International Journal of Innovative Approaches in Science Research
Abbreviation: IJIASR | ISSN (Print): 2602-4810 | ISSN (Online): 2602-4535 | DOI: 10.29329/ijiasr

Review article    |    Open Access
International Journal of Innovative Approaches in Science Research 2020, Vol. 4(4) 153-190

CRISPR-Of-Things: Applications and Challenges of the Most Popular Gene Editing Tool in the Fields of Health, Agriculture and Environment

Cıhan Tastan, Sulhattin Yasar, Muhammed Bahattin Tanyolac, Kenan Turgut, Ufuk Tansel Şireli, Cimen Atak, Kamil Haliloglu, Kemal Benlioglu, Kemal Melih Taşkın, Nurhayat Barlas & Gultekin Yildiz

pp. 153 - 190   |  DOI:

Published online: December 22, 2020  |   Number of Views: 1195  |  Number of Download: 942


Almost all cells of any living organism contain DNA, a hereditary molecule that passes from generation to generation during reproduction. The term "genome" generally refers to the total DNA sequences in an organism. The genome consists of DNA sequences called “gene”, which plays a role in the basic biological processes involved in many phenotypic and genotypic characteristics, such as performing cellular functions, controlling numbers and species, regulating energy production, metabolism, and combating diseases.

Gene editing is the process of pre-designing and modifying a particular DNA sequence in a targeted gene. The most widely used technique is CRISPR-Cas technology. For this purpose, the DNA helix is ​​cut at a certain point, to form a double-strand break (DSB), and naturally existing cellular repair mechanisms repair the DSB. Modes of the repair mechanisms may affect the gene function. When DSB is formed, gene editing techniques can be applied to remove, insert, or replace a newly modified sequence using a synthetic donor template DNA.

In developed and developing countries, CRISPR-Cas studies in addition to research and development studies are rapidly increasing. In addition to increasing population, changing weather conditions, declining farmland, increasing biotic and abiotic stresses are other important barriers to agricultural production, food, and feed supply. In this report, CRISPR-Cas applications are introduced in detail from the studies that carried out gene modifications in the fields of health, animals, plants, microorganisms, and food supply. Besides, these technologies and applications have been examined in terms of world biosafety legislation and the scientific risk assessment of the products developed using the CRISPR-Cas technique.

Keywords: CRISPR, Cas9, health, animal, plant, agriculture

How to Cite this Article

APA 6th edition
Tastan, C., Yasar, S., Tanyolac, M.B., Turgut, K., Sireli, U.T., Atak, C., Haliloglu, K., Benlioglu, K., Taskin, K.M., Barlas, N. & Yildiz, G. (2020). CRISPR-Of-Things: Applications and Challenges of the Most Popular Gene Editing Tool in the Fields of Health, Agriculture and Environment . International Journal of Innovative Approaches in Science Research, 4(4), 153-190. doi: 10.29329/ijiasr.2020.312.6

Tastan, C., Yasar, S., Tanyolac, M., Turgut, K., Sireli, U., Atak, C., Haliloglu, K., Benlioglu, K., Taskin, K., Barlas, N. and Yildiz, G. (2020). CRISPR-Of-Things: Applications and Challenges of the Most Popular Gene Editing Tool in the Fields of Health, Agriculture and Environment . International Journal of Innovative Approaches in Science Research, 4(4), pp. 153-190.

Chicago 16th edition
Tastan, Cihan, Sulhattin Yasar, Muhammed Bahattin Tanyolac, Kenan Turgut, Ufuk Tansel Sireli, Cimen Atak, Kamil Haliloglu, Kemal Benlioglu, Kemal Melih Taskin, Nurhayat Barlas and Gultekin Yildiz (2020). "CRISPR-Of-Things: Applications and Challenges of the Most Popular Gene Editing Tool in the Fields of Health, Agriculture and Environment ". International Journal of Innovative Approaches in Science Research 4 (4):153-190. doi:10.29329/ijiasr.2020.312.6.

  1. Abdelrahman M, Al-Sadi AM, Pour-Aboughadareh A, Burritt DJ, Tran LP. (2018). Genome editing using CRISPR-Cas9–targeted mutagenesis: An opportunity for yield improvements of crop plants grown under environmental stresses. Plant Physiology and Biochemistry, 131: 31-36. [Google Scholar]
  2. Akbari OS, Bellen HJ, Bier E, Bullock SL, Burt A, Church GM, Cook KR, Duchek P, Edwards OR, Esvelt KM, Gantz VM, Golic KG, Gratz SJ, Harrison MM, Hayes KR, James AA, Kaufman TC, Knoblich J, Malik HS, Matthews KA, O'Connor-Giles KM, Parks AL, Perrimon N, Port F, Russell S, Ueda R, Wildonger J. (2015). Safeguarding gene drive experiments in the laboratory. Science, 349(6251): 927-929. [Google Scholar]
  3. Ali, Z., Abulfaraj, A., Idris, A., Ali, S., Tashkandi, M., Mahfouz, M.M. (2015). CRISPR-Cas9- mediated viral interference in plants. Genome Biol. 16: 238. [Google Scholar]
  4. Alimov, I., Menon, S., Cochran, N., Maher, R., Wang, Q., Alford, J., … Cai, X. (2019). Bile acid analogues are activators of pyrin inflammasome. The Journal of biological chemistry, 294(10), 3359–3366. doi:10.1074/jbc.RA118.005103 [Google Scholar] [Crossref] 
  5. Arazoe, T., Miyoshi, K., Yamato, T., Ogawa, T., Ohsato, S., Arie, T., & Kuwata, S. (2015). Tailor‐made CRISPR/Cas system for highly efficient targeted gene replacement in the rice blast fungus. Biotechnology and bioengineering, 112(12), 2543-2549. [Google Scholar]
  6. Baltes, N.J., Hummel, A.W., Konecna, E., Cegan, R., Bruns, A.N., Bisaro, D.M., Voytas, D.F. (2015). Conferring resistance to geminiviruses with the CRISPR–Cas prokaryoticimmune system. Nat. Plants, 1: 15145. [Google Scholar]
  7. Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, Romero DA, Horvath P. (2007). CRISPR provides acquired resistance against viruses in prokaryotes. Science 315:1709-1712. [Google Scholar] [Crossref] 
  8. Barrangou R, van der Oost J (2013). CRISPR-Cas Systems: RNA-Mediated Adaptive Immunity in Bacteria and Archaea. Springer. Verlag Berlin Heidelberg. [Google Scholar]
  9. Başer, İ., Bilgin, O., Korkut, K. Z.,  Balkan, A. (2007). Makarnalık buğdayda mutasyon ıslahı ile bazı kantitatif karakterlerin geliştirilmesi. Türk Tarım Dergisi, 13(4): 346-353. [Google Scholar]
  10. Bevacqua RJ, Fernandez-Martín R, Savy V, Canel NG, Gismondi MI, Kues WA, Carlson DF, Fahrenkrug SC, Niemann H, Taboga OA, Ferraris S, Salamone DF (2016). Efficient edition of the bovine PRNP prion gene in somatic cells and IVF embryos using the CRISPR-Cas9 system. Theriogenology 86(8): 1886-1896. [Google Scholar]
  11. Bikard D, Euler CW, Jiang W, Nussenzweig PM, Goldberg GW, Duportet X, Fischetti VA, Marraffini LA.(2014).“Exploiting CRISPR-Cas nucleases to produce sequence-specific antimicrobials.” Nature Biotechnol. 32(11): 1146-50. PubMed: PMID 25282355. PubMed Central: PMCID PMC4317352. [Google Scholar]
  12. Bolotin A, Quinquis B, Sorokin A, Ehrlich SD. (2005). Clustered regularly interspaced short palindrome repeats (CRISPRs) have spacers of extrachromosomal origin. Microbiology 151:2551–2561. [Google Scholar] [Crossref] 
  13. Boodman E. (2015). With potential to save human lives, CRISPR already sparing mice. STAT news, 7 December. [Google Scholar]
  14. Bonafont, J., Mencía, Á., García, M., Torres, R., Rodríguez, S., Carretero, M., … Larcher, F. (2019). Clinically Relevant Correction of Recessive Dystrophic Epidermolysis Bullosa by Dual sgRNA CRISPR/Cas9-Mediated Gene Editing. Molecular therapy : the journal of the American Society of Gene Therapy, 27(5), 986–998. doi:10.1016/j.ymthe.2019.03.007 [Google Scholar] [Crossref] 
  15. Brooks K, Burns G, Spencer TE (2015). Biological Roles of Hydroxysteroid (11-Beta) Dehydrogenase 1 (HSD11B1), HSD11B2, and Glucocorticoid Receptor (NR3C1) in Sheep Conceptus Elongation. Biology of Reproduction 93 (2): 38. [Google Scholar]
  16. Bubela T, Mansour Y, Nicol D (2017). The ethics of genome editing in the clinic: A dose of realism for healthcare leaders, Healthcare Management Forum Vol. 30(3):159-163. [Google Scholar]
  17. Cai, Y., Chen, L., Liu, X., Guo, C., Sun, S., Wu, C., Jiang, B., Han, T. Hou, W. (2018). CRISPR-Cas9-mediated targeted mutagenesis of GmFT2a delays flowering time in soya bean. Plant Biotechnology Journal, 16 (1): 176-185. [Google Scholar]
  18. Carter, S., & Doyon, Y. (2017). Gene Therapy in Tyrosinemia: Potential and Pitfalls. Advances in experimental medicine and biology, 959, 231–243. doi:10.1007/978-3-319-55780-9_21 [Google Scholar] [Crossref] 
  19. Chen, B. X., Wei, T., Ye, Z. W., Yun, F., Kang, L. Z., Tang, H. B., ... Lin, J. F. (2018). Efficient CRISPR-Cas9 gene disruption system in edible-medicinal mushroom Cordyceps militaris. Frontiers in microbiology, 9: 1157. [Google Scholar]
  20. Chen, J., Lai, Y., Wang, L., Zhai, S., Zou, G., Zhou, Z.C.C., Wang, S. (2017). CRISPR/Cas9-mediated efficient genome editing via blastospore-based transformation in entomopathogenic fungus Beauveria bassiana. Scientific reports, 7: 45763. [Google Scholar]
  21. Chen, K., Wang, Y., Zhang, R., Zhang, H., Gao, C. (2019). CRISPR-Cas genome editing and precision plant breeding in agriculture. Annual review of plant biology, 70: 667-697. [Google Scholar]
  22. Chen, X., Kozhaya, L.,  Taştan, C.,  Placek, L., Doğan, M., Horne, M., Abblett, R., Karhan, E., Vaeth, M., Feske, S., Unutmaz, D. (2018). Functional Interrogation of Primary Human T Cells via CRISPR Genetic Editing. J Immunol. [Google Scholar]
  23. Choi W, Yum S, Lee S, Lee W, Lee J, Kim S, Koo O, Lee B, Jang G (2015). Disruption of exogenous eGFP gene using RNA-guided endonuclease in bovine transgenic somatic cells. Zygote 23 (6): 916-923. [Google Scholar]
  24. Citorik RJ, Mimee M, Lu TK. (2014). “Sequence-specific antimicrobials using efficientlydelivered RNA-guided nucleases.” Nature Biotechnol. 32(11): 1141-1145. [Google Scholar]
  25. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F. (2013). Multiplex genome engineering using CRISPR/ Cas systems. Science 339:819–823. [Google Scholar] [Crossref] 
  26. Cook C.,, Martin L., Bastow R., (2014). Opportunities in plant synthetic biology, Journal of Experimental Botany, 65 (8):1921–1926, [Google Scholar] [Crossref] 
  27. Crispo M, Mulet AP, Tesson L, Barrera N, Cuadro F, dos Santos-Neto PC, Nguyen TH, Crénéguy A, Brusselle L, Anegón I, Menchaca A (2015). Efficient Generation of Myostatin Knock-Out Sheep Using CRISPR-Cas9 Technology and Microinjection into Zygotes. PLoS One 10 (8): e0136690. DOI:10.1371/journal. pone.0136690. [Google Scholar]
  28. Curtin, S. J., Xiong, Y., Michno, J. M., Campbell, B. W., Stec, A. O., Čermák, T., Stupar, R. M. (2018). CRISPR-Cas9 and talen s generate heritable mutations for genes involved in small rna processing of glycine max and medicago truncatula. Plant biotechnology journal, 16(6): 1125-1137. [Google Scholar]
  29. Cyranovski D (2014). Marmosets are stars of Japan’s ambitious brain project. Nature 514: 151-152. [Google Scholar]
  30. Cyranovski D (2016). Monkey kingdom. Nature, 532: 300-302. [Google Scholar]
  31. Darma, R., Lutz, A., Elliott, C. E., Idnurm, A. (2019). Identification of a gene cluster for the synthesis of the plant hormone abscisic acid in the plant pathogen Leptosphaeria maculans. Fungal Genetics and Biology, 130: 62-71. [Google Scholar]
  32. De Oliveira Collet, S.A., Collet, M.A., Maria de Fátima, P. (2005). Differential gene expression for isozymes in somatic mutants of Vitis vinifera L.(Vitaceae). Biochemical Systematics and Ecology, 33 (7): 691-703. [Google Scholar]
  33. Demirci, S., Leonard, A., Haro-Mora, J. J., Uchida, N., & Tisdale, J. F. (2019). CRISPR/Cas9 for Sickle Cell Disease: Applications, Future Possibilities, and Challenges. Advances in experimental medicine and biology, 1144, 37–52. doi:10.1007/5584_2018_331 [Google Scholar] [Crossref] 
  34. Demorest, Z.L., Coffman, A., Baltes, N.J., Stoddard, T.J., Clasen, B.M., Luo, S., Retterath, A., Yabandith, A., Gamo, M.E., Bissen, J., Mathis, L., Voytas, D.F., Zhang, F. (2016).  Direct stacking of sequence-specific nuclease-induced mutations to produce high oleic and low linolenic soybean oil. BMC Plant Biology 16: 225. [Google Scholar]
  35. Deng, H., Gao, R., Liao, X., Cai, Y. (2017a). Genome editing in Shiraia bambusicola using CRISPR-Cas9 system. Journal of biotechnology, 259: 228-234. [Google Scholar]
  36. Deng, H., Gao, R., Liao, X., Cai, Y. (2017b). Characterization of a major facilitator superfamily transporter in Shiraia bambusicola. Research in microbiology, 168(7): 664-672. [Google Scholar]
  37. Dow LE (2015). Modeling disease in vivo with CRISPR-Cas9. Trends Mol. Med. 21: 609-621.  [Google Scholar]
  38. Dvořák, P., Nikel PI, Damborský J, de Lorenzo V. (2017).  Bioremediation 3.0: Engineering pollutant-removing bacteria in the times of systemic biology, Biotechnology Advances, 35(7):845-866. [Google Scholar]
  39. Eisenstein M. (2018). CRISPR takes on Huntington's disease. Nature, 557(7707), S42–S43. doi:10.1038/d41586-018-05177-y [Google Scholar] [Crossref] 
  40. Esvelt, K.M., Smidler AL, Catteruccia F, Church GM. (2014). Concerning RNA-guided gene drives for the alteration of wild populations. Elife,: p.e03401. [Google Scholar]
  41. Fang, Y., Tyler, B. M. (2016). Efficient disruption and replacement of an effector gene in the oomycete P hytophthora sojae using CRISPR/C as9. Molecular plant pathology, 17(1): 127-139. [Google Scholar]
  42. Fister AS, Landherr L, Maximova SN, Guiltinan MJ. (2018). Transient expression of CRISPR-Cas9 machinery targeting TcNPR3 enhances defense response in Theobroma cacao. Frontiers in plant science, 9: 268. [Google Scholar]
  43. Forster BP, Shub QY. (2011).Plant Mutagenesis in Crop Improvement: Basic Terms and Applications. In: Plant Mutation Breeding and Biotechnology. Ed. Shu Q.Y, Forster , B.P., Nakagawa H. Plant Breeding and Genetics Section Joint FAO/IAEA. Division of Nuclear Techniques in Food and Agriculture International Atomic Energy Agency, Vienna, Austria. [Google Scholar]
  44. Franks, T., Botta, R., Thomas, M., Franks, J. (2002). Chimerism in grapevines: implications for cultivar identity, ancestry and genetic improvement. Theoretical and Applied Genetics, 104 (2-3): 192-199. [Google Scholar]
  45. Fuller KK, Chen S, Loros JJ, Dunlap JC. (2015). Development of the CRISPR/Cas9 system for targeted gene disruption in Aspergillus fumigatus. Eukaryotic Cell, 14(11): 1073-1080. [Google Scholar]
  46. Gantz V.M., Bier E. (2015). Genome editing. The mutagenic chain reaction: a method for converting heterozygous to homozygous mutations. Science, 348(6233): 442-444. [Google Scholar]
  47. Gao, C. (2018). The future of CRISPR technologies in agriculture. Nat Rev Mol Cell Biol, 19(5): 275-276. [Google Scholar]
  48. Gardiner DM, Kazan K. (2018). Selection is required for efficient Cas9-mediated genome editing in Fusarium graminearum. Fungal biology, 122(2-3): 131-137. [Google Scholar]
  49. Gasiunas G, Barrangou R, Horvath P, Siksnys V. (2012). Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Proc Natl Acad Sci U S A 109: E2579 – E2586. [Google Scholar] [Crossref] 
  50. Gearing, M. (2015). History o CRISPR. CRISPR 101: A Desktop Resource, 12. [Google Scholar]
  51. Griffiths, A., J, F, Miller J. H, Susuki D, Lewontin R. C, Gelbart W. M (1996). Gene Mutation. W.H. Freeman and Company, New York, 181- 210. [Google Scholar]
  52. Harvey-Samuel T, Ant T, Alphey L. (2017). Towards the genetic control of invasive species, Biol Invasions,19: 1683. [Google Scholar] [Crossref] 
  53. Heo YT, Quan X, Xu YN, Baek S, Choi H, Kim NH, Kim J (2015). CRISPR-Cas9 Nuclease-Mediated Gene Knock-In in Bovine-Induced Pluripotent Cells. Stem Cells and Development 24 (3): 393-402. [Google Scholar]
  54. Holkenbrink, C. , Dam, M. I., Kildegaard, K. R., Beder, J. , Dahlin, J. , Doménech Belda, D., Borodina, I. (2018), EasyCloneYALI: CRISPR-Cas9‐Based Synthetic Toolbox for Engineering of the Yeast Yarrowia lipolytica. Biotechnol. J., 13: 1700543. doi:10.1002/biot.201700543 [Google Scholar] [Crossref] 
  55. Haapaniemi E, Botla S, Persson J, Schmierer B, and Taipale, 2018. CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response. Nature Medicine, 24:927-930. [Google Scholar]
  56. Ihry RJ, Worringer KA, Salick MR, Frias E, Ho D, Theriault K, Kommineni S, Chen J, Sondey M, Ye C, Randhawa R, Kulkarni T, Yang Z, McAllister G, Russ C, Reece-Hoyes J, Forrester W, Hoffman GR, Dolmetsch R, and Kaykas. 2018. p53 inhibits CRISPR–Cas9 engineering in human pluripotent stem cells. Nature Medicine,24:939-946 [Google Scholar]
  57. IAEA Mutant Variety Database, 6.9.2019.!Search?page=1&size=15&sortby=Registration&sort=DESC [Google Scholar]
  58. Idnurm, A., Urquhart, A. S., Vummadi, D. R., Chang, S., Van de Wouw, A. P., López-Ruiz, F.J. (2017). Spontaneous and CRISPR/Cas9-induced mutation of the osmosensor histidine kinase of the canola pathogen Leptosphaeria maculans. Fungal biology and biotechnology, 4(1): 12. [Google Scholar]
  59. Igbalajobi, O., Yu, Z., Fischer, R. (2019). Red-and Blue-Light Sensing in the Plant Pathogen Alternaria alternata Depends on Phytochrome and the White-Collar Protein LreA. mBio, 10(2): e00371-19. [Google Scholar]
  60. Ishino Y, Shinagawa H, Makino K, Amemura M, Nakata A. (1987). Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product. J Bacteriol 169:5429 –5433. [Google Scholar] [Crossref] 
  61. Jaganathan D, Ramasamy K, Sellamuthu G, Jayabalan S, Venkataraman G (2018) CRISPR for Crop Improvement: An Update Review. Front. Plant Sci. 9:985. [Google Scholar]
  62. Jaganathan, D., Ramasamy, K., Sellamuthu, G., Jayabalan, S., Venkataraman, G. (2018). CRISPR for crop improvement: an update review. Frontiers in plant science, 9. [Google Scholar]
  63. Jansen R, Embden JD, Gaastra W, Schouls LW. (2002). Identification of genes that are associated with DNA repeats in prokaryotes. Mol Microbiol 43:1565–1575. [Google Scholar] [Crossref] 
  64. Ji X, Si X, Zhang Y, Zhang H, Zhang F, Gao C. (2018). Conferring DNA virüs resistance with high specificity in plants using virus-inducible genome editing system. Genome Biology, 19 (1): 197 [Google Scholar]
  65. Jiménez A, Muñoz-Fernández G, Ledesma-Amaro R, Buey RM, Revuelta JL (2019). One-vector CRISPR/Cas9 genome engineering of the industrial fungus Ashbya gossypii. Microb Biotechnol 0(0):1-9. [Google Scholar]
  66. Jinek, M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E (2012). A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science, 337: 816–821. [Google Scholar]
  67. Karkute, S. G., Singh, A. K., Gupta, O. P., Singh, P. M., & Singh, B. (2017). CRISPR/Cas9 mediated genome engineering for improvement of horticultural crops. Frontiers in plant science, 8, 1635. [Google Scholar]
  68. Karl B,  Travis B. (2012). Engineering microbial consortia to enhance biomining and bioremediation. Frontiers in Microbiology, 3:203.    [Google Scholar]
  69. Katayama T, Tanaka Y, Okabe T, Nakamura H, Fujii W, Kitamoto K, Maruyama J (2016). Development of a genome editing technique using the CRISPR/Cas9 system in the industrial filamentous fungus Aspergillus oryzae. Biotechnol Lett, 38:637–642. [Google Scholar]
  70. Katayama T, Nakamura H, Zhang Y, Pascal A, Fujii W, Maruyama JI (2019). Forced recycling of an AMA1-based genome-editing plasmid allows for efficient multiple gene deletion/integration in the industrial filamentous fungus Aspergillus oryzae. Appl Environ Microbiol, 85(3):e01896–e01818. [Google Scholar]
  71.  Kim JS (2016). Genome editing comes of age. Nature Protocols 11 (9): 1573-1578. [Google Scholar]
  72. Kuivanen J, Wang YJ, Richard P (2016). Engineering Aspergillus niger for galactaric acid production: elimination of galactaric acid catabolism by using RNA sequencing and CRISPR/Cas9. Microb Cell Factories, 15:210. [Google Scholar]
  73. Kuivanen J, Richard P (2018). NADPH-dependent 5-keto-D-gluconate reductase is a part of the fungal pathway for D-glucuronate catabolism. FEBS Lett, 592:71–77.  [Google Scholar]
  74. Kuivanen J, Arvas M, Richard P (2017). Clustered genes encoding 2-keto-l-gulonate reductase and l-idonate 5-dehydrogenase in the novel fungal d-glucuronic acid pathway. Front Microbiol, 8:225. [Google Scholar]
  75. Kuivanen J, Korja V, Holmström S, Richard P (2019). Development of microtiter plate scale CRISPR/Cas9 transformation method for Aspergillus niger based on in vitro assembled ribonucleoprotein complexes. Fungal Biol Biotechnol, 6:3. [Google Scholar]
  76. Lau, C-H (2018). 'Applications of CRISPR-Cas in Bioengineering, Biotechnology, and Translational Research' The CRISPR Journal, 1(6):379–404. [Google Scholar]
  77. Leynaud-Kieffer LMC, Curran SC, Kim I, Magnuson JK, Gladden JM, Baker SE, Simmons BA (2019). A new approach to Cas9-based genome editing in Aspergillus niger that is precise, efficient and selectable. PLoS One 14(1):e0210243. [Google Scholar]
  78. Li, W. Y., Gao, Q. P., & Liu, H. (2018). Zhongguo shi yan xue ye xue za zhi, 26(6), 1863–1867. doi:10.7534/j.issn.1009-2137.2018.06.048 [Google Scholar] [Crossref] 
  79. Li Q, Zhang D, Chen M, Liang W, Wei J, Qİ Y, Yuan Z (2016). Development of japonica photo-sensitive genic male sterile rice lines by editing carbon starved anther using CRISPR-Cas9. J. Genet. Genom. 43:415–19 [Google Scholar]
  80. Li, A., Jia, S., Yobi, A., Ge, Z., Sato, S. J., Zhang, C.,  Angelovici R, Clemente TE, Holding, D. R. (2018). Editing of an Alpha-Kafirin gene family increases, digestibility and protein quality in sorghum. Plant physiology, 177(4): 1425-1438. [Google Scholar]
  81. Li, J., Zhang, H., Si, X., Tian, Y., Chen, K., Liu, J., Chen, H., Gao, C. (2017). Generation of thermosensitive male-sterile maize by targeted knockout of the ZmTMS5 gene. Journal of genetics and genomics= Yi chuan xue bao, 44(9): 465. [Google Scholar]
  82. Li, M., Li, X., Zhou, Z., Wu, P., Fang, M., Pan, X., Lin Q, Luo W, Wu G, Li H. (2016). Reassessment of the four yield-related genes Gn1a, DEP1, GS3, and IPA1 in rice using a CRISPR-Cas9 system. Frontiers in plant science, 7: 377. [Google Scholar]
  83. Li, Q., Qin, Z., Wang, Q., Xu, T., Yang, Y., & He, Z. (2019). Applications of Genome Editing Technology in Animal Disease Modeling and Gene Therapy. Computational and structural biotechnology journal, 17, 689–698. doi:10.1016/j.csbj.2019.05.006 [Google Scholar] [Crossref] 
  84. Li, Z., Liu, Z. B., Xing, A., Moon, B. P., Koellhoffer, J. P., Huang, L., Ward RT, Clifton E, Falco SC, Cigan, A. M. (2015). Cas9-guide RNA directed genome editing in soybean. Plant physiology, 169(2): 960-970. [Google Scholar]
  85. Liang Y, Han Y, Wang C, Jiang C, Xu JR (2018). Targeted deletion of the USTA and UvSLT2 genes efficiently in Ustilaginoidea virens with the CRISPR-Cas9 system. Front Plant Sci, 9:699 [Google Scholar]
  86. Liao JC, Mi L, Pontrelli S, Luo S (2016). Fuelling the future: microbial engineering for the production of sustainable biofuels, Nature Reviews Microbiology, 14: 288–304. [Google Scholar]
  87. Lim, K., Yoon, C., & Yokota, T. (2018). Applications of CRISPR/Cas9 for the Treatment of Duchenne Muscular Dystrophy. Journal of personalized medicine, 8(4), 38. doi:10.3390/jpm8040038 [Google Scholar] [Crossref] 
  88. Liu H, Chen Y, Niu Y, Zhang K, Kang Y, Ge W, Liu X, Zhao E, Wang C, Lin S, Jing B, Si C, Lin Q, Chen X, Lin H, Pu X, Wang Y, Qin B, Wang F, Wang H, Si W, Zhou J, Tan T, Li T, Ji S, Xue Z, Luo Y, Cheng L, Zhou Q, Li S, Sun YE, Ji W. (2014). TALEN-mediated gene mutagenesis in rhesus and cynomolgus monkeys. Cell Stem Cell, 14: 323-328. [Google Scholar]
  89. Liu X, Wu S, Xu J, Sui C,  Wei J. (2017). Application of CRISPR-Cas9 in plant biology. Acta Pharmaceutica Sinica B.,7(3): 292-302. [Google Scholar]
  90. Liu X, Xie C, Si H, Yang J. (2017). CRISPR-Cas9-mediated genome editing in plants. Methods, 121: 94-102. [Google Scholar]
  91. Liu R, Chen L, Jiang Y, Zhou Z, Zou G (2015). Efficient genome editing in filamentous fungus Trichoderma reesei using the CRISPR/Cas9 system. Cell Discov, 1:15007. [Google Scholar]
  92. Loubna Y, Valentin W, Nicole H, Xi Y, Hildebrand HG, Birgit S, Marius K, Birgit HF, Andrew D, Reinhard F (2019). Intercellular communication is required for trap formation in the nematode-trapping fungus Duddingtonia flagrans. PLoS Genet [Google Scholar]
  93. Lu, Y.,  Zhu, J. K. (2017). Precise editing of a target base in the rice genome using a modified CRISPR-Cas9 system. Molecular plant, 10(3): 523-525. [Google Scholar]
  94. Luengo M, Garcı́a JB, Sandoval A, Naharro G, Olivera ER (2003). Bioplastics from microorganisms. Current Opinion in Microbiology,6(3):251-260. [Google Scholar]
  95. Ma X, Zhang Q, Zhu Q, Liu W, Chen Y, Qiu R, Wang B, Yang Z, Li H, Lin Y, Xie Y, Shen R, Chen S, Wang Z, Chen Y, Guo J, Chen L, Zhao X, Dong Z, Liu YG (2015). A robust CRISPR/Cas9 system for convenient, high-efficiency multiplex genome editing in monocot and dicot plants. Mol Plant, 8:1274–1284. [Google Scholar]
  96. McFarlane GR, Whitelaw CBA, Lillico SG. (2017). CRISPR-Based Gene Drives for Pest Control, Trends in Biotechnology, 36(2):130 – 133. [Google Scholar]
  97. Makarova KS, Wolf YI, Alkhnbashi OS, Costa F, Shah SA, Saunders SJ, Barrangou R, Brouns SJ, Charpentier E, Haft DH, Horvath P, Moineau S, Mojica FJ, Terns RM, Terns MP, White MF, Yakunin AF, Garrett RA, van der Oost J, Backofen R, Koonin EV. (2015). An updated evolutionary classification of CRISPR-Cas systems. Nat Rev Microbiol. Nov;13(11):722-36. [Google Scholar]
  98. Ma, N., Zhang, J. Z., Itzhaki, I., Zhang, S. L., Chen, H., Haddad, F., … Wu, J. C. (2018). Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells. Circulation, 138(23), 2666–2681. doi:10.1161/CIRCULATIONAHA.117.032273 [Google Scholar] [Crossref] 
  99. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, Norville JE, Church GM. (2013). RNA-guided human genome engineering via Cas9.Science, 339:823– 826.  [Google Scholar]
  100. Matsuda Y, Bai T, Phippen C, Nodvig CS, Kjaerbolling I, Vesth TC, Andersen MR, Mortensen UH, Gotfredsen CH, Abe I, Larsen TO (2018). Novofumigatonin biosynthesis involves a non-heme iron-dependent endoperoxide isomerase for orthoester formation. Nat Commun, 9:2587.  [Google Scholar]
  101. Marangi, M., & Pistritto, G. (2018). Innovative Therapeutic Strategies for Cystic Fibrosis: Moving Forward to CRISPR Technique. Frontiers in pharmacology, 9, 396. doi:10.3389/fphar.2018.00396 [Google Scholar] [Crossref] 
  102. Matsu-Ura T, Baek M, Kwon J, Hong C (2015). Efficient gene editing in Neurospora crassa with CRISPR technology. Fungal Biol Biotechnol, 2:4.  [Google Scholar]
  103. McNamara, J. W., Li, A., Lal, S., Bos, J. M., Harris, S. P., Van Der Velden, J., ...  Dos Remedios, C. G. (2018). MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy. PloS one, 12(6): e0180064. [Google Scholar]
  104. Miao, C., Xiao, L., Hua, K., Zou, C., Zhao, Y., Bressan, R.A., Zhu, J.K. (2018). Mutations in a subfamily of abscisic acid receptor genes promote rice growth and productivity. Proceedings of the National Academy of Sciences, 115(23): 6058-6063. [Google Scholar]
  105. Min K, Ichikawa Y, Woolford CA, Mitchell AP (2016). Candida albicans Gene deletion with a transient CRISPR-Cas9 system. mSphere 1(3):e00130–e00116. [Google Scholar]
  106. Mojica FJM, Díez-Villaseñor C, García-Martínez J, Soria E. (2005). Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements. J Mol Evol, 60:174-182. [Google Scholar] [Crossref] 
  107. Mojica MJ, Juez G, Rodríguez-Valera F. (1993). Transcription at different salinities of Haloferax mediterranei sequences adjacent to partially modified PstI sites. Mol Microbiol, 9:613– 621. [Google Scholar] [Crossref] 
  108. Moore, D., Robson, G., Trinci, A. (2019). 21st Century Guidebook to Fungi. Cambridge: Cambridge University Press. [Google Scholar]
  109. Morishige, S., Mizuno, S., Ozawa, H., Nakamura, T., Mazahery, A., Nomura, K., … Nagafuji, K. (2019). CRISPR/Cas9-mediated gene correction in hemophilia B patient-derived iPSCs. International journal of hematology, 10.1007/s12185-019-02765-0. Advance online publication. doi:10.1007/s12185-019-02765-0 [Google Scholar] [Crossref] 
  110. Mougiakos, I., Bosma, E. F., Ganguly , J., van der Oost, J., van Kranenburg, R. (2018). Hijacking CRISPR- Cas for high-throughput bacterial metabolic engineering: advances and prospects. Current Opinion in Biotechnology, 50:146-157. [Google Scholar] [Crossref] 
  111. Muñoz IV, Sarrocco S, Malfatti L, Baroncelli R, Vannacci G. (2019). CRISPR-Cas for Fungal Genome Editing: A New Tool for the Management of Plant Diseases. Front. Plant Sci., 10:1–5. [Google Scholar]
  112. Nagaraju S, Davies NK, Walker DJF, Köpke M, Simpson SD (2016) Biotechnol Biofuels, 9:219 DOI 10.1186/s13068-016-0638-3 [Google Scholar]
  113. Nagy G, Szebenyi C, Csernetics A, Vaz AG, Toth EJ, Vagvolgyi C, Papp T (2017). Development of a plasmid free CRISPR-Cas9 system for the genetic modification of Mucor circinelloides. Sci Rep, 7:16800. [Google Scholar]
  114. Nagy G, Vaz AG, Szebenyi C, Takó M, Tóth EJ, Csernetics A, Bencsik O, Szekeres A, Homa M, Ayaydin F, Galgóczy L, Vágvölgyi C, Papp T (2019). CRISPR-Cas9-mediated disruption of the HMG-CoA reductase genes of Mucor circinelloides and subcellular localization of the encoded enzymes. Fungal Genet Biol, 129:30–39. [Google Scholar]
  115. Ni W, Qiao J, Hu S, Zhao X, Regouski M, Yang M, Polejaeva IA, Chen C (2014). Efficient Gene Knockout in Goats Using CRISPR-Cas9 System. PLoS One 9(9): e106718. DOI: 10.1371/journal.pone.0106718. [Google Scholar]
  116. Nielsen ML, Isbrandt T, Rasmussen KB, Thrane U, Hoof JB, Larsen TO, Mortensen UH (2017). Genes linked to production of secondary metabolites in Talaromyces atroroseus revealed using CRISPR-Cas9. PLoS One 12:e169712. [Google Scholar]
  117. Niu Y, Shen B, Cui Y, Chen Y, Wang J, Wang L, Kang Y, Zhao X, Si W, Li W, Xiang AP, Zhou J, Guo X, Bi Y, Si C, Hu B, Dong G, Wang H, Zhou Z, Li T, Tan T, Pu X, Wang F, Ji S, Zhou Q, Huang X, Ji W, Sha J. (2014). Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos. Cell, 156(4):836-843 [Google Scholar]
  118. Niu Y, Jin M, Li Y, Li P, Zhou J, Wang X, Petersen B, Huang X, Kou Q, Chen Y (2016). Biallelic beta-carotene oxygenase 2 knockout results in yellow fat in sheep via CRISPR-Cas9. Animal Genetics. DOI: 10.1111/age.12515. [Google Scholar]
  119. Nodvig CS, Nielsen JB, Kogle ME, Mortensen UH (2015). A CRISPR-Cas9 system for genetic engineering of filamentous fungi. PLoS One 10:e133085.  [Google Scholar]
  120. Nodvig CS, Hoof JB, Kogle ME, Jarczynska ZD, Lehmbeck J, Klitgaard DK, Mortensen UH (2018). Efficient oligo nucleotide mediated CRISPR-Cas9 gene editing in Aspergilli. Fungal Genet Biol 115:78–89. [Google Scholar]
  121. Normile D. (2018). CRISPR bombshell: Chinese researcher claims to have created gene-edited twins. Science. doi:10.1126/science.aaw1839 [Google Scholar] [Crossref] 
  122. Nymark M, Sharma AK,  Sparstad T, Bones AM, Winge P (2016). A CRISPR-Cas9 system adapted for gene editing in marine algae.Sci. Rep. 6, 24951; doi: 10.1038/srep24951. [Google Scholar] [Crossref] 
  123. O'Geen H, Yu AS, Segal DJ (2015). How specific is CRISPR-Cas9 really? Current Opinion in Chemical Biology 29: 72-78. [Google Scholar]
  124. Oishi I, Yoshii K, Miyahara D, Kagami H, Tagami T (2016). Targeted mutagenesis in chicken using CRISPR-Cas9 system. Scientific Reports 6. DOI: 10.1038/srep23980. [Google Scholar]
  125. Oladosu Y, Rafii MY, Abdullah N, Hussein G, Ramli A, Rahim H A, Miah G,  Usman M. (2016).Principle and application of plant mutagenesis in crop improvement. Biotechnology & Biotechnological Equipment, 30(1):1-16,  DOI: 10.1080/13102818.2015.1087333. [Google Scholar]
  126. Pacher M, Puchta H. (2017).  From classical mutagenesis to nuclease-based breeding – directing natural DNA repair for a natural end-product. The Plant Journal, 90: 819–83. [Google Scholar]
  127. Papasavva, P., Kleanthous, M., & Lederer, C. W. (2019). Rare Opportunities: CRISPR/Cas-Based Therapy Development for Rare Genetic Diseases. Molecular diagnosis & therapy, 23(2), 201–222. doi:10.1007/s40291-019-00392-3 [Google Scholar] [Crossref] 
  128. Peng, A., Chen, S., Lei, T., Xu, L., He, Y., Wu, L., Zou, X. (2017). Engineering canker‐resistant plants through CRISPR-Cas9‐targeted editing of the susceptibility gene Cs LOB 1 promoter in citrus. Plant biotechnology journal, 15(12): 1509-1519. [Google Scholar]
  129. Petersen B, Niemann H (2015). Molecular scissors and their application in genetically modified farm animals. Transgenic Research 24 (3): 381-396. [Google Scholar]
  130. Peng, Y. Q., Tang, L. S., Yoshida, S., & Zhou, Y. D. (2017). Applications of CRISPR/Cas9 in retinal degenerative diseases. International journal of ophthalmology, 10(4), 646–651. doi:10.18240/ijo.2017.04.23 [Google Scholar] [Crossref] 
  131. Pohl C, Kiel JA, Driessen AJ, Bovenberg RA, Nygard Y (2016). CRISPR/Cas9 based genome editing of Penicillium chrysogenum. ACS Synth Biol, 5:754–764. [Google Scholar]
  132. Pourcel C, Salvignol G, Vergnaud G. (2005). CRISPR elements in Yersinia pestis acquire new repeats by preferential uptake of bacteriophage DNA, and provide additional tools for evolutionary studies. Microbiology 151:653–663. [Google Scholar] [Crossref] 
  133. Proudfoot C, Carlson DF, Huddart R, Long CR, Pryor JH, King TJ, Lillico SG, Mileham AJ, McLaren DG, Whitelaw CBA, Fahrenkrug SC (2015). Genome edited sheep and cattle. Transgenic Research. 24 (1): 147-153. [Google Scholar]
  134. Pursey E, Su¨nderhauf D, Gaze WH, Westra ER, van Houte S (2018). CRISPR-Cas antimicrobials: Challenges and future prospects. PLoS Pathog 14(6): e1006990. 10.1371/journal.ppat.1006990 [Google Scholar] [Crossref] 
  135. Pyott DE, Sheehan E, Molnar A. (2016). Engineering of CRISPR-Cas9-mediated potyvirus resistance in transgene-free Arabidopsis plants. Mol. Plant Pathol. 17: 1276–1288. [Google Scholar]
  136. Raaijmakers, R., Ripken, L., Ausems, C., & Wansink, D. G. (2019). CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities. International journal of molecular sciences, 20(15), 3689. doi:10.3390/ijms20153689 [Google Scholar] [Crossref] 
  137. Romero-Moya, D., Santos-Ocaña, C., Castaño, J., Garrabou, G., Rodríguez-Gómez, J. A., Ruiz-Bonilla, V., … Menendez, P. (2017). Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency. Stem cells (Dayton, Ohio), 35(7), 1687–1703. doi:10.1002/stem.2634 [Google Scholar] [Crossref] 
  138. Qin H, Xiao H, Zou G, Zhou Z, Zhong J (2017). CRISPR-Cas9 assisted gene disruption in the higher fungus Ganoderma species. Process Biochem, 56:57–61. [Google Scholar]
  139. Safari, F., Hatam, G., Behbahani, A. B., Rezaei, V., Barekati-Mowahed, M., Petramfar, P., & Khademi, F. (2019). CRISPR System: A High-throughput Toolbox for Research and Treatment of Parkinson's Disease. Cellular and molecular neurobiology, 10.1007/s10571-019-00761-w. Advance online publication. doi:10.1007/s10571-019-00761-w [Google Scholar] [Crossref] 
  140. Schuster M, Schweizer G, Reissmann S, Kahmann R (2016). Genome editing in Ustilago maydis using the CRISPR-Cas system. Fungal Genet Biol, 89:3–9.  [Google Scholar]
  141. Schuster M, Schweizer G, Kahmann R (2018). Comparative analyses of secreted proteins in plant pathogenic smut fungi and related basidiomycetes. Fungal Genet Biol, 112:21–30. [Google Scholar]
  142. Shapiro RS, Chavez A, Porter C, Hamblin M, Kaas CS, DiCarlo JE, Zeng G, Xu X, Revtovich AV, Kirienko NV, Wang Y, Church GM, Collins JJ (2018). A CRISPR-Cas9-based gene drive platform for genetic interaction analysis in Candida albicans. Nat Microbiol 3:73–82. [Google Scholar]
  143. Shi, J., Gao, H., Wang, H., Lafitte, H. R., Archibald, R. L., Yang, M., Habben, J. E. (2017). ARGOS 8 variants generated by CRISPR‐Cas9 improve maize grain yield under field drought stress conditions. Plant biotechnology journal, 15(2): 207-216. [Google Scholar]
  144. Song, R., Zhai, Q., Sun, L., Huang, E., Zhang, Y., Zhu, Y.,  Qingyun G, Tian Y, Zhao B,  Lu H. (2019). CRISPR/Cas9 genome editing technology in filamentous fungi: progress and perspective. Applied microbiology and biotechnology, 103(17): 6919-6932. [Google Scholar]
  145. Soyk, S., Müller, N.A., Park, S.J., Schmalenbach, I., Jiang, K., Hayama, R., Zhang, L., Van Eck, J., Jiménez-Gómez, J.M., Lippman, Z.B. (2017). Variation in the flowering gene SELF PRUNING 5G promotes day-neutrality and early yield in tomato. Nature Genetics, 49 (1): 162–168. [Google Scholar]
  146. Spencer-Lopes MM, Forster BP,  Jankuloski L. (2018). Manual on Mutation Breeding. Plant Breeding and Genetics Subprogramme Joint FAO/IAEA Division of Nuclear Techniques in Food and Agriculture Vienna, Austria. 2018. Volumes 121–122, 15 May 2017, Pages 94-102. [Google Scholar] [Crossref] 
  147. (Recommended citation=) FAO/IAEA. 2018. Manual on Mutation Breeding - Third edition. Spencer-Lopes, M.M., Forster, B.P. and Jankuloski, L. (eds.), Food and Agriculture Organization of the United Nations. Rome, Italy. 301 pp [Google Scholar]
  148. Stephens, C. J., Lauron, E. J., Kashentseva, E., Lu, Z. H., Yokoyama, W. M., & Curiel, D. T. (2019). Long-term correction of hemophilia B using adenoviral delivery of CRISPR/Cas9. Journal of controlled release : official journal of the Controlled Release Society, 298, 128–141. doi:10.1016/j.jconrel.2019.02.009 [Google Scholar] [Crossref] 
  149. Sun YW, Zhang X, Wu CY, He YB, Ma Y, Hou H, Guo X, Du W, Zhao Y, Xia L (2016). Engineering Herbicide-Resistant Rice Plants through CRISPR-Cas9-Mediated Homologous Recombination of Acetolactate Synthase. Molecular Plant, 9(4):628-631 [Google Scholar]
  150. Svitashev S, Young JK, Schwartz C, Gao H, Falco SC,  Cigan AM (2015). Targeted mutagenesis, precise gene editing, and site-specific gene insertion in maize using Cas9 and guide RNA. Plant physiology, 169(2): 931-945. [Google Scholar]
  151. Sweeney, C. L., Choi, U., Liu, C., Koontz, S., Ha, S. K., & Malech, H. L. (2017). CRISPR-Mediated Knockout of Cybb in NSG Mice Establishes a Model of Chronic Granulomatous Disease for Human Stem-Cell Gene Therapy Transplants. Human gene therapy, 28(7), 565–575. doi:10.1089/hum.2017.005 [Google Scholar] [Crossref] 
  152. Taştan C, Sakartepe E. (2018).  CRISPR Genom Modifikasyonları T101. Ed.: Taştan C. (Tercüme edilmiştir: AddGene CRISPR 101. P1-255, 2017. Version 2. Editörler:Wyatt D, Ramsden D, Doench J, MacPherson CR,  Wong A, Ward J, Esvelt K, Gearing M, McDade J, Ford TJ, Cortez C, Fan M, Patrick M, Waxmonsky N, LaManna C, Morgan K.) Modifikasyonlari _ T101. Erişim Tarihi: 11.10.2019. [Google Scholar]
  153. Tastan, C. (2019). Yapay Zeka ve Genetik Mühendisliği. In Sağlık Bilimlerinde Yapay Zeka (Vol. 1, pp. 153–162). Çağlayan Kitabevi. [Google Scholar]
  154. Tian S, Jiang L, Gao Q, Zhang J, Zong M, Zhang H, Ren Y, Guo S, Gong G, Liu F, Xu Y. (2016). Efficient CRISPR-Cas9-based gene knockout in watermelon.  Plant Cell Reports, 36 (3): 399–406. [Google Scholar]
  155. Véron N, Qu Z, Kipen PAS, Hirst CE, Marcelle C (2015). CRISPR mediated somatic cell genome engineering in the chicken. Developmental Biology, 407(1): 68-74. [Google Scholar]
  156. Vyas VK, Bushkin GG, Bernstein DA, Getz MA, Sewastianik M, Barrasa MI, Bartel DP, Fink GR (2018). New CRISPR Mutagenesis Strategies Reveal Variation in Repair Mechanisms among Fungi. mSphere 3(2): e00154-18. [Google Scholar]
  157. Waltz E. (2016a). CRISPR-edited crops free to enter market, skip regulation. [Google Scholar]
  158. Walton, J. B., Farquharson, M., Mason, S., Port, J., Kruspig, B., Dowson, S., … McNeish, I. A. (2017). CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity. Scientific reports, 7(1), 16827. doi:10.1038/s41598-017-17119-1 [Google Scholar] [Crossref] 
  159. Wallmeier, J., Shiratori, H., Dougherty, G. W., Edelbusch, C., Hjeij, R., Loges, N. T., … Omran, H. (2016). TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization. American journal of human genetics, 99(2), 460–469. doi:10.1016/j.ajhg.2016.06.014 [Google Scholar] [Crossref] 
  160. Waltz E. (2016b). Gene-edited CRISPR mushroom escapes US regulation. Nature News, 532(7599): 293. [Google Scholar]
  161. Wang L, Yang L, Guo Y, Du W, Yin Y, Zhang T, Lu H (2017). Enhancing Targeted Genomic DNA Editing in Chicken Cells Using the CRISPR-Cas9 System. PLoS ONE 12(1): e0169768. doi:10.1371/journal.pone.0169768. [Google Scholar] [Crossref] 
  162. Wang P (2018). Two distinct approaches for CRISPR-Cas9-mediated gene editing in Cryptococcus neoformans and related species. mSphere 3:e00208–e00218. [Google Scholar]
  163. Wang X, Cai B, Zhou J, Zhu H, Niu Y, Ma B, Yu H, Lei A, Yan H, Shen X, Shi L, Zhao X, Hua J, Huang X, Qu L, Chen Y (2016a). Disruption of FGF5 in Cashmere Goats Using CRISPR-Cas9 Results in More Secondary Hair Follicles and Longer Fibers. PLoS One 11 (10). DOI: 10.1371/journal.pone.0164640. [Google Scholar]
  164. Wang X, Niu Y, Zhou J, Yu H, Kou Q, Lei A, Zhao X, Yan H, Cai B, Shen Q, Zhou S, Zhu H, Zhou G, Niu W, Hua J, Jiang Y, Huang X, Ma B, Chen Y (2016b). Multiplex gene editing via CRISPR-Cas9 exhibits desirable muscle hypertrophy without detectable off-target effects in sheep. Scientific Reports 6. DOI: 10.1038/srep32271. [Google Scholar]
  165. Wang, L., Yang, Y., Breton, C. A., White, J., Zhang, J., Che, Y., … Wilson, J. M. (2019). CRISPR/Cas9-mediated in vivo gene targeting corrects hemostasis in newborn and adult factor IX-knockout mice. Blood, 133(26), 2745–2752. doi:10.1182/blood.2019000790 [Google Scholar] [Crossref] 
  166. Wang X, Yu H, Lei A, Zhou J, Zeng W, Zhu H, Dong Z, Niu Y, Shi B, Cai B, Liu J, Huang S, Yan H, Zhao X, Zhou G, He X, Chen X, Yang Y, Jiang Y, Shi L, Tian X, Wang Y, Ma B, Huang X, Qu L, Chen Y (2015). Generation of gene-modified goats targeting MSTN and FGF5 via zygote injection of CRISPR-Cas9 system. Scientific Reports 5: 13878. DOI: 10.1038/srep13878. [Google Scholar]
  167. Wang, F., Wang, C., Liu, P., Lei, C., Hao, W., Gao, Y., Zhao, K. (2016). Enhanced rice blast resistance by CRISPR-Cas9-targeted mutagenesis of the ERF transcription factor gene OsERF922. PloS one, 11(4): e0154027. [Google Scholar]
  168. Wang, N., Pierson, E. A., Setubal, J. C., Xu, J., Levy, J. G., Zhang, Y. Martins Jr, J. (2017). The Candidatus Liberibacter–host interface: insights into pathogenesis mechanisms and disease control. Annual review of phytopathology, 55: 451-482. [Google Scholar]
  169. Wang, Y., Geng, L., Yuan, M., Wei, J., Jin C., Li, M., Yu K., Zhang Y., Jin, H., Wang, E., Chai, Z., Fu, X., Li, X. (2017). Deletion of a target gene in Indica rice via CRISPR-Cas9. Plant Cell Reports, 36 (8): 1333–1343. [Google Scholar]
  170. Weber J, Valiante V, Nodvig CS, Mattern DJ, Slotkowski RA, Mortensen UH, Brakhage AA (2017). Functional reconstitution of a fungal natural product gene cluster by advanced genome editing. ACS Synth Biol, 6:62–68 [Google Scholar]
  171. Wenderoth M, Pinecker C, Voss B, Fischer R (2017). Establishment of CRISPR/Cas9 in Alternaria alternata. Fungal Genet Biol, 101:55–60. [Google Scholar]
  172. Wendt KE, Ungerer J, Cobb RE, Zhao H, Pakrasi HP (2016). CRISPR-Cas9 mediated targeted mutagenesis of the fast growing cyanobacterium Synechococcus elongatus UTEX 2973. Microb Cell Fact., 15:115. [Google Scholar]
  173. Weyda I, Yang L, Vang J, Ahring BK, Lubeck M, Lubeck PS (2017). A comparison of Agrobacterium-mediated transformation and protoplast-mediated transformation with CRISPR-Cas9 and bipartite gene targeting substrates, as effective gene targeting tools for Aspergillus carbonarius. J Microbiol Methods, 135:26–34. [Google Scholar]
  174. Wu M, Wei C, Lian Z, Liu R, Zhu C, Wang H, Cao J, Shen Y, Zhao F, Zhang L, Mu Z, Wang Y, Wang X, Du L, Wang C (2016). Rosa26-targeted sheep gene knock-in via CRISPR-Cas9 system. Scientific. Reports. 6: 24360; DOI: 10.1038/srep24360. [Google Scholar]
  175. Wu, Y., Liang, D., Wang, Y., Bai, M., Tang, W., Bao, S., … Li, J. (2013). Correction of a genetic disease in mouse via use of CRISPR-Cas9. Cell stem cell, 13(6), 659–662. doi:10.1016/j.stem.2013.10.016 [Google Scholar] [Crossref] 
  176. Xie, Y., Niu, B., Long, Y., Li, G., Tang, J., Zhang, Y., Chen, L. (2017a). Suppression or knockout of SaF/SaM overcomes the Sa‐mediated hybrid male sterility in rice. Journal of integrative plant biology, 59(9): 669-679. [Google Scholar]
  177. Xie, Y., Xu, P., Huang, J., Ma, S., Xie, X., Tao, D., Liu, Y. G. (2017b). Interspecific hybrid sterility in rice is mediated by OgTPR1 at the S1 locus encoding a peptidase-like protein. Molecular plant, 10(8): 1137-1140. [Google Scholar]
  178. Xu, R., Yang, Y., Qin, R., Li, H., Qiu, C., Li, L., Wei, P., & Yang, J. (2016). Rapid improvement of grain weight via highly efficient CRISPR/Cas9-mediated multiplex genome editing in rice. Journal of Genetics and Genomics, 43(8), 529–532. [Google Scholar] [Crossref] 
  179. Yamaguchi H. (2018) Mutation breeding of ornamental plants using ion beams. Breeding Science, 68: 71–78,  doi:10.1270/jsbbs.17086. [Google Scholar] [Crossref] 
  180. Yao, X., Liu, X., Zhang, Y., Li, Y., Zhao, C., Yao, S., & Wei, Y. (2017). Gene Therapy of Adult Neuronal Ceroid Lipofuscinoses with CRISPR/Cas9 in Zebrafish. Human gene therapy, 28(7), 588–597. doi:10.1089/hum.2016.190 [Google Scholar] [Crossref] 
  181. Yamamoto T (2015). Targeted Genome Editing Using Site-Specific Nucleases: ZFNs, TALENs and the CRISPR-Cas9 System. Springer, Japan. DOI: 10.1007/978-4-431-55227-7 [Google Scholar]
  182. Yao R,  Liu Di, Jia X, Zheng Y, Liu W, Xiao Y. (2018). CRISPR-Cas9/Cas12a biotechnology and application in bacteria, Synthetic and Systems Biotechnology,3(3):135-149. [Google Scholar]
  183. Yang, Y., Wang, L., Bell, P., McMenamin, D., He, Z., White, J., … Wilson, J. M. (2016). A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nature biotechnology, 34(3), 334–338. doi:10.1038/nbt.3469 [Google Scholar] [Crossref] 
  184. Yin, H., Kauffman, K. J.,  Anderson, D. G. (2017). Delivery technologies for genome editing. Nature reviews Drug discovery, 16(6), 387. [Google Scholar]
  185. Yuan M, Zhu J, Gong L, He L, Lee C, Han S, Chen C, He G. (2019). Mutagenesis of FAD2 genes in peanut with CRISPR-Cas9 based gene editing. BMC Biotechnology, 19:24. [Google Scholar] [Crossref] 
  186. Zaidi SS, Vanderschuren H, Qaim M, Mahfouz MM, Kohli A, Mansoor S, Tester M. (2019). New plant breeding technologies for food security. Improved crops can contribute to a world without hunger, if properly managed.  Science, 363(6434):  1390-1391. DOI: 10.1126/science.aav6316. [Google Scholar]
  187. Zarei A, Razban V, Hosseini SE,  Tabei SMB (2019). Creating cell and animal models of human disease by genome editing using CRISPR-Cas9, J Gene Med; 21:e3082. [Google Scholar] [Crossref] 
  188. Zhang X, Li W, Wu Y, Peng X, Lou B, Wang L, Liu M (2017a). Disruption of the sheep BMPR-IB gene by CRISPR-Cas9 in in vitro-produced embryos. Theriogenology. 91: 163-172. [Google Scholar]
  189. Zhang, Y., Liang, Z., Zong, Y., Wang, Y., Liu, J., Chen, K., Gao, C. (2016). Efficient and transgene-free genome editing in wheat through transient expression of CRISPR-Cas9 DNA or RNA. Nature communications, 7:12617. [Google Scholar]
  190. Zhao H, Wolt JD. (2017). Risk associated with off-target plant genome editing and methods for its limitation. Emerging Topics in Life Sciences, 1: 231–240, [Google Scholar] [Crossref] 
  191. Zheng YM, Lin FL, Gao H, Zou G, Zhang JW, Wang GQ, Chen GD, Zhou ZH, Yao XS, Hu D (2017). Development of a versatile and conventional technique for gene disruption in filamentous fungi based on CRISPR-Cas9 technology. Sci Rep, 7:9250.  [Google Scholar]
  192. Zheng X, Zheng P, Zhang K, Cairns TC, Meyer V, Sun J, Ma Y (2018). 5S rRNA promoter for guide RNA expression enabled highly efficient CRISPR/Cas9 genome editing in Aspergillus niger. ACS Synth Biol. Zhou H, He M, Li J, Chen L, Huang Z, et al. 2016. Development of commercial thermo-sensitive genic male sterile rice accelerates hybrid rice breeding using the CRISPR-Cas9-mediated TMS5 editing system. Sci. Rep., 6:37395 [Google Scholar]
  193. Zhou, J., Peng, Z., Long, J., Sosso, D., Liu, B., Eom, J. S., ... & White, F. F. (2015). Gene targeting by the TAL effector PthXo2 reveals cryptic resistance gene for bacterial blight of rice. The Plant Journal, 82(4): 632-643. [Google Scholar]
  194. Zhou H, He M, Li J, Chen L, Huang Z, Zheng S, Zhu L, Ni E, Jiang D, Zhao B, Zhuang C (2016). Development of commercial thermo-sensitive genic male sterile rice accelerates hybrid rice breeding using the CRISPR-Cas9-mediated TMS5 editing system. Sci. Rep. 6:37395 [Google Scholar]
  195. Zhou J,Peng R, hang R, Li J. (2018) The applications of CRISPR-Cas system in molecular detection, J Cell Mol Med.,22:5807–5815. [Google Scholar]
  196. Zsögön A, Čermák T, Naves ER, Notini MM, Ede KH, Wein S, Freschi L, Voytas DF, Kudla J,  Peres LEP. (2018). De novo domestication of wild tomato using genome editing. Nature Biotechnology, 36: (12): 1211-1216.  [Google Scholar]