Connecting past and present: single-cell lineage tracing

Abstract

Central to the core principle of cell theory, depicting cells’ history, state and fate is a fundamental goal in modern biology. By leveraging clonal analysis and single-cell RNA-seq technologies, single-cell lineage tracing provides new opportunities to interrogate both cell states and lineage histories. During the past few years, many strategies to achieve lineage tracing at single-cell resolution have been developed, and three of them (integration barcodes, polylox barcodes, and CRISPR barcodes) are noteworthy as they are amenable in experimentally tractable systems. Although the above strategies have been demonstrated in animal development and stem cell research, much care and effort are still required to implement these methods. Here we review the development of single-cell lineage tracing, major characteristics of the cell barcoding strategies, applications, as well as technical considerations and limitations, providing a guide to choose or improve the single-cell barcoding lineage tracing.

Keywords

single-cell lineage tracing / integration barcodes / polylox barcodes / CRISPR barcodes

References

[1] Adair JE, Enstrom MR (2021) A key toolbox for cellular barcoding analysis. Nat Comput Sci 1: 251- 252

[2] Alemany A, Florescu M, Baron CS, Peterson-Maduro J, van Oudenaarden A (2018) Whole-organism clone tracing using single-cell sequencing. Nature 556: 108- 112

[3] Andrews TS, Kiselev VY, McCarthy D, Hemberg M (2021) Tutorial:guidelines for the computational analysis of single-cell RNA sequencing data. Nat Protoc 16: 1- 9

[4] Baron CS, van Oudenaarden A (2019) Unravelling cellular relationships during development and regeneration using genetic lineage tracing. Nat Rev Mol Cell Biol 20: 753- 765

[5] Bergen V, Lange M, Peidli S, Wolf FA, Theis FJ (2020) Generalizing RNA velocity to transient cell states through dynamical modeling. Nat Biotechnol 38: 1408- 1414

[6] Biddy BA, Kong W, Kamimoto K, Guo C, Waye SE, Sun T, Morris SA (2018) Single-cell mapping of lineage and identity in direct reprogramming. Nature 564: 219- 224

[7] Bizzotto S, Dou Y, Ganz J, Doan RN, Kwon M, Bohrson CL, Kim SN, Bae T, Abyzov A, Network NBSM (2021) Landmarks of human embryonic development inscribed in somatic mutations. Science 371: 1249- 1253

[8] Blanpain C, Simons BD (2013) Unravelling stem cell dynamics by lineage tracing. Nat Rev Mol Cell Biol 14: 489- 502

[9] Bock C, Boutros M, Camp JG, Clarke L, Clevers H, Knoblich JA, Liberali P, Regev A, Rios AC, Stegle O et al (2021) The organoid cell atlas. Nat Biotechnol 39: 13- 17

[10] Bowling S, Sritharan D, Osorio FG, Nguyen M, Cheung P, Rodriguez-Fraticelli A, Patel S, Yuan WC, Fujiwara Y, Li BE, et al (2020) An engineered CRISPR-Cas9 mouse line for simultaneous readout of lineage histories and gene expression profiles in single cells. Cell 181 (6): 1410- 1422

[11] Bramlett C, Jiang D, Nogalska A, Eerdeng J, Contreras J, Lu R (2020) Clonal tracking using embedded viral barcoding and high-throughput sequencing. Nat Protoc 15: 1436- 1458

[12] Briggs JA, Weinreb C, Wagner DE, Megason S, Peshkin L, Kirschner MW, Klein AM (2018) The dynamics of gene expression in vertebrate embryogenesis at single-cell resolution. Science 360: eaar5780

[13] Buckingham ME, Meilhac SM (2011) Tracing cells for tracking cell lineage and clonal behavior. Dev Cell 21: 394- 409

[14] Bystrykh LV, Belderbos ME (2016) Clonal analysis of cells with cellular barcoding: when numbers and sizes matter. Methods Mol Biol 1516: 57- 89

[15] Bystrykh LV, de Haan G, Verovskaya E (2014) Barcoded vector libraries and retroviral or lentiviral barcoding of hematopoietic stem cells. Methods Mol Biol 1185: 345- 360

[16] Camp JG, Treutlein B (2017) Human organomics: a fresh approach to understanding human development using single-cell transcriptomics. Development 144: 1584- 1587

[17] Cao J, Spielmann M, Qiu X, Huang X, Ibrahim DM, Hill AJ, Zhang F, Mundlos S, Christiansen L, Steemers FJ et al (2019) The singlecell transcriptional landscape of mammalian organogenesis. Nature 566: 496- 502

[18] Chan MM, Smith ZD, Grosswendt S, Kretzmer H, Norman TM, Adamson B, Jost M, Quinn JJ, Yang D, Jones MG et al (2019) Molecular recording of mammalian embryogenesis. Nature 570: 77- 82

[19] Chow KK, Budde MW, Granados AA, Cabrera M, Yoon S, Cho S, Huang TH, Koulena N, Frieda K L, Cai L et al (2021) Imaging cell lineage with a synthetic digital recording system. Science 372: eabb3099

[20] Clarke R, Terry AR, Pennington H, Hasty C, MacDougall MS, Regan M, Merrill BJ (2020) Sequential activation of guide RNAs to enable successive CRISPR-Cas9 activities. Mol Cell 81 (2): 226- 238

[21] Cotterell J, Vila-Cejudo M, Batlle-Morera L, Sharpe J (2020) Endogenous CRISPR/Cas9 arrays for scalable whole-organism lineage tracing. Development 147 (9): dev184481

[22] Denoth-Lippuner A, Jaeger BN, Liang T, Royall LN, Chie SE, Buthey K, Machado D, Korobeynyk VI, Kruse M, Munz CM et al (2021) Visualization of individual cell division history in complex tissues using iCOUNT. Cell Stem Cell 28 (11): 2020- 2034

[23] Drakhlis L, Biswanath S, Farr CM, Lupanow V, Teske J, Ritzenhoff K, Franke A, Manstein F, Bolesani E, Kempf H et al (2021) Human heart-forming organoids recapitulate early heart and foregut development. Nat Biotechnol 39: 737- 746

[24] Egli D, Zuccaro MV, Kosicki M, Church GM, Bradley A, Jasin M (2018) Inter-homologue repair in fertilized human eggs. Nature 560: E5- E7

[25] Eid A, Alshareef S, Mahfouz MM (2018) CRISPR base editors:genome editing without double-stranded breaks. Biochem J 475: 1955- 1964

[26] Espinosa-Medina , I , Garcia-Marques , J , Cepko , C , and Lee, T (2019) High-throughput dense reconstruction of cell lineages. Open Biol 9: 190229

[27] Espinoza DA, Mortlock RD, Koelle SJ, Wu C, Dunbar CE (2021) Interrogation of clonal tracking data using barcodetrackR. Nat Comput Sci 1: 280- 289

[28] Farrell JA, Wang Y, Riesenfeld SJ, Shekhar K, Regev A, Schier AF (2018) Single-cell reconstruction of developmental trajectories during zebrafish embryogenesis. Science 360: eaar3131

[29] Feng J, DeWitt WS III, McKenna A, Simon N, Willis AD, Matsen FA IV (2021) Estimation of cell lineage trees by maximum-likelihood phylogenetics. Ann Appl Stat 15 (343-362): 320

[30] Figueres-Onate M, Sanchez-Gonzalez R, Lopez-Mascaraque L (2020) Deciphering neural heterogeneity through cell lineage tracing. Cell Mol Life Sci 78 (5): 1971- 1982

[31] Forrow A, Schiebinger G (2021) LineageOT is a unified framework for lineage tracing and trajectory inference. Nat Commun 12: 4940

[32] Frieda KL, Linton JM, Hormoz S, Choi J, Chow KK, Singer ZS, Budde MW, Elowitz MB, Cai L (2017) Synthetic recording and in situ readout of lineage information in single cells. Nature 541: 107- 111

[33] Garcia-Marques J, Yang CP, Espinosa-Medina I, Mok K, Koyama M, Lee T (2019) Unlimited genetic switches for cell-type-specific manipulation. Neuron 104: 227- 238 e227

[34] Garcia-Marques J, Espinosa-Medina I, Ku KY, Yang CP, Koyama M, Yu HH, Lee T (2020) A programmable sequence of reporters for lineage analysis. Nat Neurosci 23 (12): 1618- 1628

[35] Garrison BS, Yant SR, Mikkelsen JG, Kay MA (2007) Postintegrative gene silencing within the Sleeping Beauty transposition system. Mol Cell Biol 27: 8824- 8833

[36] Gerrits A, Dykstra B, Kalmykowa OJ, Klauke K, Verovskaya E, Broekhuis MJ, de Haan G, Bystrykh LV (2010) Cellular barcoding tool for clonal analysis in the hematopoietic system. Blood 115: 2610- 2618

[37] Girskis K, Woodworth M (2016) Genetic Techniques for cell lineage tracing in the nervous system. Short Course 31.

[38] Gong W, Granados AA, Hu J, Jones MG, Raz O, Salvador-Martinez I, Zhang H, Chow KK, Kwak IY, Retkute R et al (2021) Benchmarked approaches for reconstruction of in vitro cell lineages and in silico models of C. elegans and M. musculus developmental trees. Cell Syst 12 (8): 810- 826

[39] Haapaniemi E, Botla S, Persson J, Schmierer B, Taipale J (2018) CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response. Nat Med 24: 927- 930

[40] Han X, Chen H, Huang D, Chen H, Fei L, Cheng C, Huang H, Yuan GC, Guo G (2018) Mapping human pluripotent stem cell differentiation pathways using high throughput single-cell RNA-sequencing. Genome Biol 19: 47

[41] He J, Zhang G, Almeida AD, Cayouette M, Simons BD, Harris WA (2012) How variable clones build an invariant retina. Neuron 75: 786- 798

[42] He Z, Maynard A, Jain A, Gerber T, Petri R, Lin HC, Santel M, Ly K, Dupre JS, Sidow L et al (2022) Lineage recording in human cerebral organoids. Nat Methods 19: 90- 99

[43] Hofbauer P, Jahnel SM, Mendjan S (2021a) In vitro models of the human heart. Development 148 (16): dev199672

[44] Hofbauer P, Jahnel SM, Papai N, Giesshammer M, Deyett A, Schmidt C, Penc M, Tavernini K, Grdseloff N, Meledeth C, et al (2021b) Cardioids reveal self-organizing principles of human cardiogenesis. Cell 184: 3299- 3317 e3222

[45] Hsu YC (2015) Theory and practice of lineage tracing. Stem Cells 33: 3197- 3204

[46] Huang Q, Garrett A, Bose S, Blocker S, Rios AC, Clevers H, Shen X (2021) The frontier of live tissue imaging across space and time. Cell Stem Cell 28: 603- 622

[47] Hwang B, Lee JH, Bang D (2018) Single-cell RNA sequencing technologies and bioinformatics pipelines. Exp Mol Med 50: 96

[48] Hwang B, Lee W, Yum SY, Jeon Y, Cho N, Jang G, Bang D (2019) Lineage tracing using a Cas9-deaminase barcoding system targeting endogenous L1 elements. Nat Commun 10: 1234

[49] Ihry RJ, Worringer KA, Salick MR, Frias E, Ho D, Theriault K, Kommineni S, Chen J, Sondey M, Ye C et al (2018) p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat Med 24: 939- 946

[50] Jones MG, Khodaverdian A, Quinn JJ, Chan MM, Hussmann JA, Wang R, Xu C, Weissman JS, Yosef N (2020) Inference of singlecell phylogenies from lineage tracing data using Cassiopeia. Genome Biol 21: 92

[51] Kalhor K, Church GM (2019) Single-cell CRISPR-based lineage tracing in mice. Biochemistry 58: 4775- 4776

[52] Kalhor R, Kalhor K, Mejia L, Leeper K, Graveline A, Mali P, Church GM (2018) Developmental barcoding of whole mouse via homing CRISPR. Science 361.

[53] Kebschull JM, Zador AM (2018) Cellular barcoding: lineage tracing, screening and beyond. Nat Methods 15: 871- 879

[54] Kester L, van Oudenaarden A (2018) Single-cell transcriptomics meets lineage tracing. Cell Stem Cell 23: 166- 179

[55] Kim IS, Wu J, Rahme GJ, Battaglia S, Dixit A, Gaskell E, Chen H, Pinello L, Bernstein BE (2020) Parallel single-cell RNA-Seq and genetic recording reveals lineage decisions in developing embryoid bodies. Cell Rep 33: 108222

[56] Klein AM, Simons BD (2011) Universal patterns of stem cell fate in cycling adult tissues. Development 138: 3103- 3111

[57] Klein AM, Nakagawa T, Ichikawa R, Yoshida S, Simons BD (2010) Mouse germ line stem cells undergo rapid and stochastic turnover. Cell Stem Cell 7: 214- 224

[58] Kong W, Biddy BA, Kamimoto K, Amrute JM, Butka EG, Morris SA (2020) Cell tagging: combinatorial indexing to simultaneously map lineage and identity at single-cell resolution. Nat Protoc 15: 750- 772

[59] Kwon GS, Viotti M, Hadjantonakis AK (2008) The endoderm of the mouse embryo arises by dynamic widespread intercalation of embryonic and extraembryonic lineages. Dev Cell 15: 509- 520

[60] La Manno G, Soldatov R, Zeisel A, Braun E, Hochgerner H, Petukhov V, Lidschreiber K, Kastriti ME, Lonnerberg P, Furlan A et al (2018) RNA velocity of single cells. Nature 560: 494- 498

[61] Lafzi A, Moutinho C, Picelli S, Heyn H (2018) Tutorial: guidelines for the experimental design of single-cell RNA sequencing studies. Nat Protoc 13: 2742- 2757

[62] Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA (2013) Cerebral organoids model human brain development and microcephaly. Nature 501: 373- 379

[63] Lareau CA, Ludwig LS, Muus C, Gohil SH, Zhao T, Chiang Z, Pelka K, Verboon JM, Luo W, Christian E et al (2021) Massively parallel single-cell mitochondrial DNA genotyping and chromatin profiling. Nat Biotechnol 39: 451- 461

[64] Lederer AR, La Manno G (2020) The emergence and promise of single-cell temporal-omics approaches. Curr Opin Biotechnol 63: 70- 78

[65] Liu K, Deng S, Ye C, Yao Z, Wang J, Gong H, Liu L, He X (2021) Mapping single-cell-resolution cell phylogeny reveals cell population dynamics during organ development. Nat Methods 18: 1506- 1514

[66] Liu K, Jin H, Zhou B (2020) Genetic lineage tracing with multiple DNA recombinases: a user’s guide for conducting more precise cell fate mapping studies. J Biol Chem 295: 6413- 6424

[67] Lu R, Neff NF, Quake SR, Weissman IL (2011) Tracking single hematopoietic stem cells in vivo using high-throughput sequencing in conjunction with viral genetic barcoding. Nat Biotechnol 29: 928- 933

[68] Ludwig LS, Lareau CA, Ulirsch JC, Christian E, Muus C, Li LH, Pelka K, Ge W, Oren Y, Brack A, et al (2019) Lineage tracing in humans enabled by mitochondrial mutations and single-cell genomics. Cell 176: 1325- 1339 e1322

[69] MacLean AL, Lo Celso C, Stumpf MP (2017) Concise review: stem cell population biology: insights from hematopoiesis. Stem Cells 35: 80- 88

[70] Marx V (2021) Method of the year: spatially resolved transcriptomics. Nat Methods 18: 9- 14

[71] McKenna A, Gagnon JA (2019) Recording development with single cell dynamic lineage tracing. Development 146 (12): dev169730

[72] McKenna A, Findlay GM, Gagnon JA, Horwitz M S, Schier AF, Shendure J (2016) Whole-organism lineage tracing by combinatorial and cumulative genome editing. Science 353: aaf7907

[73] Mittnenzweig M, Mayshar Y, Cheng S, Ben-Yair R, Hadas R, Rais Y, Chomsky E, Reines N, Uzonyi A, Lumerman L, et al (2021) A single-embryo, single-cell time-resolved model for mouse gastrulation. Cell 184: 2825- 2842 e2822

[74] Naik SH, Schumacher TN, Perie L (2014) Cellular barcoding: a technical appraisal. Exp Hematol 42: 598- 608

[75] Packer JS, Zhu Q, Huynh C, Sivaramakrishnan P, Preston E, Dueck H, Stefanik D, Tan K, Trapnell C, Kim J et al (2019) A lineageresolved molecular atlas of C. elegans embryogenesis at singlecell resolution. Science 365: eaax1971

[76] Papapetrou EP, Schambach A (2016) Gene insertion into genomic safe harbors for human gene therapy. Mol Ther 24: 678- 684

[77] Pei W, Feyerabend TB, Rossler J, Wang X, Postrach D, Busch K, Rode I, Klapproth K, Dietlein N, Quedenau C et al (2017) Polylox barcoding reveals haematopoietic stem cell fates realized in vivo. Nature 548: 456- 460

[78] Pei W, Wang X, Rossler J, Feyerabend TB, Hofer T, Rodewald HR (2019) Using Cre-recombinase-driven Polylox barcoding for in vivo fate mapping in mice. Nat Protoc 14: 1820- 1840

[79] Pei W, Shang F, Wang X, Fanti AK, Greco A, Busch K, Klapproth K, Zhang Q, Quedenau C, Sauer S et al (2020) Resolving fates and single-cell transcriptomes of hematopoietic stem cell clones by polyloxexpress barcoding. Cell Stem Cell 27 (3): 383- 395

[80] Peikon ID, Gizatullina DI, Zador AM (2014) In vivo generation of DNA sequence diversity for cellular barcoding. Nucleic Acids Res 42: e127

[81] Peng G, Suo S, Cui G, Yu F, Wang R, Chen J, Chen S, Liu Z, Chen G, Qian Y et al (2019) Molecular architecture of lineage allocation and tissue organization in early mouse embryo. Nature 572: 528- 532

[82] Peng G, Cui G, Ke J, Jing N (2020) Using single-cell and spatial transcriptomes to understand stem cell lineage specification during early embryo development. Annu Rev Genomics Hum Genet 21: 163- 181

[83] Petit AC, Legue E, Nicolas JF (2005) Methods in clonal analysis and applications. Reprod Nutr Dev 45: 321- 339

[84] Pijuan-Sala B, Griffiths JA, Guibentif C, Hiscock TW, Jawaid W, Calero-Nieto FJ, Mulas C, Ibarra-Soria X, Tyser RCV, Ho DLL et al (2019) A single-cell molecular map of mouse gastrulation and early organogenesis. Nature 566: 490- 495

[85] Potter SS (2018) Single-cell RNA sequencing for the study of development, physiology and disease. Nat Rev Nephrol 14: 479- 492

[86] Qiu X, Mao Q, Tang Y, Wang L, Chawla R, Pliner HA, Trapnell C (2017) Reversed graph embedding resolves complex single-cell trajectories. Nat Methods 14: 979- 982

[87] Quinn JJ, Jones MG, Okimoto RA, Nanjo S, Chan MM, Yosef N, Bivona TG, Weissman JS (2021) Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts. Science eabc1944.

[88] Raj B, Wagner DE, McKenna A, Pandey S, Klein AM, Shendure J, Gagnon JA, Schier AF (2018) Simultaneous single-cell profiling of lineages and cell types in the vertebrate brain. Nat Biotechnol 36: 442- 450

[89] Rees HA, Liu DR (2018) Base editing: precision chemistry on the genome and transcriptome of living cells. Nat Rev Genet 19: 770- 788

[90] Regev A, Teichmann SA, Lander ES, Amit I, Benoist C, Birney E, Bodenmiller B, Campbell P, Carninci P, Clatworthy M et al (2017) The human cell atlas. Elife 6: e27041

[91] Rodriguez-Fraticelli AE, Wolock SL, Weinreb CS, Panero R, Patel SH, Jankovic M, Sun J, Calogero RA, Klein AM, Camargo FD (2018) Clonal analysis of lineage fate in native haematopoiesis. Nature 553: 212- 216

[92] Rodriguez-Fraticelli AE, Weinreb C, Wang SW, Migueles RP, Jankovic M, Usart M, Klein AM, Lowell S, Camargo FD (2020) Single-cell lineage tracing unveils a role for TCF15 in haematopoiesis. Nature 583: 585- 589

[93] Rosenberg AB, Roco CM, Muscat RA, Kuchina A, Sample P, Yao Z, Graybuck LT, Peeler DJ, Mukherjee S, Chen W et al (2018) Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding. Science 360: 176- 182

[94] Rossi G, Broguiere N, Miyamoto M, Boni A, Guiet R, Girgin M, Kelly RG, Kwon C, Lutolf MP (2021) Capturing cardiogenesis in gastruloids. Cell Stem Cell 28: 230- 240 e236

[95] Saelens W, Cannoodt R, Todorov H, Saeys Y (2019) A comparison of single-cell trajectory inference methods. Nat Biotechnol 37: 547- 554

[96] Sagner A, Briscoe J (2019) Establishing neuronal diversity in the spinal cord: a time and a place. Development 146 (22): dev182154

[97] Salvador-Martinez I, Grillo M, Averof M, Telford MJ (2019) Is it possible to reconstruct an accurate cell lineage using CRISPR recorders? Elife 8: e40292

[98] Semrau S, Goldmann JE, Soumillon M, Mikkelsen TS, Jaenisch R, van Oudenaarden A (2017) Dynamics of lineage commitment revealed by single-cell transcriptomics of differentiating embryonic stem cells. Nat Commun 8: 1096

[99] Sivasubbu S, Balciunas D, Amsterdam A, Ekker SC (2007) Insertional mutagenesis strategies in zebrafish. Genome Biol 8: S9

[100] Smith T, Heger A, Sudbery I (2017) UMI-tools: modeling sequencing errors in unique molecular identifiers to improve quantification accuracy. Genome Res 27: 491- 499

[101] Spanjaard B, Hu B, Mitic N, Olivares-Chauvet P, Janjuha S, Ninov N, Junker JP (2018) Simultaneous lineage tracing and cell-type identification using CRISPR-Cas9-induced genetic scars. Nat Biotechnol 36: 469- 473

[102] Spencer Chapman M, Ranzoni AM, Myers B, Williams N, Coorens THH, Mitchell E, Butler T, Dawson KJ, Hooks Y, Moore L et al (2021) Lineage tracing of human development through somatic mutations. Nature 595 (7865): 85- 90

[103] Sulston JE, Schierenberg E, White JG, Thomson JN (1983) The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev Biol 100: 64- 119

[104] Svensson V, Pachter L (2018) RNA velocity: molecular kinetics from single-cell RNA-Seq. Mol Cell 72: 7- 9

[105] Svensson V, Vento-Tormo R, Teichmann SA (2018) Exponential scaling of single-cell RNA-seq in the past decade. Nat Protoc 13: 599- 604

[106] Tam PPL, Ho JWK (2020) Cellular diversity and lineage trajectory:insights from mouse single cell transcriptomes. Development 147 (2): dev179788

[107] Tanay A, Regev A (2017) Scaling single-cell genomics from phenomenology to mechanism. Nature 541: 331- 338

[108] Thielecke L, Cornils K, Glauche I (2020) genBaRcode: a comprehensive R-package for genetic barcode analysis. Bioinformatics 36: 2189- 2194

[109] Treutlein B, Lee QY, Camp JG, Mall M, Koh W, Shariati SA, Sim S, Neff NF, Skotheim JM, Wernig M et al (2016) Dissecting direct reprogramming from fibroblast to neuron using single-cell RNAseq. Nature 534: 391- 395

[110] Trinh le A, and Fraser, S E, (2013) Enhancer and gene traps for molecular imaging and genetic analysis in zebrafish. Dev Growth Differ 55: 434- 445

[111] Tritschler S, Buttner M, Fischer DS, Lange M, Bergen V, Lickert H, Theis FJ (2019) Concepts and limitations for learning developmental trajectories from single cell genomics. Development 146 (12): dev170506

[112] Van den Berge K, Roux de Bezieux H, Street K, Saelens W, Cannoodt R, Saeys Y, Dudoit S, Clement L (2020) Trajectorybased differential expression analysis for single-cell sequencing data. Nat Commun 11: 1201

[113] VanHorn S, Morris SA (2020) Next-generation lineage tracing and fate mapping to interrogate development. Dev Cell 56 (1): 7- 21

[114] Wagner DE, Klein AM (2020) Lineage tracing meets single-cell omics: opportunities and challenges. Nat Rev Genet 21 (7): 410- 427

[115] Wagner DE, Weinreb C, Collins ZM, Briggs JA, Megason SG, Klein AM (2018) Single-cell mapping of gene expression landscapes and lineage in the zebrafish embryo. Science 360: 981- 987

[116] Wasserstrom A, Frumkin D, Adar R, Itzkovitz S, Stern T, Kaplan S, Shefer G, Shur I, Zangi L, Reizel Y, et al (2008) Estimating cell depth from somatic mutations. PLoS Comput Biol 4: e1000058

[117] Weber TS, Dukes M, Miles DC, Glaser SP, Naik SH, Duffy KR (2016) Site-specific recombinatorics: in situ cellular barcoding with the Cre Lox system. BMC Syst Biol 10: 43

[118] Weinreb C, Klein AM (2020) Lineage reconstruction from clonal correlations. Proc Natl Acad Sci USA 117: 17041- 17048

[119] Weinreb C, Rodriguez-Fraticelli A, Camargo FD, Klein AM (2020) Lineage tracing on transcriptional landscapes links state to fate during differentiation. Science 367: eaaw3381

[120] Weissman TA, Pan YA (2015) Brainbow: new resources and emerging biological applications for multicolor genetic labeling and analysis. Genetics 199: 293- 306

[121] Willnow D, Benary U, Margineanu A, Vignola ML, Konrath F, Pongrac IM, Karimaddini Z, Vigilante A, Wolf J, Spagnoli FM (2021) Quantitative lineage analysis identifies a hepato-pancreato-biliary progenitor niche. Nature 597: 87- 91

[122] Woodworth MB, Girskis KM, Walsh CA (2017) Building a lineage from single cells: genetic techniques for cell lineage tracking. Nat Rev Genet 18: 230- 244

[123] Wu Y, Zhang K (2020) Tools for the analysis of high-dimensional single-cell RNA sequencing data. Nat Rev Nephrol 16: 408- 421

[124] Wu SS, Lee JH, Koo BK (2019) Lineage tracing: computational reconstruction goes beyond the limit of imaging. Mol Cells 42: 104- 112

[125] Ye C, Chen Z, Liu Z, Wang F, He X (2020) Defining endogenous barcoding sites for CRISPR/Cas9-based cell lineage tracing in zebrafish. J Genet Genomics 47: 85- 91

[126] Zafar H, Lin C, Bar-Joseph Z (2020) Single-cell lineage tracing by integrating CRISPR-Cas9 mutations with transcriptomic data. Nat Commun 11: 3055

[127] Zechner C, Nerli E, Norden C (2020) Stochasticity and determinism in cell fate decisions. Development 147 (14): dev181495

[128] Zhong S, Zhang S, Fan X, Wu Q, Yan L, Dong J, Zhang H, Li L, Sun L, Pan N et al (2018) A single-cell RNA-seq survey of the developmental landscape of the human prefrontal cortex. Nature 555: 524- 528

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