Abstract
Efforts for the genetic improvement of apple have tremendously benefited from the availability of modern tools of genomics, transcriptomics, metabolomics, proteomics, bioinformatics, as well as of genetic engineering, among others, over the past two decades. These tools are continuing to expand, and they have become more critical for use in modern apple breeding programs. All current and future ‘omics’ technologies should be fully exploited to develop a better understanding of the complex system and biology of apple trees, as well as for pursuing efficient and robust genetic enhancement efforts to develop well-adapted apple cultivars with enhanced resistance to biotic and abiotic stress conditions, as well as those cultivars with desirable targeted nutritional and palatable preferences for consumers and for commercial markets alike. This chapter will cover the prospects of ‘omics’ technologies that are currently having an impact as well as those with potential impacts on apple biology and genetic enhancement efforts for the near future.
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References
Alberti A, Zielinski AAF, Couto M, Judacewski P, Nogueira A (2017) Distribution of phenolic compounds and antioxidant capacity in apples tissues during ripening. J Food Sci Technol 54:1511–1518
Amyotte B, Bowen AJ, Banks T, Rajcan I, Somers DJ (2017) Mapping the sensory perception of apple using descriptive sensory evaluation in a genome wide association study. PLoS One 12:e0171710. https://doi.org/10.1371/journal.pone.0171710
Ballester AR, Norelli J, Burchard E, Abdelfattah A, Levin E, González-Candelas L, Droby S, Wisniewski M (2017) Transcriptomic response of resistant (PI613981-Malus sieversii) and susceptible (‘Royal Gala’) genotypes of apple to blue mold (Penicillium expansum) infection. Front Plant Sci 8:1981. https://doi.org/10.3389/fpls.2017.01981
Ben Sadok I, Tiecher A, Galvez-Lopez D, Lahaye M, Lasserre-Zuber P, Bruneau M, Hanteville S, Robic R, Cournol R, Laurens F (2015) Apple fruit texture QTLs: year and cold storage effects on sensory and instrumental traits. Tree Genet Genomes 11:119. https://doi.org/10.1007/s11295-015-0947-x
Bianco L, Cestaro A, Sargent DJ, Banchi E, Derdak S, Di Guardo M, Salvi S, Jansen J, Viola R, Gut I, Laurens F, Chagné D, Velasco R, van de Weg E, Troggio M (2014) Development and validation of a 20K single nucleotide polymorphism (SNP) whole genome genotyping array for apple (Malus × domestica Borkh.). PLoS One 9(10):e110377. https://doi.org/10.1371/journal.pone.0110377.
Bianco L, Cestaro A, Linsmith G, Muranty H, Denancé C, Théron A, Poncet C, Micheletti D, Kerschbamer E, Di Pierro EA, Larger S, Pindo M, Van de Weg E, Davassi A, Laurens F, Velasco R, Durel C-E, Troggio M (2016) Development and validation of the Axiom® Apple 480K SNP genotyping array. Plant J 86:62–74. https://doi.org/10.1111/tpj.13145
Biswas N, Chakrabarti S (2020) Artificial Intelligence (AI)-based systems biology approaches in multi-omics data analysis of cancer. Front Oncol 10:588221. https://doi.org/10.3389/fonc.2020.588221
Boyer J, Liu RH (2004) Apple phytochemicals and their health benefits. Nutr J 3:5. https://doi.org/10.1186/1475-2891-3-5
Busatto N, Matsumoto D, Tadiello A, Vrhovsek U, Costa F (2019) Multifaceted analyses disclose the role of fruit size and skin-russeting in the accumulation pattern of phenolic compounds in apple. PLoS One 14(7):e0219354. https://doi.org/10.1371/journal.pone.0219354
Chagné D, Crowhurst RN, Troggio M, Davey MW, Gilmore B, Lawley C, Vanderzande S, Hellens RP, Kumar S, Cestaro A, Velasco R, Main D, Rees JD, Iezzoni A, Mockler T, Wilhelm L, Van de Weg E, Gardiner SE, Bassil N, Peace C (2012) Genome-wide SNP detection, validation, and development of an 8K SNP array for apple. PLoS One 7:e31745
Chagné D, Krieger C, Rassam M, Sullivan M, Fraser J, André C, Pindo M, Troggio M, Gardiner SE, Henry RA, Allan AC, McGhie TK, Laing WA (2012) QTL and candidate gene mapping for polyphenolic composition in apple fruit. BMC Plant Biol 12:12. https://doi.org/10.1186/1471-2229-12-12
Chagné D, Lin-Wang K, Espley RV, Volz RK, How NM, Rouse S, Brendolise C, Carlisle CM, Kumar S, De Silva N, Micheletti D, McGhie T, Crowhurst RN, Storey RD, Velasco R, Hellens RP, Gardiner SE, Allan AC (2013) An ancient duplication of apple MYB transcription factors is responsible for novel red fruit-flesh phenotypes. Plant Physiol 161:225. https://doi.org/10.1104/pp.112.206771
Charrier A, Vergne E, Dousset N, Richer A, Petiteau A Chevreau E (2019) Efficient targeted mutagenesis in apple and first time edition of pear using the CRISPR-Cas9 system. Front Plant Sci 10:40. https://doi.org/10.3389/fpls.2019.00040.
Corollaro ML, Endrizzi I, Bertolini A, Aprea E, Dematte L, Costa F, Biasioli F, Gasperi F (2013) Sensory profiling of apple: methodological aspects, cultivar characterisation and postharvest changes. Postharvest Biol Tec 77:111–120. https://doi.org/10.1016/j.postharvbio.2012.10.010
Cuthbertson D, Andrews PK, Reganold JP, Davies NM, Lange BM (2012) Utility of metabolomics toward assessing the metabolic basis of quality traits in apple fruit with an emphasis on antioxidants. J Agric Food Chem 60:8552–8560
D’accord N, Celton JM, Linsmith G, Becker C, Choisne N, Schijlen E, van de Geest H, Bianco L, Micheletti D, Velasco R, Di Pierro EA, Gouzy J, Rees DJG, Guérif P, Muranty H, Durel CE, Laurens F, Lespinasse Y, Gaillard S, Aubourg S, Quesneville H, Weigel D, van de Weg E, Troggio M, Bucher E (2017) High-quality de novo assembly of the apple genome and methylome dynamics of early fruit development. Nat Genet 49:1099–1106
De Tayrac M, Lê S, Aubry M, Mosser J, Husson F (2009) Simultaneous analysis of distinct Omics datasets with integration of biological knowledge: multiple Factor Analysis approach. BMC Genomics 10:32. https://doi.org/10.1186/1471-2164-10-32
Drogoudi PD, Michailidis Z, Pantelidis G (2008) Peel and flesh antioxidant content and harvest quality characteristics of seven apple cultivars. Sci Hortic 115:149–153
Espley RV, Brendolise C, Chagne D, Kutty-Amma S, Green S, Volz R, Putterill J, Schouten HJ, Gardiner SE, Hellens RP, Allan AC (2009) Multiple repeats of a promoter segment causes transcription factor autoregulation in red apples. Plant Cell 21:168–183
Evans K, Peace C (2017) Advances in marker-assisted breeding of apples. In: Evans K (ed) Achieving sustainable cultivation of apples. Burleigh Dodds Science Publish, pp 165–191. https://doi.org/10.19103/AS.2016.0017.09
Fahlgren N, Gehan MA, Baxter I (2015) Lights, camera, action: high-throughput plant phenotyping is ready for a close-up. Curr Opin Plant Biol 24:93–99. https://doi.org/10.1016/j.pbi.2015.02.006
Flachowsky H, Hanke M-V, Peil A, Strauss SH, Fladung M (2009) A review of transgenic approaches to accelerate breeding of woody plants. Plant Breed 128:217–226. https://doi.org/10.1111/j.1439-0523.2008.01591.x
Fu J, Swertz MA, Keurentjes JJB, Jansen RC (2007) MetaNetwork: a computational protocol for the genetic study of metabolic networks. Nat Protoc 2:685–694
Hansen L, Dragsted LO, Olsen A, Christensen J, Tjønneland A, Schmidt EB, Overvad K (2010) Fruit and vegetable intake and risk of acute coronary syndrome. Br J Nutr 104:248–255
Henry-Kirk RA, McGhie TK, Andre CM, Hellens RP, Allan AC (2012) Transcriptional analysis of apple fruit proanthocyanidin biosynthesis. J Exp Bot 15:5437–5450
Hodgson JM, Prince RL, Woodman RJ, Bondonno CP, Ivey KL, Bondonno N, Rimm EB, Ward NC, Croft KD, Lewis JR (2016) Apple intake is inversely associated with all-cause and disease-specific mortality in elderly women. Br J Nutr 115:860–867
Hofmann T, Schölkopf B, Smola AJ (2008) Kernel methods in machine learning. Ann Stat 36:1171–1220. https://doi.org/10.1214/009053607000000677
Horton RH, Lucassen AM (2019) Recent developments in genetic/genomic medicine. Clin Sci 133(5):697–708
Ichwan M, Walker TL, Nicola Z, Ludwig-Müller J, Böttcher C, Overall RW, Adusumilli VS, Bulut M, Sykes AM, Hübner N, Ramirez-Rodriguez G, Ortiz-López L, Lugo-Hernández EA, Kempermann G (2021) Apple peel and flesh contain pro-neurogenic compounds. Stem Cell Rep. https://doi.org/10.1016/j.stemcr.2021.01.005
Jain S, Shukla S, Yang C, Zhang M, Fatma Z, Lingamaneni M, Abesteh S, Lane ST, Xiong X, Wang Y, Schroeder CM, Selvin PR (2021) Zhao H (2021) TALEN outperforms Cas9 in editing heterochromatin target sites. Nat Commun 12:606. https://doi.org/10.1038/s41467-020-20672-5
Jedrychowski W, Maugeri U (2009) An apple a day may hold colorectal cancer at bay: recent evidence from a case-control study. Rev Environ Health 24:59–74
Jia D, Shen F, Wang Y, Wu T, Xu X, Zhang X, Han Z (2018) Apple fruit acidity is genetically diversified by natural variations in three hierarchical epistatic genes: MdSAUR37, MdPP2CH and MdALMTII. Plant J 95:427–443. https://doi.org/10.1111/tpj.13957
Knecht AC, Campbell MT, Caprez A, Swanson DR, Walia H (2016) Image Harvest: an open-source platform for high-throughput plant image processing and analysis. J Exp Bot 67:3587–3599. https://doi.org/10.1093/jxb/erw176
Kobeissy FH, Gulbakan B, Alawieh A, Karam P, Zhang Z, Guingab-Cagmat JD, Mondello S, Tan W, Anagli J, Wang K (2014) Post-genomics nanotechnology is gaining momentum: nanoproteomics and applications in life sciences. OMICS 18(2):111–131. https://doi.org/10.1089/omi.2013.0074
Khan MA, Korban SS (2012) Association mapping in forest trees and fruit crops. J Exp Bot 63:4045–4060. https://doi.org/10.1093/jxb/ers105
Khan SA, Chibon PY, de Vos RC, Schipper BA, Walraven E, Beekwilder J, van Dijk T, Finkers R, Visser RG, van de Weg EW, Bovy A, Cestaro A, Velasco R, Jacobsen E, Schouten HJ (2012) Genetic analysis of metabolites in apple fruits indicates an mQTL hotspot for phenolic compounds on linkage group 16. J Exp Bot 63:2895–2908
Kim I-Y, Pusey PL, Zhao Y, Korban SS, Choi H, Kim K (2012) Controlled release of Pantoea agglomerans E325 for biocontrol of fire blight disease of apple. J Control Release 161:109–115. https://doi.org/10.1016/j.jconrel.2012.03.028
Koutsos A, Riccadonna S, Ulaszewska MM, Franceschi P, Trošt K, Galvin A, Braune T, Fava F, Perenzoni D, Mattivi F, Tuohy KM, Lovegrove JA (2020) Two apples a day lower serum cholesterol and improve cardiometabolic biomarkers in mildly hypercholesterolemic adults: a randomized, controlled, crossover trial. Am J Clin Nutr 111:307–318. https://doi.org/10.1093/ajcn/nqz282
Koutsos A, Tuohy KM, Lovegrove JA (2015) Apples and cardiovascular health—is the gut microbiota a core consideration? Nutrients 7:3959–3998
Kschonsek J, Wolfram T, Stöckl A, Böhm V (2018) Polyphenolic compounds analysis of old and new apple cultivars and contribution of polyphenolic profile to the in vitro antioxidant capacity. Antioxidants 7:20. https://doi.org/10.3390/antiox7010020
Kumar S, Garrick DG, Bink MC, Whitworth C, Chagne D, Volz RK (2013) Novel genomic approaches unravel genetic architecture of complex traits in apple. BMC Genomics 14:393. https://doi.org/10.1186/1471-2164-14-393
Kumar S, Raulier P, Chagne D, Withworth C (2014) Molecular-level and trait-level differentiation between the cultivated apple (Malus x domestica Borkh.) and its main progenitor Malus sieversii. Plant Genet Resour 12:330–340. https://doi.org/10.1017/S1479262114000136
Legay S, Guerriero G, Deleruelle A, Lateur M, Evers D, André CM, Hausman J-F (2015) Apple russeting as seen through the RNA-seq lens: strong alterations in the exocarp cell wall. Plant Mol Biol 88:21–40. https://doi.org/10.1007/s11103-015-0303-4
Legay S, Cocco E, André CM, Guignard C, Hausman J-F, Guerriero G (2017) Differential lipid composition and gene expression in the semi-russeted ‘Cox Orange Pippin’ apple variety. Front Plant Sci 8:1656. https://doi.org/10.3389/fpls.2017.01656
Li Q, Sapkota M, van der Knapp E (2020) Perspectives of CRISPR/Cas-mediated cis-engineering in horticulture: unlocking the neglected potential for crop improvement. Hortic Res 7:36. https://doi.org/10.1038/s41438-020-0258-8
Longhi S, Moretto M, Viola R, Velasco R, Costa F (2012) Comprehensive QTL mapping survey dissects the complex fruit texture physiology in apple (Malus × domestica Borkh). J Exp Bot 63:1107–1121. https://doi.org/10.1093/jxb/err326
Malnoy M, Viola R, Jung M-H, Koo O-J, Kim S, Kim J-S, Velasco R, Kanchiswamy CN (2016) DNA-free genetically edited grapevine and apple protoplast using CRISPR/Cas9 ribonucleo proteins. Front Plant Sci 7:1904
McClure KA, Gong Y, Song J, Vinqvist-Tymchuk M, Palmer LC, Fan L, Burgher-MacLellan K, Zhang ZQ, Celton J-M, Forney CF, Migicovsky Z, Myles S (2019) Genome-wide association studies in apple reveal loci of large effect controlling apple polyphenols. Hortic Res 6:107. https://doi.org/10.1038/s41438-019-0190-y
Misra BB, Carl Langefeld C, Olivier M, Cox LA (2019) Integrated omics: tools, advances and future approaches. J Mol Endocrinol 62:R21–R45. https://doi.org/10.1530/JME-18-0055
Nibbe RK, Koyutürk M, Chance MR (2010) An integrative-omics approach to identify functional sub-networks in human colorectal cancer. PLoS Comput Biol 6:e1000639. https://doi.org/10.1371/journal.pcbi.1000639
Ochoa-Fernandez R, Abel NB, Wieland F-G, Schlegel J, Koch L-A, Miller JB, Engesser R, Giuriani G, Brandl SM, Timmer J, Weber W, Ott T, Simon R, Zurbriggen MD (2020) Optogenetic control of gene expression in plants in the presence of ambient white light. Nat Meth. https://doi.org/10.1038/s41592-020-0868-y
Palermo G, Piraino P, Zucht HD (2009) Performance of PLS regression coefficients in selecting variables for each response of a multivariate PLS for omics-type data. Adv Appl Bioinform Chem 2:57. https://doi.org/10.2147/AABC.S3619
Parkhomenko E, Tritchler D, Beyene J (2009) Sparse canonical correlation analysis with application to genomic data integration. Stat Appl Genet Mol Biol 8:Article 1. https://doi.org/10.2202/1544-6115.1406
Pavel AB, Sonkin D, Reddy A (2016) Integrative modeling of multi-omics data to identify cancer drivers and infer patient-specific gene activity. BMC Syst Biol 10:1. https://doi.org/10.1186/s12918-016-0260-9
Peace CP, Bianco L, Troggio, M, van de Weg,E, Howard NP, Cornille A, Durel C-E, Myles S, Migicovsky Z, Schaffer RJ, Costes E, Fazio G, Yamane H, van Nocker S, Gottschalk C, Costa F, Chagné D, Zhang X, Patocchi A, Gardiner SE, Hardner C, Kumar S, Laurens F, Bucher E, Main D, Jung S, Vanderzande S (2019) Apple whole genome sequences: recent advances and new prospects. Hortic Res 6:59 (2019). https://doi.org/10.1038/s41438-019-0141-7
Pieruschka R, Schurr U (2019) Plant phenotyping: past, present, and future. Plant Phenom 2019: Article ID 7507131. https://doi.org/10.34133/2019/7507131
Pompili V, Costa LD, Piazza S, Pindo M, Malnoy M (2019) Reduced fire blight susceptibility in apple cultivars using a high-efficiency CRISPR/Cas9-FLP/FRT-based gene editing system. Plant Biotechnol J 18:845–858
Ritchie MD, Holzinger ER, Li R, Pendergrass SA, Kim D (2015) Methods of integrating data to uncover genotype-phenotype interactions. Nat Rev Genet 16:85–97. https://doi.org/10.1038/nrg3868
Ronan T, Qi Z, Naegle KM (2016) Avoiding common pitfalls when clustering biological data. Sci Signal 9 (432):re6. https://doi.org/10.1126/scisignal.aad1932
Schlathölter I, Jänsch M, Flachowsky H, Broggini GAL, Hanke M-V, Patocchi A (2018) Generation of advanced fire blight-resistant apple (Malus × domestica) selections of the fifth generation within 7 years of applying the early flowering approach. Planta 247:1475–1488. https://doi.org/10.1007/s00425-018-2876-z
Schmidt C, Pacher M, Puchta H (2019) DNA break repair in plants and its application for genome engineering. Meth Mol Biol 1864:237–266. https://doi.org/10.1007/978-1-4939-8778-8_17
Simidjievski N, Bodnar C, Tariq I, Scherer P, Andres Terre H, Shams Z, Jamnik M, Liò P (2019) Variational autoencoders for cancer data integration: design principles and computational practice. Front Genet 10:1205. https://doi.org/10.3389/fgene.2019.01205
Stracke BA, Rufer CE, Weibel FP, Bub A, Watzl B (2009) Three-year comparison of the polyphenol contents and antioxidant capacities in organically and conventionally produced apples (Malus domestica Borkh. cultivar ‘Golden Delicious’). J Agric Food Chem 57:4598–4605
Sun J, Rui HL (2008) Apple phytochemical extracts inhibit proliferation of estrogen-dependent and estrogen-independent human breast cancer cells through cell cycle modulation. J Agric Food Chem 56:11661–11667
Swinnen G, Goossens A, Pauwels L (2016) Lessons from domestication: targeting cis-regulatory elements for crop improvement. Trends Plant Sci 21:506–515
Ubbens JR, Stavness I (2017) Deep Plant Phenomics: A deep learning platform for complex plant phenotyping tasks. Front Plant Sci 8:1190. https://doi.org/10.3389/fpls.2017.01190
Vanderzande S, Howard NP, Cai L, Da Silva LC, Antanaviciute L, Bink MCAM, Kruisselbrink JW, Bassil N, Gasic K, Iezzoni A, Van de Weg E, Peace C (2019) High-quality, genome-wide SNP genotypic data for pedigreed germplasm of the diploid outbreeding species apple, peach, and sweet cherry through a common workflow. PLoS One 14:e0210928. https://doi.org/10.1371/journal.pone.0210928
Velasco R, Zharkikh A, Affourtit J, Dhingra A, Cestaro A, Kalyanaraman A, Fontana P, Bhatnagar SK, Troggio M, Pruss D, Dhingra A, Cestaro A, Kalyanaraman A, Fontana P, Bhatnagar SK, Troggio M, Pruss D, Salvi S, Pindo M, Baldi P, Castelletti S, Cavaiuolo M, Coppola G, Costa F, Cova V, Ri AD, Goremykin V, Komjanc M, Longhi S, Magnago P, Malacarne G, Malnoy M, Micheletti D, Moretto M, Perazzolli M, Si-Ammour A, Vezzulli S, Zini E, Eldredge G, Fitzgerald LM, Gutin N, Lanchbury G, Macalma T, Mitchell JT, Reid J, Wardell B, Kodira C, Chen Z, Desany B, Niazi F, Palmer M, Koepke T, Jiwan D, Schaeffer S, Krishnan V, Wu C, Chu VT, King ST, Vick J, Tao Q, Mraz A, Stormo A, Stormo K, Bogden R, Ederle D, Stella A, Vecchietti A, Kater MM, Masiero S, Lasserre P, Lespinasse Y, Allan AC, Bus V, Chagné D, Crowhurst RN, Gleave AP, Lavezzo E, Fawcett JA, Proost S, Rouzé P, Sterck L, Toppo S, Lazzari B, Hellens RP, Durel C-E, Gutin A, Bumgarner R, Gardiner SE, Skolnick M, Egholm M, Van de Peer Y, Salamini F, Viola R (2010) The genome of the domesticated apple (Malus × domestica Borkh.). Nat Genet 42:833–839
Verdu CF, Guyot S, Childebrand N, Bahut M, Celton J-M, Gaillard S, Lasserre-Zuber P, Troggio M, Guilet D, Laurens F (2014) QTL analysis and candidate gene mapping for the polyphenol content in cider apple. PLoS One 9:e107103. https://doi.org/10.1371/journal.pone.0107103
Volz RK, McGhie TK (2011) Genetic variability in apple fruit polyphenol composition in Malus x domestica and Malus sieversii germplasm grown in New Zealand. J Agric Food Chem 59:11509–11521
Wang D, Gu J (2016) Integrative clustering methods of multi-omics data for molecule-based cancer classifications. Quant Biol 4:58–67. https://doi.org/10.1007/s40484-016-0063-4
Wanichthanarak K, Fahrmann JF, Grapov D (2015) Genomic, proteomic, and metabolomic data integration strategies. Biomark Insigh 10:1–6. https://doi.org/10.4137/BMI.S29511
Weigl K, Wenzel S, Flachowsky H, Peil A, Hanke M-V (2015) Integration of BPMADS4 on various linkage groups improves the utilization of the rapid cycle breeding system in apple. Plant Biotechnol J 13:246–258. https://doi.org/10.1111/pbi.12267
Wolter F, Schindele P, Puchta H (2019) Plant breeding at the speed of light: the power of CRISPR/Cas to generate directed genetic diversity at multiple sites. BMC Plant Biol 19:176. https://doi.org/10.1186/s12870-019-1775-1
Woods R, Walter H, Raven J, Wolfe R, Ireland P, Thien F, Abramson M (2003) Food and nutrient intakes and asthma risk in young adults. Am J Clin Nutr 78:414–421
Xu D, Keller JM, Popescu M, Bondugula R (2008) Applications of Fuzzy Logic in Bioinformatics, vol 9, World Scient
Yugi K, Kubota H, Hatano A, Kuroda S (2016) Trans-omics: how to reconstruct biochemical networks across multiple 'Omic' layers. Trends Biotechnol 34:276–290. https://doi.org/10.1016/j.tibtech.2015.12.013
Zhang L, Hu J, Han X, Li J, Gao Y, Richards CM, Zhang C, Tian Y, Liu G, Gul H, Wang D, Tian Y, Yang C, Meng M, Yuan G, Kang G, Wu Y, Wang K, Zhang H, Wang D, Con P (2019) A high-quality apple genome assembly reveals the association of a retrotransposon and red fruit colour. Nat Commun 10:1494. https://doi.org/10.1038/s41467-019-09518-x
Zhao C, Zhang Y, Du J, Guo X, Wen W, Gu S, Wang J, Fan J (2019) Crop phenomics: current status and perspectives. Front Plant Sci 10:714. https://doi.org/10.3389/fpls.2019.00714
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Korban, S.S. (2021). Future Prospects of ‘Omics’ and of Other Technologies for Genetic Improvement of Apple. In: Korban, S.S. (eds) The Apple Genome. Compendium of Plant Genomes. Springer, Cham. https://doi.org/10.1007/978-3-030-74682-7_18
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