| 
					
						|  |  
    					|  |  
    					| Base editing in pigs for precision breeding |  
						| Ruigao SONG1,2, Yu WANG3, Yanfang WANG3(  ), Jianguo ZHAO1,2(  ) |  
						| 1. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China 2. Medical School, University of Chinese Academy of Sciences, Beijing 100049, China
 3. State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100081, China
 |  
						|  |  
					
						| 
								
									|  
          
          
            
              
				
								                
													
													    |  |  
														| 
													
													    | Abstract Pigs are one of the most important domesticated animals and have great value in agriculture and biomedicine. Single nucleotide polymorphisms (SNPs) are a dominant type of genetic variation among individual pigs and contribute to the formation of traits. Precision single base substitution provides a strategy for accurate genetic improvement in pig production with the characterization of functional SNPs and genetic variants in pigs. Base editing has recently been developed as the latest gene-editing tool that can directly make changes in single nucleotides without introducing double-stranded DNA breaks (DSBs), providing a promising solution for precise genetic modification in large animals. This review summarizes gene-editing developments and highlights recent genetic dissection related to SNPs in major economic traits which may have the potential to be modified using SNP-editing applications. In addition, limitations and future directions of base editing in pig breeding are discussed. |  
															| Keywords 
																																																				base editing  
																		  																																				genetic improvement  
																		  																																				pigs  
																		  																																				single nucleotide polymorphisms |  
															| Corresponding Author(s):
																Yanfang WANG,Jianguo ZHAO |  
															| Just Accepted Date: 02 March 2020  
																																														Online First Date: 27 March 2020   
																																														Issue Date: 28 April 2020 |  |  
								            
								                
																																												
															| 1 | H S Park, B Min, S H Oh. Research trends in outdoor pig production—a review. Asian-Australasian Journal of Animal Sciences, 2017, 30(9): 1207–1214 https://doi.org/10.5713/ajas.17.0330
														     															     															     		pmid: 28728401
 |  
															| 2 | M A M Groenen, A L Archibald, H Uenishi, C K Tuggle, Y Takeuchi, M F Rothschild, C Rogel-Gaillard, C Park, D Milan, H J Megens, S Li, D M Larkin, H Kim, L A F Frantz, M Caccamo, H Ahn, B L Aken, A Anselmo, C Anthon, L Auvil, B Badaoui, C W Beattie, C Bendixen, D Berman, F Blecha, J Blomberg, L Bolund, M Bosse, S Botti, Z Bujie, M Bystrom, B Capitanu, D Carvalho-Silva, P Chardon, C Chen, R Cheng, S H Choi, W Chow, R C Clark, C Clee, R P M A Crooijmans, H D Dawson, P Dehais, F De Sapio, B Dibbits, N Drou, Z Q Du, K Eversole, J Fadista, S Fairley, T Faraut, G J Faulkner, K E Fowler, M Fredholm, E Fritz, J G R Gilbert, E Giuffra, J Gorodkin, D K Griffin, J L Harrow, A Hayward, K Howe, Z L Hu, S J Humphray, T Hunt, H Hornshøj, J T Jeon, P Jern, M Jones, J Jurka, H Kanamori, R Kapetanovic, J Kim, J H Kim, K W Kim, T H Kim, G Larson, K Lee, K T Lee, R Leggett, H A Lewin, Y Li, W Liu, J E Loveland, Y Lu, J K Lunney, J Ma, O Madsen, K Mann, L Matthews, S McLaren, T Morozumi, M P Murtaugh, J Narayan, D Truong Nguyen, P Ni, S J Oh, S Onteru, F Panitz, E W Park, H S Park, G Pascal, Y Paudel, M Perez-Enciso, R Ramirez-Gonzalez, J M Reecy, S Rodriguez-Zas, G A Rohrer, L Rund, Y Sang, K Schachtschneider, J G Schraiber, J Schwartz, L Scobie, C Scott, S Searle, B Servin, B R Southey, G Sperber, P Stadler, J V Sweedler, H Tafer, B Thomsen, R Wali, J Wang, J Wang, S White, X Xu, M Yerle, G Zhang, J Zhang, J Zhang, S Zhao, J Rogers, C Churcher, L B Schook. Analyses of pig genomes provide insight into porcine demography and evolution. Nature, 2012, 491(7424): 393–398 https://doi.org/10.1038/nature11622
														     															     															     		pmid: 23151582
 |  
															| 3 | K Chen, T Baxter, W M Muir, M A Groenen, L B Schook. Genetic resources, genome mapping and evolutionary genomics of the pig (Sus scrofa). International Journal of Biological Sciences, 2007, 3(3): 153–165 https://doi.org/10.7150/ijbs.3.153
														     															     															     		pmid: 17384734
 |  
															| 4 | H Gilbert, Y Billon, L Brossard, J Faure, P Gatellier, F Gondret, E Labussière, B Lebret, L Lefaucheur, N Le Floch, I Louveau, E Merlot, M C Meunier-Salaün, L Montagne, P Mormede, D Renaudeau, J Riquet, C Rogel-Gaillard, J van Milgen, A Vincent, J Noblet. Review: divergent selection for residual feed intake in the growing pig. Animal, 2017, 11(9): 1427–1439 https://doi.org/10.1017/S175173111600286X
														     															     															     		pmid: 28118862
 |  
															| 5 | M E Goddard, B J Hayes. Mapping genes for complex traits in domestic animals and their use in breeding programmes. Nature Reviews: Genetics, 2009, 10(6): 381–391 https://doi.org/10.1038/nrg2575
														     															     															     		pmid: 19448663
 |  
															| 6 | R E Hammer, V G Pursel, C E Rexroad Jr, R J Wall, D J Bolt, K M Ebert, R D Palmiter, R L Brinster. Production of transgenic rabbits, sheep and pigs by microinjection. Nature, 1985, 315(6021): 680–683 https://doi.org/10.1038/315680a0
														     															     															     		pmid: 3892305
 |  
															| 7 | M R Capecchi. Altering the genome by homologous recombination. Science, 1989, 244(4910): 1288–1292 https://doi.org/10.1126/science.2660260
														     															     															     		pmid: 2660260
 |  
															| 8 | I Wilmut, A E Schnieke, J McWhir, A J Kind, K H S Campbell. Viable offspring derived from fetal and adult mammalian cells. Nature, 1997, 385(6619): 810–813 https://doi.org/10.1038/385810a0
														     															     															     		pmid: 9039911
 |  
															| 9 | D Yang, H Yang, W Li, B Zhao, Z Ouyang, Z Liu, Y Zhao, N Fan, J Song, J Tian, F Li, J Zhang, L Chang, D Pei, Y E Chen, L Lai. Generation of PPARg mono-allelic knockout pigs via zinc-finger nucleases and nuclear transfer cloning. Cell Research, 2011, 21(6): 979–982 https://doi.org/10.1038/cr.2011.70
														     															     															     		pmid: 21502977
 |  
															| 10 | H I Ahmad, M J Ahmad, A R Asif, M Adnan, M K Iqbal, K Mehmood, S A Muhammad, A A Bhuiyan, A Elokil, X Du, C Zhao, X Liu, S Xie. A review of CRISPR-based genome editing: survival, evolution and challenges. Current Issues in Molecular Biology, 2018, 28: 47–68 https://doi.org/10.21775/cimb.028.047
														     															     															     		pmid: 29428910
 |  
															| 11 | Y Yang, S Liu, Y Cheng, L Nie, C Lv, G Wang, Y Zhang, L Hao. Highly efficient and rapid detection of the cleavage activity of Cas9/gRNA via a fluorescent reporter. Applied Biochemistry and Biotechnology, 2016, 180(4): 655–667 https://doi.org/10.1007/s12010-016-2122-8
														     															     															     		pmid: 27209600
 |  
															| 12 | J J Whyte, J Zhao, K D Wells, M S Samuel, K M Whitworth, E M Walters, M H Laughlin, R S Prather. Gene targeting with zinc finger nucleases to produce cloned eGFP knockout pigs. Molecular Reproduction and Development, 2011, 78(1): 2 https://doi.org/10.1002/mrd.21271
														     															     															     		pmid: 21268178
 |  
															| 13 | X J Huang, H X Zhang, H Wang, K Xiong, L Qin, H Liu. Disruption of the myostatin gene in porcine primary fibroblasts and embryos using zinc-finger nucleases. Molecules and Cells, 2014, 37(4): 302–306 https://doi.org/10.14348/molcells.2014.2209
														     															     															     		pmid: 24802055
 |  
															| 14 | Y Yin, H Hao, X Xu, L Shen, W Wu, J Zhang, Q Li. Generation of an MC3R knock-out pig by CRSPR/Cas9 combined with somatic cell nuclear transfer (SCNT) technology. Lipids in Health and Disease, 2019, 18(1): 122 https://doi.org/10.1186/s12944-019-1073-9
														     															     															     		pmid: 31138220
 |  
															| 15 | W Yang, S Li, X J Li. A CRISPR monkey model unravels a unique function of PINK1 in primate brains. Molecular Neurodegeneration, 2019, 14(1): 17 https://doi.org/10.1186/s13024-019-0321-9
														     															     															     		pmid: 31046796
 |  
															| 16 | D Paquet, D Kwart, A Chen, A Sproul, S Jacob, S Teo, K M Olsen, A Gregg, S Noggle, M Tessier-Lavigne. Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9. Nature, 2016, 533(7601): 125–129 https://doi.org/10.1038/nature17664
														     															     															     		pmid: 27120160
 |  
															| 17 | K M Whitworth, K Lee, J A Benne, B P Beaton, L D Spate, S L Murphy, M S Samuel, J Mao, C O’Gorman, E M Walters, C N Murphy, J Driver, A Mileham, D McLaren, K D Wells, R S Prather. Use of the CRISPR/Cas9 system to produce genetically engineered pigs from in vitro-derived oocytes and embryos. Biology of Reproduction, 2014, 91(3): 78 https://doi.org/10.1095/biolreprod.114.121723
														     															     															     		pmid: 25100712
 |  
															| 18 | K M Whitworth, R R R Rowland, C L Ewen, B R Trible, M A Kerrigan, A G Cino-Ozuna, M S Samuel, J E Lightner, D G McLaren, A J Mileham, K D Wells, R S Prather. Gene-edited pigs are protected from porcine reproductive and respiratory syndrome virus. Nature Biotechnology, 2016, 34(1): 20–22 https://doi.org/10.1038/nbt.3434
														     															     															     		pmid: 26641533
 |  
															| 19 | G Xiang, J Ren, T Hai, R Fu, D Yu, J Wang, W Li, H Wang, Q Zhou. Editing porcine IGF2 regulatory element improved meat production in Chinese Bama pigs. Cellular and Molecular Life Sciences, 2018, 75(24): 4619–4628 https://doi.org/10.1007/s00018-018-2917-6
														     															     															     		pmid: 30259067
 |  
															| 20 | Q Zheng, J Lin, J Huang, H Zhang, R Zhang, X Zhang, C Cao, C Hambly, G Qin, J Yao, R Song, Q Jia, X Wang, Y Li, N Zhang, Z Piao, R Ye, J R Speakman, H Wang, Q Zhou, Y Wang, W Jin, J Zhao. Reconstitution of UCP1 using CRISPR/Cas9 in the white adipose tissue of pigs decreases fat deposition and improves thermogenic capacity. Proceedings of the National Academy of Sciences of the United States of America, 2017, 114(45): E9474–E9482 https://doi.org/10.1073/pnas.1707853114
														     															     															     		pmid: 29078316
 |  
															| 21 | Z Xie, D Pang, H Yuan, H Jiao, C Lu, K Wang, Q Yang, M Li, X Chen, T Yu, X Chen, Z Dai, Y Peng, X Tang, Z Li, T Wang, H Guo, L Li, C Tu, L Lai, H Ouyang. Genetically modified pigs are protected from classical swine fever virus. PLoS Pathogens, 2018, 14(12): e1007193 https://doi.org/10.1371/journal.ppat.1007193
														     															     															     		pmid: 30543715
 |  
															| 22 | A Oladzad, T Porch, J C Rosas, S M Moghaddam, J Beaver, S E Beebe, J Burridge, C N Jochua, M A Miguel, P N Miklas, B Ratz, J W White, J Lynch, P E McClean. Single and multi-trait GWAS identify genetic factors associated with production traits in common bean under abiotic stress environments. Genetics, 2019, 9(6): 1881–1892 pmid: 31167806
 |  
															| 23 | S Yang, X Li, K Li, B Fan, Z Tang. A genome-wide scan for signatures of selection in Chinese indigenous and commercial pig breeds. BMC Genetics, 2014, 15(1): 7 https://doi.org/10.1186/1471-2156-15-7
														     															     															     		pmid: 24422716
 |  
															| 24 | L Silió, C Barragán, A I Fernández, J García-Casco, M C Rodríguez. Assessing effective population size, coancestry and inbreeding effects on litter size using the pedigree and SNP data in closed lines of the Iberian pig breed. Journal of Animal Breeding and Genetics, 2016, 133(2): 145–154 https://doi.org/10.1111/jbg.12168
														     															     															     		pmid: 26059912
 |  
															| 25 | B Servin, T Faraut, N Iannuccelli, D Zelenika, D Milan. High-resolution autosomal radiation hybrid maps of the pig genome and their contribution to the genome sequence assembly. BMC Genomics, 2012, 13(1): 585 https://doi.org/10.1186/1471-2164-13-585
														     															     															     		pmid: 23153393
 |  
															| 26 | K T Lee, Y M Lee, M Alam, B H Choi, M R Park, K S Kim, T H Kim, J J Kim. A whole genome association study on meat quality traits using high density SNP chips in a cross between Korean native pig and Landrace. Asian-Australasian Journal of Animal Sciences, 2012, 25(11): 1529–1539 https://doi.org/10.5713/ajas.2012.12474
														     															     															     		pmid: 25049513
 |  
															| 27 | X Ma, P H Li, M X Zhu, L C He, S P Sui, S Gao, G S Su, N S Ding, Y Huang, Z Q Lu, X G Huang, R H Huang. Genome-wide association analysis reveals genomic regions on Chromosome 13 affecting litter size and candidate genes for uterine horn length in Erhualian pigs. Animal, 2018, 12(12): 2453–2461 https://doi.org/10.1017/S1751731118000332
														     															     															     		pmid: 29534777
 |  
															| 28 | A S Hess, Z Islam, M K Hess, R R R Rowland, J K Lunney, A Doeschl-Wilson, G S Plastow, J C M Dekkers. Comparison of host genetic factors influencing pig response to infection with two North American isolates of porcine reproductive and respiratory syndrome virus. Genetics, Selection, Evolution, 2016, 48(1): 43 https://doi.org/10.1186/s12711-016-0222-0
														     															     															     		pmid: 27324857
 |  
															| 29 | L Andersson, C S Haley, H Ellegren, S A Knott, M Johansson, K Andersson, L Andersson-Eklund, I Edfors-Lilja, M Fredholm, I Hansson, J Håkansson. Genetic mapping of quantitative trait loci for growth and fatness in pigs. Science, 1994, 263(5154): 1771–1774 https://doi.org/10.1126/science.8134840
														     															     															     		pmid: 8134840
 |  
															| 30 | P Uimari, A Sironen, M L Sevån-Aimonen. Whole-genome SNP association analysis of reproduction traits in the Finnish Landrace pig breed. Genetics, Selection, Evolution, 2011, 43(1): 42 https://doi.org/10.1186/1297-9686-43-42
														     															     															     		pmid: 22132733
 |  
															| 31 | P Sellier, L Maignel, J P Bidanel. Genetic parameters for tissue and fatty acid composition of backfat, perirenal fat and longissimus muscle in Large White and Landrace pigs. Animal, 2010, 4(4): 497–504 https://doi.org/10.1017/S1751731109991261
														     															     															     		pmid: 22444036
 |  
															| 32 | J Hernández-Sánchez, M Amills, R N Pena, A Mercadé, A Manunza, R Quintanilla. Genomic architecture of heritability and genetic correlations for intramuscular and back fat contents in Duroc pigs. Journal of Animal Science, 2013, 91(2): 623–632 https://doi.org/10.2527/jas.2012-5270
														     															     															     		pmid: 23230112
 |  
															| 33 | R Ding, M Yang, J Quan, S Li, Z Zhuang, S Zhou, E Zheng, L Hong, Z Li, G Cai, W Huang, Z Wu, J Yang. Single-locus and multi-locus genome-wide association studies for intramuscular fat in Duroc pigs. Frontiers in Genetics, 2019, 10: 619 https://doi.org/10.3389/fgene.2019.00619
														     															     															     		pmid: 31316554
 |  
															| 34 | M Zappaterra, D Luise, P Zambonelli, M Mele, A Serra, L N Costa, R Davoli. Association study between backfat fatty acid composition and SNPs in candidate genes highlights the effect of FASN polymorphism in large white pigs. Meat Science, 2019, 156: 75–84 https://doi.org/10.1016/j.meatsci.2019.05.013
														     															     															     		pmid: 31132591
 |  
															| 35 | R N Pena, J L Noguera, M J García-Santana, E González, J F Tejeda, R Ros-Freixedes, N Ibáñez-Escriche. Five genomic regions have a major impact on fat composition in Iberian pigs. Scientific Reports, 2019, 9(1): 2031 https://doi.org/10.1038/s41598-019-38622-7
														     															     															     		pmid: 30765794
 |  
															| 36 | S Casiró, D Velez-Irizarry, C W Ernst, N E Raney, R O Bates, M G Charles, J P Steibel. Genome-wide association study in an F2 Duroc x Pietrain resource population for economically important meat quality and carcass traits. Journal of Animal Science, 2017, 95(2): 545–558 https://doi.org/10.2527/jas2016.1003
														     															     															     		pmid: 28380601
 |  
															| 37 | A S Van Laere, M Nguyen, M Braunschweig, C Nezer, C Collette, L Moreau, A L Archibald, C S Haley, N Buys, M Tally, G Andersson, M Georges, L Andersson. A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig. Nature, 2003, 425(6960): 832–836 https://doi.org/10.1038/nature02064
														     															     															     		pmid: 14574411
 |  
															| 38 | L Criado-Mesas, M Ballester, D Crespo-Piazuelo, A Castelló, R Benítez, A I Fernández, J M Folch. Analysis of porcine IGF2 gene expression in adipose tissue and its effect on fatty acid composition. PLoS One, 2019, 14(8): e0220708 https://doi.org/10.1371/journal.pone.0220708
														     															     															     		pmid: 31393967
 |  
															| 39 | J Ma, J Yang, L Zhou, J Ren, X Liu, H Zhang, B Yang, Z Zhang, H Ma, X Xie, Y Xing, Y Guo, L Huang. A splice mutation in the PHKG1 gene causes high glycogen content and low meat quality in pig skeletal muscle. PLoS Genetics, 2014, 10(10): e1004710 https://doi.org/10.1371/journal.pgen.1004710
														     															     															     		pmid: 25340394
 |  
															| 40 | C S Bruun, C B Jørgensen, V H Nielsen, L Andersson, M Fredholm. Evaluation of the porcine melanocortin 4 receptor (MC4R) gene as a positional candidate for a fatness QTL in a cross between Landrace and Hampshire. Animal Genetics, 2006, 37(4): 359–362 https://doi.org/10.1111/j.1365-2052.2006.01488.x
														     															     															     		pmid: 16879346
 |  
															| 41 | C P Allison, R C Johnson, M E Doumit. The effects of halothane sensitivity on carcass composition and meat quality in HAL-1843-normal pigs. Journal of Animal Science, 2005, 83(3): 671–678 https://doi.org/10.2527/2005.833671x
														     															     															     		pmid: 15705764
 |  
															| 42 | S K Onteru, J W Ross, M F Rothschild. The role of gene discovery, QTL analyses and gene expression in reproductive traits in the pig. Society of Reproduction and Fertility Supplement, 2009, 66: 87–102 pmid: 19848272
 |  
															| 43 | Pig Quantitative Trait Locus (QTL) Database (Pig QTLdb). Pig QTL/associations data summary, 2019. Available at Pig QTLdb website on February 14, 2020 |  
															| 44 | Y Wang, X Ding, Z Tan, K Xing, T Yang, Y Pan, Y Wang, D Sun, C Wang. Genome-wide association study for reproductive traits in a Large White pig population. Animal Genetics, 2018, 49(2): 127–131 https://doi.org/10.1111/age.12638
														     															     															     		pmid: 29411893
 |  
															| 45 | M Bosse, H J Megens, L A F Frantz, O Madsen, G Larson, Y Paudel, N Duijvesteijn, B Harlizius, Y Hagemeijer, R P M A Crooijmans, M A M Groenen. Genomic analysis reveals selection for Asian genes in European pigs following human-mediated introgression. Nature Communications, 2014, 5(1): 4392 https://doi.org/10.1038/ncomms5392
														     															     															     		pmid: 25025832
 |  
															| 46 | D Bjerre, L B Madsen, T Mark, S Cirera, K Larsen, C B Jørgensen, M Fredholm. Potential role of the porcine superoxide dismutase 1 (SOD1) gene in pig reproduction. Animal Biotechnology, 2013, 24(1): 1–9 https://doi.org/10.1080/10495398.2012.723083
														     															     															     		pmid: 23394364
 |  
															| 47 | N Boddicker, E H Waide, R R R Rowland, J K Lunney, D J Garrick, J M Reecy, J C M Dekkers. Evidence for a major QTL associated with host response to porcine reproductive and respiratory syndrome virus challenge. Journal of Animal Science, 2012, 90(6): 1733–1746 https://doi.org/10.2527/jas.2011-4464
														     															     															     		pmid: 22205662
 |  
															| 48 | N J Boddicker, D J Garrick, R R R Rowland, J K Lunney, J M Reecy, J C M Dekkers. Validation and further characterization of a major quantitative trait locus associated with host response to experimental infection with porcine reproductive and respiratory syndrome virus. Animal Genetics, 2014, 45(1): 48–58 https://doi.org/10.1111/age.12079
														     															     															     		pmid: 23914972
 |  
															| 49 | N J Boddicker, A Bjorkquist, R R R Rowland, J K Lunney, J M Reecy, J C M Dekkers. Genome-wide association and genomic prediction for host response to porcine reproductive and respiratory syndrome virus infection. Genetics, Selection, Evolution, 2014, 46(1): 18 https://doi.org/10.1186/1297-9686-46-18
														     															     															     		pmid: 24592976
 |  
															| 50 | N V L Serão, R A Kemp, B E Mote, P Willson, J C S Harding, S C Bishop, G S Plastow, J C M Dekkers. Genetic and genomic basis of antibody response to porcine reproductive and respiratory syndrome (PRRS) in gilts and sows. Genetics, Selection, Evolution, 2016, 48(1): 51 https://doi.org/10.1186/s12711-016-0230-0
														     															     															     		pmid: 27417876
 |  
															| 51 | C Burkard, S G Lillico, E Reid, B Jackson, A J Mileham, T Ait-Ali, C B Whitelaw, A L Archibald. Precision engineering for PRRSV resistance in pigs: Macrophages from genome edited pigs lacking CD163 SRCR5 domain are fully resistant to both PRRSV genotypes while maintaining biological function. PLoS Pathogens, 2017, 13(2): e1006206 https://doi.org/10.1371/journal.ppat.1006206
														     															     															     		pmid: 28231264
 |  
															| 52 | P Skallerup, S M Thamsborg, C B Jørgensen, H Mejer, H H Göring, A L Archibald, M Fredholm, P Nejsum. Detection of a quantitative trait locus associated with resistance to infection with Trichuris suis in pigs. Veterinary Parasitology, 2015, 210(3–4): 264–269 https://doi.org/10.1016/j.vetpar.2015.03.014
														     															     															     		pmid: 25858116
 |  
															| 53 | J Estellé, A I Fernández, M Pérez-Enciso, A Fernández, C Rodríguez, A Sánchez, J L Noguera, J M Folch. A non-synonymous mutation in a conserved site of the MTTP gene is strongly associated with protein activity and fatty acid profile in pigs. Animal Genetics, 2009, 40(6): 813–820 https://doi.org/10.1111/j.1365-2052.2009.01922.x
														     															     															     		pmid: 19496770
 |  
															| 54 | B J Jungerius, A S van Laere, M F Te Pas, B A van Oost, L Andersson, M A Groenen. The IGF2-intron3-G3072A substitution explains a major imprinted QTL effect on backfat thickness in a Meishan x European white pig intercross. Genetical Research, 2004, 84(2): 95–101 https://doi.org/10.1017/S0016672304007098
														     															     															     		pmid: 15678747
 |  
															| 55 | Q Yin, H W Yang, X L Han, B Fan, B Liu. Isolation, mapping, SNP detection and association with backfat traits of the porcine CTNNBL1 and DGAT2 genes. Molecular Biology Reports, 2012, 39(4): 4485–4490 https://doi.org/10.1007/s11033-011-1238-8
														     															     															     		pmid: 21997828
 |  
															| 56 | Z G Chen, Z X Ma, B Zuo, M G Lei, Y Z Xiong. Molecular characterization and association with carcass traits of the porcine SLC39A7 gene. Journal of Animal Breeding and Genetics, 2009, 126(4): 288–295 https://doi.org/10.1111/j.1439-0388.2008.00740.x
														     															     															     		pmid: 19630879
 |  
															| 57 | L Fontanesi, E Scotti, L Buttazzoni, S Dall’Olio, R Davoli, V Russo. A single nucleotide polymorphism in the porcine cathepsin K (CTSK) gene is associated with back fat thickness and production traits in Italian Duroc pigs. Molecular Biology Reports, 2010, 37(1): 491–495 https://doi.org/10.1007/s11033-009-9678-0
														     															     															     		pmid: 19662513
 |  
															| 58 | E Muráni, M Murániová, S Ponsuksili, K Schellander, K Wimmers. Molecular characterization and evidencing of the porcine CRH gene as a functional-positional candidate for growth and body composition. Biochemical and Biophysical Research Communications, 2006, 342(2): 394–405 https://doi.org/10.1016/j.bbrc.2006.01.143
														     															     															     		pmid: 16483545
 |  
															| 59 | M Ballester, M Revilla, A Puig-Oliveras, J A Marchesi, A Castelló, J Corominas, A I Fernández, J M Folch. Analysis of the porcine APOA2 gene expression in liver, polymorphism identification and association with fatty acid composition traits. Animal Genetics, 2016, 47(5): 552–559 https://doi.org/10.1111/age.12462
														     															     															     		pmid: 27296287
 |  
															| 60 | L Fontanesi, F Bertolini, S Dall’Olio, L Buttazzoni, M Gallo, V Russo. Analysis of association between the MUC4 g.8227C>G polymorphism and production traits in Italian heavy pigs using a selective genotyping approach. Animal Biotechnology, 2012, 23(3): 147–155 https://doi.org/10.1080/10495398.2011.653462
														     															     															     		pmid: 22870870
 |  
															| 61 | K Hirose, T Takizawa, K Fukawa, T Ito, M Ueda, Y Hayashi, K Tanaka. Association of an SNP marker in exon 24 of a class 3 phosphoinositide-3-kinase (PIK3C3) gene with production traits in Duroc pigs. Animal Science Journal, 2011, 82(1): 46–51 https://doi.org/10.1111/j.1740-0929.2010.00816.x
														     															     															     		pmid: 21269358
 |  
															| 62 | S M An, J H Hwang, S Kwon, G E Yu, D H Park, D G Kang, T W Kim, H C Park, J Ha, C W Kim. Effect of single nucleotide polymorphisms in IGFBP2 and IGFBP3 genes on litter size traits in Berkshire pigs. Animal Biotechnology, 2018, 29(4): 301–308 https://doi.org/10.1080/10495398.2017.1395345
														     															     															     		pmid: 29200313
 |  
															| 63 | A Gunawan, M U Cinar, M J Uddin, K Kaewmala, D Tesfaye, C Phatsara, E Tholen, C Looft, K Schellander. Investigation on association and expression of ESR2 as a candidate gene for boar sperm quality and fertility. Reproduction in Domestic Animals, 2012, 47(5): 782–790 https://doi.org/10.1111/j.1439-0531.2011.01968.x
														     															     															     		pmid: 22212297
 |  
															| 64 | K Kaewmala, M J Uddin, M U Cinar, C Große-Brinkhaus, E Jonas, D Tesfaye, C Phatsara, E Tholen, C Looft, K Schellander. Investigation into association and expression of PLCz and COX-2 as candidate genes for boar sperm quality and fertility. Reproduction in Domestic Animals, 2012, 47(2): 213–223 https://doi.org/10.1111/j.1439-0531.2011.01831.x
														     															     															     		pmid: 21752105
 |  
															| 65 | K Kaewmala, M J Uddin, M U Cinar, C Grosse-Brinkhaus, E Jonas, D Tesfaye, C Phatsara, E Tholen, C Looft, K Schellander. Association study and expression analysis of CD9 as candidate gene for boar sperm quality and fertility traits. Animal Reproduction Science, 2011, 125(1–4): 170–179 https://doi.org/10.1016/j.anireprosci.2011.02.017
														     															     															     		pmid: 21398056
 |  
															| 66 | S J Wang, W J Liu, C A Sargent, S H Zhao, H B Liu, X D Liu, C Wang, G H Hua, L G Yang, N A Affara, S J Zhang. Effects of the polymorphisms of Mx1, BAT2 and CXCL12 genes on immunological traits in pigs. Molecular Biology Reports, 2012, 39(3): 2417–2427 https://doi.org/10.1007/s11033-011-0992-y
														     															     															     		pmid: 21667240
 |  
															| 67 | N Sun, D Liu, H Chen, X Liu, F Meng, X Zhang, H Chen, S Xie, X Li, Z Wu. Localization, expression change in PRRSV infection and association analysis of the porcine TAP1 gene. International Journal of Biological Sciences, 2012, 8(1): 49–58 https://doi.org/10.7150/ijbs.8.49
														     															     															     		pmid: 22211104
 |  
															| 68 | Y Sang, C R Ross, R R Rowland, F Blecha. Toll-like receptor 3 activation decreases porcine arterivirus infection. Viral Immunology, 2008, 21(3): 303–314 https://doi.org/10.1089/vim.2008.0042
														     															     															     		pmid: 18788939
 |  
															| 69 | A J Brock, O Matika, A D Wilson, J Anderson, A C Morin, H A Finlayson, G Reiner, H Willems, S C Bishop, A L Archibald, T Ait-Ali. An intronic polymorphism in the porcine IRF7 gene is associated with better health and immunity of the host during Sarcocystis infection, and affects interferon signalling. Animal Genetics, 2011, 42(4): 386–394 https://doi.org/10.1111/j.1365-2052.2010.02154.x
														     															     															     		pmid: 21749421
 |  
															| 70 | Y Liu, Y R Luo, X Lu, X T Qiu, J P Zhou, Y F Gong, X D Ding, Q Zhang. Association analysis of polymorphisms of porcine LMP2 and LMP7 genes with haematological traits. Molecular Biology Reports, 2011, 38(7): 4455–4460 https://doi.org/10.1007/s11033-010-0574-4
														     															     															     		pmid: 21140225
 |  
															| 71 | Z C Wu, Y Liu, Q H Zhao, S P Zhu, Y J Huo, G Q Zhu, S L Wu, W B Bao. Association between polymorphisms in exons 4 and 10 of the BPI gene and immune indices in Sutai pigs. Genetics and Molecular Research, 2015, 14(2): 6048–6058 https://doi.org/10.4238/2015.June.8.2
														     															     															     		pmid: 26125805
 |  
															| 72 | J D Kich, J J Uthe, M V Benavides, M E Cantão, R Zanella, C K Tuggle, S M Bearson. TLR4 single nucleotide polymorphisms (SNPs) associated with Salmonella shedding in pigs. Journal of Applied Genetics, 2014, 55(2): 267–271 https://doi.org/10.1007/s13353-014-0199-8
														     															     															     		pmid: 24566961
 |  
															| 73 | X Wu, Y Wang, Y Sun. Molecular characterization, expression analysis and association study with immune traits of porcine PSMB6 gene. Molecular Biology Reports, 2011, 38(8): 5465–5470 https://doi.org/10.1007/s11033-011-0866-3
														     															     															     		pmid: 21604174
 |  
															| 74 | J Huang, G J Ma, N N Sun, Z F Wu, X Y Li, S H Zhao. BCL10 as a new candidate gene for immune response in pigs: cloning, expression and association analysis. International Journal of Immunogenetics, 2010, 37(2): 103–110 https://doi.org/10.1111/j.1744-313X.2010.00898.x
														     															     															     		pmid: 20193035
 |  
															| 75 | J R Butler, R M N Santos, G R Martens, J M Ladowski, Z Y Wang, P Li, M Tector, A J Tector. Efficient generation of targeted and controlled mutational events in porcine cells using nuclease-directed homologous recombination. Journal of Surgical Research, 2017, 212: 238–245 https://doi.org/10.1016/j.jss.2017.01.025
														     															     															     		pmid: 28550913
 |  
															| 76 | L Tao, M Yang, X Wang, Z Zhang, Z Wu, J Tian, L An, S Wang. Efficient biallelic mutation in porcine parthenotes using a CRISPR-Cas9 system. Biochemical and Biophysical Research Communications, 2016, 476(4): 225–229 https://doi.org/10.1016/j.bbrc.2016.05.100
														     															     															     		pmid: 27221047
 |  
															| 77 | C Yue, W L Bai, Y Y Zheng, T Y Hui, J M Sun, D Guo, S L Guo, Z Y Wang. Correlation analysis of candidate gene SNP for high-yield in Liaoning cashmere goats with litter size and cashmere performance. Animal Biotechnology, 2019 [Published Online] doi: 10.1080/10495398.2019.1652188 pmid: 31424321
 |  
															| 78 | J R Chapman, M R G Taylor, S J Boulton. Playing the end game: DNA double-strand break repair pathway choice. Molecular Cell, 2012, 47(4): 497–510 https://doi.org/10.1016/j.molcel.2012.07.029
														     															     															     		pmid: 22920291
 |  
															| 79 | D B T Cox, R J Platt, F Zhang. Therapeutic genome editing: prospects and challenges. Nature Medicine, 2015, 21(2): 121–131 https://doi.org/10.1038/nm.3793
														     															     															     		pmid: 25654603
 |  
															| 80 | S Q Tsai, Z Zheng, N T Nguyen, M Liebers, V V Topkar, V Thapar, N Wyvekens, C Khayter, A J Iafrate, L P Le, M J Aryee, J K Joung. GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nature Biotechnology, 2015, 33(2): 187–197 https://doi.org/10.1038/nbt.3117
														     															     															     		pmid: 25513782
 |  
															| 81 | H Y Shin, C Wang, H K Lee, K H Yoo, X Zeng, T Kuhns, C M Yang, T Mohr, C Liu, L Hennighausen. CRISPR/Cas9 targeting events cause complex deletions and insertions at 17 sites in the mouse genome. Nature Communications, 2017, 8(1): 15464 https://doi.org/10.1038/ncomms15464
														     															     															     		pmid: 28561021
 |  
															| 82 | M Kosicki, K Tomberg, A Bradley. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nature Biotechnology, 2018, 36(8): 765–771 https://doi.org/10.1038/nbt.4192
														     															     															     		pmid: 30010673
 |  
															| 83 | J M Gehrke, O Cervantes, M K Clement, Y Wu, J Zeng, D E Bauer, L Pinello, J K Joung. An APOBEC3A-Cas9 base editor with minimized bystander and off-target activities. Nature Biotechnology, 2018, 36(10): 977–982 https://doi.org/10.1038/nbt.4199
														     															     															     		pmid: 30059493
 |  
															| 84 | H A Rees, D R Liu. Base editing: precision chemistry on the genome and transcriptome of living cells. Nature Reviews: Genetics, 2018, 19(12): 770–788 https://doi.org/10.1038/s41576-018-0059-1
														     															     															     		pmid: 30323312
 |  
															| 85 | R Dandage, P C Després, N Yachie, C R Landry. beditor: a computational workflow for designing libraries of guide RNAs for CRISPR-mediated base editing. Genetics, 2019, 212(2): 377–385 https://doi.org/10.1534/genetics.119.302089
														     															     															     		pmid: 30936113
 |  
															| 86 | A C Komor, Y B Kim, M S Packer, J A Zuris, D R Liu. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature, 2016, 533(7603): 420–424 https://doi.org/10.1038/nature17946
														     															     															     		pmid: 27096365
 |  
															| 87 | A C Komor, K T Zhao, M S Packer, N M Gaudelli, A L Waterbury, L W Koblan, Y B Kim, A H Badran, D R Liu. Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T:A base editors with higher efficiency and product purity. Science Advances, 2017, 3(8): eaao4774 |  
															| 88 | Y Zong, Q Song, C Li, S Jin, D Zhang, Y Wang, J L Qiu, C Gao. Efficient C-to-T base editing in plants using a fusion of nCas9 and human APOBEC3A. Nature Biotechnology, 2018, 36(10): 950–953 https://doi.org/10.1038/nbt.4261
														     															     															     		pmid: 30272679
 |  
															| 89 | L W Koblan, J L Doman, C Wilson, J M Levy, T Tay, G A Newby, J P Maianti, A Raguram, D R Liu. Improving cytidine and adenine base editors by expression optimization and ancestral reconstruction. Nature Biotechnology, 2018, 36(9): 843–846 https://doi.org/10.1038/nbt.4172
														     															     															     		pmid: 29813047
 |  
															| 90 | Y B Kim, A C Komor, J M Levy, M S Packer, K T Zhao, D R Liu. Increasing the genome-targeting scope and precision of base editing with engineered Cas9-cytidine deaminase fusions. Nature Biotechnology, 2017, 35(4): 371–376 https://doi.org/10.1038/nbt.3803
														     															     															     		pmid: 28191901
 |  
															| 91 | K Hua, X Tao, J K Zhu. Expanding the base editing scope in rice by using Cas9 variants. Plant Biotechnology Journal, 2019, 17(2): 499–504 https://doi.org/10.1111/pbi.12993
														     															     															     		pmid: 30051586
 |  
															| 92 | J H Hu, S M Miller, M H Geurts, W Tang, L Chen, N Sun, C M Zeina, X Gao, H A Rees, Z Lin, D R Liu. Evolved Cas9 variants with broad PAM compatibility and high DNA specificity. Nature, 2018, 556(7699): 57–63 https://doi.org/10.1038/nature26155
														     															     															     		pmid: 29512652
 |  
															| 93 | H Nishimasu, X Shi, S Ishiguro, L Gao, S Hirano, S Okazaki, T Noda, O O Abudayyeh, J S Gootenberg, H Mori, S Oura, B Holmes, M Tanaka, M Seki, H Hirano, H Aburatani, R Ishitani, M Ikawa, N Yachie, F Zhang, O Nureki. Engineered CRISPR-Cas9 nuclease with expanded targeting space. Science, 2018, 361(6408): 1259–1262 https://doi.org/10.1126/science.aas9129
														     															     															     		pmid: 30166441
 |  
															| 94 | N M Gaudelli, A C Komor, H A Rees, M S Packer, A H Badran, D I Bryson, D R Liu. Programmable base editing of A·T to G·C in genomic DNA without DNA cleavage. Nature, 2017, 551(7681): 464–471 https://doi.org/10.1038/nature24644
														     															     															     		pmid: 29160308
 |  
															| 95 | T P Huang, K T Zhao, S M Miller, N M Gaudelli, B L Oakes, C Fellmann, D F Savage, D R Liu. Circularly permuted and PAM-modified Cas9 variants broaden the targeting scope of base editors. Nature Biotechnology, 2019, 37(6): 626–631 https://doi.org/10.1038/s41587-019-0134-y
														     															     															     		pmid: 31110355
 |  
															| 96 | K Hua, X Tao, P Han, R Wang, J K Zhu. Genome engineering in rice using Cas9 variants that recognize NG PAM sequences. Molecular Plant, 2019, 12(7): 1003–1014 https://doi.org/10.1016/j.molp.2019.03.009
														     															     															     		pmid: 30928636
 |  
															| 97 | P Chatterjee, N Jakimo, J M Jacobson. Minimal PAM specificity of a highly similar SpCas9 ortholog. Science Advcances, 2018, 4(10): eaau0766 |  
															| 98 | A V Anzalone, P B Randolph, J R Davis, A A Sousa, L W Koblan, J M Levy, P J Chen, C Wilson, G A Newby, A Raguram, D R Liu. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature, 2019, 576(7785): 149–157 https://doi.org/10.1038/s41586-019-1711-4
														     															     															     		pmid: 31634902
 |  
															| 99 | R Zhang, Y Wang, L Chen, R Wang, C Li, X Li, B Fang, X Ren, M Ruan, J Liu, Q Xiong, L Zhang, Y Jin, M Zhang, X Liu, L Li, Q Chen, D Pan, R Li, D K C Cooper, H Yang, Y Dai. Reducing immunoreactivity of porcine bioprosthetic heart valves by genetically-deleting three major glycan antigens, GGTA1/β4GalNT2/CMAH. Acta Biomaterialia, 2018, 72: 196–205 https://doi.org/10.1016/j.actbio.2018.03.055
														     															     															     		pmid: 29631050
 |  
															| 100 | H M Yuan, T T Yu, L Y Wang, L Yang, Y Z Zhang, H Liu, M J Li, X C Tang, Z Q Liu, Z J Li, C Lu, X Chen, D X Pang, H S Ouyang. Efficient base editing by RNA-guided cytidine base editors (CBEs) in pigs. Cellular and Molecular Life Sciences, 2019 [Published Online] doi: 10.1007/s00018-019-03205-2 pmid: 31302752
 |  
															| 101 | J Xie, W Ge, N Li, Q Liu, F Chen, X Yang, X Huang, Z Ouyang, Q Zhang, Y Zhao, Z Liu, S Gou, H Wu, C Lai, N Fan, Q Jin, H Shi, Y Liang, T Lan, L Quan, X Li, K Wang, L Lai. Efficient base editing for multiple genes and loci in pigs using base editors. Nature Communications, 2019, 10(1): 2852 https://doi.org/10.1038/s41467-019-10421-8
														     															     															     		pmid: 31253764
 |  
															| 102 | Z Li, X Duan, X An, T Feng, P Li, L Li, J Liu, P Wu, D Pan, X Du, S Wu. Efficient RNA-guided base editing for disease modeling in pigs. Cell Discovery, 2018, 4(1): 64 https://doi.org/10.1038/s41421-018-0065-7
														     															     															     		pmid: 30588328
 |  
															| 103 | K A Molla, Y Yang. CRISPR/Cas-mediated base editing: technical considerations and practical applications. Trends in Biotechnology, 2019, 37(10): 1121–1142 https://doi.org/10.1016/j.tibtech.2019.03.008
														     															     															     		pmid: 30995964
 |  
															| 104 | E Zuo, Y Sun, W Wei, T Yuan, W Ying, H Sun, L Yuan, L M Steinmetz, Y Li, H Yang. Cytosine base editor generates substantial off-target single-nucleotide variants in mouse embryos. Science, 2019, 364(6437): 289–292 https://doi.org/10.1126/science.aav9973
														     															     															     		pmid: 30819928
 |  
								            
												
											    	
											        	|  | Viewed |  
											        	|  |  |  
												        |  | Full text 
 | 
 
 |  
												        |  |  |  
												        |  | Abstract 
 | 
 |  
												        |  |  |  
												        |  | Cited |  |  
												        |  |  |  |  
													    |  | Shared |  |  
													    |  |  |  |  
													    |  | Discussed |  |  |  |  |