J., Smith, C. M., Gagnon, R. C., Devidze, N., Banks, G. B., et al. (2017). Dramatic elevation in urinary amino terminal titin fragment excretion quantified by immunoassay in Duchenne muscular dystrophy patients and in dystrophin deficient rodents. *Neuromuscul. Disord.* 27, 635–645. doi: 10.1016/j.nmd.2017.05.009

Robertson, L., Pedrick, D., Piltz, S., White, M., Nieto, A., Ahladas, M., et al. (2018). Expanding the RNA-guided endonuclease toolkit for mouse genome editing. *CRISPR J.* 1, 431–439. doi: 10.1089/crispr.2018.0050

Rudemiller, N., Lund, H., Jacob, H. J., Geurts, A. M., Mattson, D. L., and PhysGen Knockout Program (2014). CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney. *Hypertension* 63, 559–564. doi: 10.1161/HYPERTENSIONAHA.113.02191

Rumi, M. A. K., Dhakal, P., Kubota, K., Chakraborty, D., Lei, T., Larson, M. A., et al. (2014). Generation of Esr1-knockout rats using zinc finger nuclease-mediated genome editing. *Endocrinology* 155, 1991–1999. doi: 10.1210/en.2013-2150

Samata, B., Kikuchi, T., Miyawaki, Y., Morizane, A., Mashimo, T., Nakagawa, M., et al. (2015). X-linked severe combined immunodeficiency (X-SCID) rats for xeno-transplantation and behavioral evaluation. *J. Neurosci. Methods* 243, 68–77. doi: 10.1016/j.jneumeth.2015.01.027

Sato, M., Takabayashi, S., Akasaka, E., and Nakamura, S. (2020). Recent advances and future perspectives of in vivo targeted delivery of genome-editing reagents to germ cells, embryos, and fetuses in mice. *Cells* 9:799. doi: 10.3390/cells9040799

Saunders, T. (2020). *Single Copy Transgene Integration in ROSA26 Safe Harbor. International Society for Transgenic Technologies*. Available online at: https://www.transtechsoc.org/index.php?src=blog&srctype=detail&blogid=19 (accessed September 29, 2020).

Sayers, E. W., Agarwala, R., Bolton, E. E., Brister, J. R., Canese, K., Clark, K., et al. (2019). Database resources of the national center for biotechnology information. *Nucleic Acids Res.* 47, D23–D28. doi: 10.1093/nar/gky1069

Schatoff, E. M., Zafra, M. P., and Dow, L. E. (2019). Base editing the mammalian genome. *Methods* 164–165, 100–108. doi: 10.1016/j.ymeth.2019.02.022

Scheimann, J. R., Moloney, R. D., Mahbod, P., Morano, R. L., Fitzgerald, M., Hoskins, O., et al. (2019). Conditional deletion of glucocorticoid receptors in rat brain results in sex-specific deficits in fear and coping behaviors. *eLife* 8:e44672. doi: 10.7554/eLife.44672

Schwartzberg, P. L., Goff, S. P., and Robertson, E. J. (1989). Germ-line transmission of a c-abl mutation produced by targeted gene disruption in ES cells. *Science* 246, 799–803. doi: 10.1126/science.2554496

Scott, K. E., Schormans, A. L., Pacoli, K. Y., De Oliveira, C., Allman, B. L., and Schmid, S. (2018). Altered auditory processing, filtering, and reactivity in the Cntnap2 Knock-out rat model for neurodevelopmental disorders. *J. Neurosci.* 38, 8588–8604. doi: 10.1523/JNEUROSCI.0759-18.2018

Shapiro, J., Iancu, O., Jacobi, A. M., McNeill, M. S., Turk, R., Rettig, G. R., et al. (2020). Increasing CRISPR efficiency and measuring its specificity in HSPCs using a clinically relevant system. *Mol. Ther. Methods Clin. Dev.* 17, 1097–1107. doi: 10.1016/j.omtt.2020.04.027

Shi, Q., Mattson, J. G., Fahs, S. A., Geurts, A. M., Weiler, H., and Montgomery, R. R. (2020). The severe spontaneous bleeding phenotype in a novel hemophilia A rat model is rescued by platelet FVIII expression. *Blood Adv.* 4, 55–65. doi: 10.1182/bloodadvances.2019000944

Shimoyama, M., Smith, J. R., Bryda, E., Kuramoto, T., Saba, L., and Dwinell, M. (2017). Rat Genome and Model Resources. *ILAR J.* 58, 42–58. doi: 10.1093/ilar/ ilw041

Shultz, L. D., Schweitzer, P. A., Christianson, S. W., Gott, B., Schweitzer, I. B., Tennent, B., et al. (1995). Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. *J. Immunol.* 154, 180–191.

Shuto, Y., Shibasaki, T., Otagiri, A., Kuriyama, H., Ohata, H., Tamura, H., et al. (2002). Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity. *J. Clin. Invest.* 109, 1429–1436. doi: 10.1172/JCIJ13300

Singh, P., Schimenti, J. C., and Bolcun-Filas, E. (2015). A mouse geneticist's practical guide to CRISPR applications. *Genetics* 199, 1–15. doi: 10.1534/ genetics.114.169771

Sinkevicius, K. W., Morrison, T. R., Kulkarni, P., Caffrey Cagliostro, M. K., Iriah, S., Malmberg, S., et al. (2018). RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory. *Dis. Model Mech.* 11:dmm032631. doi: 10.1242/dmm.032631

Smith, J. R., Hayman, G. T., Wang, S.-J., Laulederkind, S. J. F., Hoffman, M. J., Kaldunski, M. L., et al. (2020). The year of the rat: the rat genome database at 20: a multi-species knowledgebase and analysis platform. *Nucleic Acids Res.* 48, D731–D742. doi: 10.1093/nar/gkz1041

Sommer, D., Peters, A., Wirtz, T., Mai, M., Ackermann, J., Thabet, Y., et al. (2014). Efficient genome engineering by targeted homologous recombination in mouse embryos using transcription activator-like effector nucleases. *Nat. Commun.* 5:3045. doi: 10.1038/ncomms4045

Song, A. J., and Palmiter, R. D. (2018). Detecting and avoiding problems when using the Cre-lox system. *Trends Genet.* 34, 333–340. doi: 10.1016/j.tig.2017.12.008

Song, J., Yang, D., Xu, J., Zhu, T., Chen, Y. E., and Zhang, J. (2016). RS-1 enhances CRISPR/Cas9- and TALEN-mediated knock-in efficiency. *Nat. Commun.* 7:10548. doi: 10.1038/ncomms10548

Song, T.-J., Lan, X.-Y., Wei, M.-P., Zhai, F.-J., Boeckers, T. M., Wang, J.-N., et al. (2019). Altered behaviors and impaired synaptic function in a novel rat model with a complete Shank3 deletion. *Front. Cell Neurosci.* 13:111. doi: 10.3389/fncel.2019.00111

Stemmer, M., Thumberger, T., Keyer, M., del, S., Wittbrodt, J., and Mateo, J. L. (2015). CCTop: an intuitive, flexible and reliable CRISPR/Cas9 target prediction tool. *PLoS One* 10:e0124633. doi: 10.1371/journal.pone.0124633

Sun, J., Kouranova, E., Cui, X., Mach, R. H., and Xu, J. (2013). Regulation of dopamine presynaptic markers and receptors in the striatum of DJ-1 and Pink1 knockout rats. *Neurosci. Lett.* 557 (Pt B), 123–128. doi: 10.1016/j.neulet.2013.10.034

Sun, Y., Chen, X., and Xiao, D. (2007). Tetracycline-inducible expression systems: new strategies and practices in the transgenic mouse modeling. *Acta Biochim. Biophys. Sin.* 39, 235–246. doi: 10.1111/j.1745-7270.2007.00258.x

Sung, Y. H., Baek, I.-J., Kim, D. H., Jeon, J., Lee, J., Lee, K., et al. (2013). Knockout mice created by TALEN-mediated gene targeting. *Nat. Biotechnol.* 31, 23–24. doi: 10.1038/nbt.2477

Szabó, P. J., Ebner, J., Konig, X., Hamza, O., Watzinger, S., Trojanek, S., et al. (2021). Cardiovascular phenotype of the Dmdmdx rat – a suitable animal model for Duchenne muscular dystrophy. *Dis. Model. Mech.* 14:dmm047704. doi: 10.1242/dmm.047704

Szpirer, C. (2020). Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes. *bioRxiv [Preprint]* doi: 10.1101/ 2020.03.23.003384

Taheri-Ghafarokhi, A., Taylor, B. J. M., Nitsch, R., Lundin, A., Cavallo, A.-L., Madeyski-Bengtson, K., et al. (2018). Decoding non-random mutational signatures at Cas9 targeted sites. *Nucleic Acids Res.* 46, 8417–8434. doi: 10.1093/ nar/gky653

Takabayashi, S., Aoshima, T., Kabashima, K., Aoto, K., Ohtsuka, M., and Sato, M. (2018). i-GONAD (improved genome-editing via oviductal nucleic acids delivery), a convenient in vivo tool to produce genome-edited rats. *Sci. Rep.* 8:12059. doi: 10.1038/s41598-018-30137-x

Takahashi, G., Gurumurthy, C. B., Wada, K., Miura, H., Sato, M., and Ohtsuka, M. (2015). GONAD: genome-editing via oviductal nucleic acids delivery system: a novel microinjection independent genome engineering method in mice. *Sci. Rep.* 5:11406. doi: 10.1038/srep11406

Teixeira, M., Py, B. F., Bosc, C., Laubreton, D., Moutin, M.-J., Marvel, J., et al. (2018). Electroporation of mice zygotes with dual guide RNA/Cas9 complexes for simple and efficient cloning-free genome editing. *Sci. Rep.* 8:474. doi: 10.1038/s41598-017-18826-5

Teng, F., Cui, T., Feng, G., Guo, L., Xu, K., Gao, Q., et al. (2018). Repurposing CRISPR-Cas12b for mammalian genome engineering. *Cell Discov.* 4:63. doi: 10.1038/s41421-018-0069-3

Terao, M., Tamano, M., Hara, S., Kato, T., Kinoshita, M., and Takada, S. (2016). Utilization of the CRISPR/Cas9 system for the efficient production of mutant mice using crRNA/tracrRNA with Cas9 nickase and FokI-dCas9. *Exp. Anim.* 65, 275–283. doi: 10.1538/expanim.15-0116

Tesson, L., Charreau, B., Ménoret, S., Gilbert, E., Soulillou, J. P., and Anegon, I. (1999). Endothelial expression of Fas ligand in transgenic rats under the
temporal control of a tetracycline-inducible system. *Transplant. Proc.* 31, 1533-1534.

Tesson, L., Usal, C., Ménoret, S., Leung, E., Niles, B. J., Remy, S., et al. (2011). Knockout rats generated by embryo microinjection of TALENs. *Nat. Biotechnol.* 29, 695-696. doi: 10.1038/nbt.1940

The Commission to the European Parliament and the Council (2015-2017). *The Commission to the European Parliament and the Council 2019 Report on the Statistics of the use of Animals for Scientific Purposes in the Member States of the European Union in 2015-2017*. *Eur-lex*. Available online at: https://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1581689520921&uri=CELEX:52020DC0016 [Accessed July 9, 2020].

Thebault, P., Lhermite, N., Tilly, G., Le Texier, L., Quillard, T., Heslan, M., et al. (2009). The C-type lectin-like receptor CLEC-1, expressed by myeloid cells and endothelial cells, is up-regulated by immunoregulatory mediators and moderates T cell activation. *J. Immunol.* 183, 3099-3108.

Thomas, K. R., and Capecchi, M. R. (1987). Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. *Cell* 51, 503–512. doi: 10.1016/0092-8674(87)90646-5

Tong, C., Huang, G., Ashton, C., Wu, H., Yan, H., and Ying, Q.-L. (2012). Rapid and cost-effective gene targeting in rat embryonic stem cells by TALENs. *J. Genet. Genomics* 39, 275-280. doi: 10.1016/j.jgg.2012.04.004

Tong, C., Li, P., Wu, N. L., Yan, Y., and Ying, Q.-L. (2010). Production of p53 gene knockout rats by homologous recombination in embryonic stem cells. *Nature* 467, 211–213. doi: 10.1038/nature09368

Tran, N.-T., Bashir, S., Li, X., Rossius, J., Chu, V. T., Rajewsky, K., et al. (2019). Enhancement of precise gene editing by the association of Cas9 with homologous recombination factors. *Front. Genet.* 10:365. doi: 10.3389/fgene.2019.00365

Trimidal, S. G., Benjamin, R., Bae, J. E., Han, M. V., Kong, E., Singer, A., et al. (2019). Can designer indels be tailored by gene editing?: can indels be customized? *Bioessays* 41:e1900126. doi: 10.1002/bies.201900126

Tsuchida, T., Zheng, Y.-W., Zhang, R.-R., Takebe, T., Ueno, Y., Sekine, K., et al. (2014). The development of humanized liver with Rag1 knockout rats. *Transplant. Proc.* 46, 1191-1193. doi: 10.1016/j.transproceed.2013.12.026

Tuggle, K. L., Birket, S. E., Cui, X., Hong, J., Warren, J., Reid, L., et al. (2014). Characterization of defects in ion transport and tissue development in cystic fibrosis transmembrane conductance regulator (CFTR)-knockout rats. *PLoS One* 9:e91253. doi: 10.1371/journal.pone.0091253

Ubels, J. L., Diegel, C. R., Foxa, G. E., Ethen, N. J., Lensing, J. N., Madaj, Z. B., et al. (2020). Low-density lipoprotein receptor-related protein 5-deficient rats have reduced bone mass and abnormal development of the retinal vasculature. *CRISPR J.* 3, 284–298. doi: 10.1089/crispr.2020.0009

van Boxtel, R., Gould, M. N., Cuppen, E., and Smits, B. M. G. (2010). ENU mutagenesis to generate genetically modified rat models. *Methods Mol. Biol.* 597, 151-167. doi: 10.1007/978-1-60327-389-3_11

van Boxtel, R., Toonen, P. W., van Roekel, H. S., Verheul, M., Smits, B. M. G., Korving, J., et al. (2008). Lack of DNA mismatch repair protein MSH6 in the rat results in hereditary non-polyposis colorectal cancer-like tumorigenesis. *Carcinogenesis* 29, 1290-1297. doi: 10.1093/carcin/bgn094

van den Brandt, J., Kwon, S.-H., Hünig, T., McPherson, K. G., and Reichardt, H. M. (2005). Sustained pre-TCR expression in Notch11C-transgenic rats impairs T cell maturation and selection. *J. Immunol.* 174, 7845-7852. doi: 10.4049/jimmunol.174.12.7845

van Vuuren, A. J., van Roon, J. A. G., Walraven, V., Stuij, I., Harmsen, M. C., McLaughlin, P. M. J., et al. (2006). CD64-directed immunotoxin inhibits arthritis in a novel CD64 transgenic rat model. *J. Immunol.* 176, 5833-5838. doi: 10.4049/jimmunol.176.10.5833

Verkuijl, S. A., and Rots, M. G. (2019). The influence of eukaryotic chromatin state on CRISPR-Cas9 editing efficiencies. *Curr. Opin. Biotechnol.* 55, 68-73. doi: 10.1016/j.copbio.2018.07.005

Vichaya, E. G., Malik, S., Sominsky, L., Ford, B. G., Spencer, S. J., and Dantzer, R. (2020). Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats. *J. Neuroinflammation* 17:172. doi: 10.1186/s12974-020-01832-2

Wang, H., Hu, Y.-C., Markoulaki, S., Welstead, G. G., Cheng, A. W., Shivalila, C. S., et al. (2013a). TALEN-mediated editing of the mouse Y chromosome. *Nat. Biotechnol.* 31, 530-532. doi: 10.1038/nbt.2595

Wang, H., Yang, H., Shivalila, C. S., Dawlaty, M. M., Cheng, A. W., Zhang, F., et al. (2013b). One-step generation of mice carrying mutations in multiple

genes by CRISPR/Cas-mediated genome engineering. *Cell* 153, 910-918. doi: 10.1016/j.cell.2013.04.025

Wang, J., Dang, R., Miyasaka, Y., Hattori, K., Torigoe, D., Okamura, T., et al. (2019a). Null mutation of the endothelin receptor type B gene causes embryonic death in the GK rat. *PLoS One* 14:e0217132. doi: 10.1371/journal.pone.0217132

Wang, J., Liu, Z., Bellen, H. J., and Yamamoto, S. (2019b). Navigating MARRVEL, a web-based tool that integrates human genomics and model organism genetics information. *J. Vis. Exp.* doi: 10.3791/59542

Wang, L., Shao, Y., Guan, Y., Li, L., Wu, L., Chen, F., et al. (2015). Large genomic fragment deletion and functional gene cassette knock-in via Cas9 protein mediated genome editing in one-cell rodent embryos. *Sci. Rep.* 5:17517. doi: 10.1038/srep17517

Wang, L., Wang, J., Cai, W., Shi, Y., Zhou, X., Guo, G., et al. (2017). A critical evaluation of liver pathology in humans with danon disease and experimental correlates in a rat model of LAMP-2 deficiency. *Clin. Rev. Allergy. Immunol.* 53, 105-116. doi: 10.1007/s12016-017-8598-3

Wang, W., Kutny, P. M., Byers, S. L., Longstaff, C. J., DaCosta, M. J., Pang, C., et al. (2016). Delivery of Cas9 protein into mouse zygotes through a series of electroporation dramatically increases the efficiency of model creation. *J. Genet. Genomics* 43, 319-327. doi: 10.1016/j.jgg.2016.02.004

Wang, X., Liu, Z., Li, G., Dang, L., Huang, S., He, L., et al. (2020). Efficient gene silencing by adenine base editor-mediated start codon mutation. *Mol. Ther.* 28, 431-440. doi: 10.1016/j.ymthe.2019.11.022

Wang, Z., Wang, Y., Wang, S., Gorzalski, A. J., McSwiggin, H., Yu, T., et al. (2020). Efficient genome editing by CRISPR-Mb3Cas12a in mice. *J. Cell. Sci.* 133:jcs240705. doi: 10.1242/jcs.240705

Wang, Y., Zhou, X.-Y., Xiang, P.-Y., Wang, L.-L., Tang, H., Xie, F., et al. (2014). The meganuclease I-SceI containing nuclear localization signal (NLS-I-SceI) efficiently mediated mammalian germline transgenesis via embryo cytoplasmic microinjection. *PLoS One* 9:e108347. doi: 10.1371/journal.pone.0108347

Weber, J., Öllinger, R., Friedrich, M., Ehmer, U., Barenboim, M., Steiger, K., et al. (2015). CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice. *Proc. Natl. Acad. Sci. U.S.A.* 112, 13982-13987. doi: 10.1073/pnas.1512392112

Wefers, B., Meyer, M., Ortiz, O., Hrabé de Angelis, M., Hansen, J., Wurst, W., et al. (2013). Direct production of mouse disease models by embryo microinjection of TALENs and oligodeoxynucleotides. *Proc. Natl. Acad. Sci. U.S.A.* 110, 3782-3787. doi: 10.1073/pnas.1218721110

Wetsel, R. A., Fleischer, D. T., and Haviland, D. L. (1990). Deficiency of the murine fifth complement component (C5). A 2-base pair gene deletion in a 5'-exon. *J. Biol. Chem.* 265, 2435-2440.

Wildner, G. (2019). Are rats more human than mice? *Immunobiology* 224, 172-176. doi: 10.1016/j.imbio.2018.09.002

Xia, C.-H., Ferguson, I., Li, M., Kim, A., Onishi, A., Li, L., et al. (2018). Essential function of NHE8 in mouse retina demonstrated by AAV-mediated CRISPR/Cas9 knockdown. *Exp. Eye Res.* 176, 29-39. doi: 10.1016/j.exer.2018.06.026

Xu, C., Qi, X., Du, X., Zou, H., Gao, F., Feng, T., et al. (2017). piggyBac mediates efficient in vivo CRISPR library screening for tumorigenesis in mice. *Proc. Natl. Acad. Sci. U.S.A.* 114, 722-727. doi: 10.1073/pnas.1615735114

Xu, J., Zhang, L., Xie, M., Li, Y., Huang, P., Saunders, T. L., et al. (2018). Role of complement in a rat model of paclitaxel-induced peripheral neuropathy. *J. Immunol.* 200, 4094-4101. doi: 10.4049/jimmunol.1701716

Xu, Y., Wu, Z., Liu, L., Liu, J., and Wang, Y. (2019). Rat model of cockayne syndrome neurological disease. *Cell Rep.* 29, 800.e5-809.e5. doi: 10.1016/j.celrep.2019.09.028

Xu, Y., Zhao, X.-M., Liu, J., Wang, Y.-Y., Xiong, L.-L., He, X.-Y., et al. (2020). Complexin I knockout rats exhibit a complex neurobehavioral phenotype including profound ataxia and marked deficits in lifespan. *Pflugers. Arch.* 472, 117-133. doi: 10.1007/s00424-019-02337-5

Yamamoto, S., Ooshima, Y., Nakata, M., Yano, T., Nishimura, N., Nishigaki, R., et al. (2015). Efficient gene-targeting in rat embryonic stem cells by CRISPR/Cas and generation of human kynurenine aminotransferase II (KAT II) knock-in rat. *Transgenic Res.* 24, 991-1001. doi: 10.1007/s11248-015-909-1
Yang, J., Yi, N., Zhang, J., He, W., He, D., Wu, W., et al. (2018). Generation and characterization of a hypothyroidism rat model with truncated thyroid stimulating hormone receptor. *Sci. Rep.* 8:4004. doi: 10.1038/s41598-018-22405-7

Yang, L., Zhang, X., Wang, L., Yin, S., Zhu, B., Xie, L., et al. (2018). Increasing targeting scope of adenosine base editors in mouse and rat embryos through fusion of TadA deaminase with Cas9 variants. *Protein Cell* 9, 814–819. doi: 10.1007/s13238-018-0568-x

Yang, X., Zhou, J., He, J., Liu, J., Wang, H., Liu, Y., et al. (2018). An immune system-modified rat model for human stem cell transplantation research. *Stem Cell Rep.* 11, 514–521. doi: 10.1016/j.stemcr.2018.06.004

Yang, L., Ikeda, H., Lai, Y., Yoshiki, T., and Takada, K. (2003). Epstein-barr virus infection of rat lymphocytes expressing human CD21 results in restricted latent viral gene expression and not in immunoblastic transformation. *J. Med. Virol.* 70, 126–130. doi: 10.1002/jmv.10369

Yang, X., Lu, D., Zhang, X., Chen, W., Gao, S., Dong, W., et al. (2019). Knockout of ISCA1 causes early embryonic death in rats. *Anim. Model. Exp. Med.* 2, 18–24. doi: 10.1002/ame2.12059

Yao, X., and Verkman, A. S. (2017a). Complement regulator CD59 prevents peripheral organ injury in rats made seropositive for neuromyelitis optica immunoglobulin G. *Acta Neuropathol. Commun.* 5:57. doi: 10.1186/s40478-017-0462-4

Yao, X., and Verkman, A. S. (2017b). Marked central nervous system pathology in CD59 knockout rats following passive transfer of Neuromyelitis optica immunoglobulin G. *Acta Neuropathol. Commun.* 5:15. doi: 10.1186/s40478-017-0417-9

Yao, X., Wang, X., Hu, X., Liu, Z., Liu, J., Zhou, H., et al. (2017). Homology-mediated end joining-based targeted integration using CRISPR/Cas9. *Cell Res.* 27, 801–814. doi: 10.1038/cr.2017.76

Ye, L., Park, J. J., Dong, M. B., Yang, Q., Chow, R. D., Peng, L., et al. (2019). In vivo CRISPR screening in CD8 T cells with AAV-sleeping beauty hybrid vectors identifies membrane targets for improving immunotherapy for glioblastoma. *Nat Biotechnol* 37, 1302–1313. doi: 10.1038/s41587-019-0246-4

Yeh, C. D., Richardson, C. D., and Corn, J. E. (2019). Advances in genome editing through control of DNA repair pathways. *Nat. Cell Biol.* 21, 1468–1478. doi: 10.1038/s41556-019-0425-z

Yeo, J. H., Jung, B. K., Lee, H., Baek, I.-J., Sung, Y. H., Shin, H.-S., et al. (2019). Development of a Pde6b gene knockout rat model for studies of degenerative retinal diseases. *Invest. Ophthalmol. Vis. Sci.* 60, 1519–1526. doi: 10.1167/iovs.18-25556

Yoon, Y., Wang, D., Tai, P. W. L., Riley, J., Gao, G., and Rivera-Pérez, J. A. (2018). Streamlined ex vivo and in vivo genome editing in mouse embryos using recombinant adeno-associated viruses. *Nat. Commun.* 9:412. doi: 10.1038/s41467-017-02706-7

Yoshimi, K., Kunihiro, Y., Kaneko, T., Nagahora, H., Voigt, B., and Mashimo, T. (2016). ssODN-mediated knock-in with CRISPR-Cas for large genomic regions in zygotes. *Nat. Commun.* 7:10431. doi: 10.1038/ncomms10431

You, P., Hu, H., Chen, Y., Zhao, Y., Yang, Y., Wang, T., et al. (2016). Effects of melanocortin 3 and 4 receptor deficiency on energy homeostasis in rats. *Sci. Rep.* 6:34938. doi: 10.1038/srep34938

Yu, D., Zhong, Y., Li, X., Li, Y., Li, X., Cao, J., et al. (2016). Generation of TALEN-mediated FH knockout rat model. *Oncotarget* 7, 61656–61669. doi: 10.18632/oncotarget.11429

Yu, H., Koilkonda, R. D., Chou, T.-H., Porciatti, V., Mehta, A., Hentall, I. D., et al. (2015). Consequences of zygote injection and germline transfer of mutant human mitochondrial DNA in mice. *Proc. Natl. Acad. Sci. U.S.A.* 112, E5689–E5698. doi: 10.1073/pnas.1506129112

Yu, Q., Liu, Y.-Z., Zhu, Y.-B., Wang, Y.-Y., Li, Q., and Yin, D.-M. (2019). Genetic labeling reveals temporal and spatial expression pattern of D2 dopamine receptor in rat forebrain. *Brain Struct. Funct.* 224, 1035–1049. doi: 10.1007/s00429-018-01824-2

Yu, Y., Guo, Y., Tian, Q., Lan, Y., Yeh, H., Zhang, M., et al. (2020). An efficient gene knock-in strategy using 5'-modified double-stranded DNA donors with short homology arms. *Nat. Chem. Biol.* 16, 387–390. doi: 10.1038/s41589-019-0432-1

Yu-Taeger, L., Ott, T., Bonsi, P., Tomczak, C., Wassouf, Z., Martella, G., et al. (2020). Impaired dopamine- and adenosine-mediated signaling and plasticity in a novel rodent model for DYT25 dystonia. *Neurobiol. Dis.* 134:104634. doi: 10.1016/j.nbd.2019.104634

Zallar, L. J., Tunstall, B. J., Richie, C. T., Zhang, Y. J., You, Z. B., Gardner, E. L., et al. (2019). Development and initial characterization of a novel ghrelin receptor CRISPR/Cas9 knockout wistar rat model. *Int. J. Obes.* 43, 344–354. doi: 10.1038/s41366-018-0013-5

Zan, Y., Haag, J. D., Chen, K.-S., Shepel, L. A., Wigington, D., Wang, Y.-R., et al. (2003). Production of knockout rats using ENU mutagenesis and a yeast-based screening assay. *Nat. Biotechnol.* 21, 645–651. doi: 10.1038/nbt830

Zhang, H., Pan, H., Zhou, C., Wei, Y., Ying, W., Li, S., et al. (2018). Simultaneous zygotic inactivation of multiple genes in mouse through CRISPR/Cas9-mediated base editing. *Development* 145:dev168906. doi: 10.1242/dev.168906

Zhang, T., Jiang, X., Xu, M., Wang, H., Sang, X., Qin, M., et al. (2018). Sleep and circadian abnormalities precede cognitive deficits in R521C FUS knockin rats. *Neurobiol. Aging* 72, 159–170. doi: 10.1016/j.neurobiolaging.2018.08.025

Zhang, J.-P., Li, X.-L., Li, G.-H., Chen, W., Arakaki, C., Botimer, G. D., et al. (2017). Efficient precise knockin with a double cut HDR donor after CRISPR/Cas9-mediated double-stranded DNA cleavage. *Genome Biol.* 18:35. doi: 10.1186/s13059-017-1164-8

Zhang, L., Shao, Y., Li, L., Tian, F., Cen, J., Chen, X., et al. (2016). Efficient liver repopulation of transplanted hepatocyte prevents cirrhosis in a rat model of hereditary tyrosinemia type I. *Sci. Rep.* 6:31460. doi: 10.1038/srep31460

Zhang, X., Liang, P., Ding, C., Zhang, Z., Zhou, J., Xie, X., et al. (2016). Efficient production of gene-modified mice using *Staphylococcus aureus* Cas9. *Sci. Rep.* 6:32565. doi: 10.1038/srep32565

Zhao, Y., Yang, Y., Xing, R., Cui, X., Xiao, Y., Xie, L., et al. (2018). Hyperlipidemia induces typical atherosclerosis development in Ldlr and apoe deficient rats. *Atherosclerosis* 271, 26–35. doi: 10.1016/j.atherosclerosis.2018.02.015

Zheng, R., Fang, X., He, L., Shao, Y., Guo, N., Wang, L., et al. (2018). Generation of a primary hyperoxaluria type 1 disease model via CRISPR/Cas9 system in rats. *Curr. Mol. Med.* 18, 436–447. doi: 10.2174/1566524019666181212092440

Zheng, R., Li, Y., Wang, L., Fang, X., Zhang, J., He, L., et al. (2020). CRISPR/Cas9-mediated metabolic pathway reprogramming in a novel humanized rat model ameliorates primary hyperoxaluria type 1. *Kidney Int.* 98, 947–957. doi: 10.1016/j.kint.2020.04.049

Zhou, X., Xu, C., Zou, Z., Shen, X., Xie, T., Zhang, R., et al. (2019). The characteristics of glucose metabolism in the sulfonylurea receptor 1 knockout rat model. *Mol. Med.* 25:2. doi: 10.1186/s10020-018-0067-9

Zijlstra, M., Li, E., Sajjadi, F., Subramani, S., and Jaenisch, R. (1989). Germ-line transmission of a disrupted beta 2-microglobulin gene produced by homologous recombination in embryonic stem cells. *Nature* 342, 435–438. doi: 10.1038/342435a0

Zschemisch, N.-H., Glage, S., Wedekind, D., Weinstein, E. J., Cui, X., Dorsch, M., et al. (2012). Zinc-finger nuclease mediated disruption of Rag1 in the LEW/Ztm rat. *BMC Immunol.* 13:60. doi: 10.1186/1471-2172-13-60

**Conflict of Interest:** YC and VC are genOway employees.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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