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Left, skin from the back of a cadaver; right, skin surrounding a basal cell carcino\ ma. b, Expression profiles clas:97)/F 4/H/N/Rect[56.9045 173.52 64.3241 163.34]/Subtype/Link/Type/Annot>> endobj 4 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:14. Macaulay, I. C. etal. Separation and parallel sequencing of the genomes and trans\ criptomes of single cells using G&T-seq. Nat. Protocols 11, 2081 2103 \(2016\).\r:98)/F 4/H/N/Rect[240.516 55.2704 245.474 45.0899]/Subtype/Link/Type/Annot>> endobj 5 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:15. Macaulay, I. C. etal. G&T-seq: parallel sequencing of single-cell genomes and tra\ nscriptomes. Nat. Methods 12, 519 522 \(2015\).\r:99)/F 4/H/N/Rect[246.881 55.2704 251.545 45.0899]/Subtype/Link/Type/Annot>> endobj 6 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 1 | A workflow to genotype individual skin cells. a, Examples of healthy s\ kin from which we genotyped individual cells. Left, skin from the back of a cadaver; right, skin surrounding a basal cell carcin\ oma. b, Expression profiles cla:100)/F 4/H/N/Rect[446.529 248.77 454.531 238.59]/Subtype/Link/Type/Annot>> endobj 7 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 1 | A workflow to genotype individual skin cells. a, Examples of healthy \ skin from which we genotyped individual cells. Left, skin from the back of a cadaver; right, skin surrounding a basal cell carci\ noma. b, Expression profiles cl:101)/F 4/H/N/Rect[548.365 162.77 555.996 152.59]/Subtype/Link/Type/Annot>> endobj 8 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:16. Lodato, M. A. etal. Aging and neurodegeneration are associated with increased mut\ ations in single human neurons. Science 359, 555 559 \(2018\).\r:102)/F 4/H/N/Rect[401.701 98.2704 406.552 88.0899]/Subtype/Link/Type/Annot>> endobj 9 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:17. Bohrson, C. L. etal. Linked-read analysis identifies mutations in single-cell DNA\ -sequencing data. Nat. Genet. 51, 749 754 \(2019\).\r:103)/F 4/H/N/Rect[407.914 98.2704 412.576 88.0899]/Subtype/Link/Type/Annot>> endobj 10 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 1 | A workflow to genotype individual skin cells. a, Examples of healthy\ skin from which we genotyped individual cells. 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Belote Andrew S. McNeal Tuyet M. Tan Iwei Yeh Sarah T. Arron Robert L. Judson-Torres Boris C. Bastian A. Hunter Shain 10.1038/s41586-020-2785-8 http://dx.doi.org/10.1038/s41586-020-2785-8 journal Nature © 2020, The Author(s), under exclusive licence to Springer Nature Limited 1476-4687 10.1038/s41586-020-2785-8 springer.com springerlink.com 2010-04-23 True 10.1038/s41586-020-2785-8 springer.com springerlink.com Springer 2020-10-01T09:22:22+05:30 2020-10-01T09:21:26+05:30 2020-10-01T09:22:22+05:30 True uuid:ef03df87-2d3f-4074-9e8f-2428436a533b uuid:eec4d04f-435a-42ed-bc45-60e34115c204 default 1 converted uuid:4728c4a1-161c-442e-8d53-d7c828198385 converted to PDF/A-2b pdfToolbox 2020-10-01T09:22:22+05:30 2 B http://ns.adobe.com/pdf/1.3/ pdf Adobe PDF Schema internal A name object indicating whether the document has been modified to include trapping information Trapped Text http://ns.adobe.com/pdfx/1.3/ pdfx pdfx internal ID of PDF/X standard GTS_PDFXVersion Text internal Conformance level of PDF/X standard GTS_PDFXConformance Text internal Company creating the PDF Company Text internal Date when document was last modified SourceModified Text external Mirrors crossmark:CrosMarkDomains CrossMarkDomains Seq Text internal Mirrors crossmark:DOI doi Text http://ns.adobe.com/xap/1.0/mm/ xmpMM XMP Media Management Schema internal UUID based identifier for specific incarnation of a document InstanceID URI internal The common identifier for all versions and renditions of a document. OriginalDocumentID URI http://www.aiim.org/pdfa/ns/id/ pdfaid PDF/A ID Schema internal Part of PDF/A standard part Integer internal Amendment of PDF/A standard amd Text internal Conformance level of PDF/A standard conformance Text http://crossref.org/crossmark/1.0/ crossmark crossmark internal CrossMarkDomains CrossMarkDomains Seq Text internal CrossmarkDomainExclusive CrossmarkDomainExclusive Text internal Usual same as prism:doi DOI Text external The date when a publication was published. MajorVersionDate Text http://prismstandard.org/namespaces/basic/2.0/ prism Prism external The aggregation type specifies the unit of aggregation for a content collection. Comment PRISM recommends that the PRISM Aggregation Type Controlled Vocabulary be used to provide values for this element. Note: PRISM recommends against the use of the #other value currently allowed in this controlled vocabulary. In lieu of using #other please reach out to the PRISM group at info@prismstandard.org to request addition of your term to the Aggregation Type Controlled Vocabulary. aggregationType Text external Copyright copyright Text external The Digital Object Identifier for the article. The DOI may also be used as the dc:identifier. If used as a dc:identifier, the URI form should be captured, and the bare identifier should also be captured using prism:doi. If an alternate unique identifier is used as the required dc:identifier, then the DOI should be specified as a bare identifier within prism:doi only. If the URL associated with a DOI is to be specified, then prism:url may be used in conjunction with prism:doi in order to provide the service endpoint (i.e. the URL). doi Text external ISSN for an electronic version of the issue in which the resource occurs. 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Left, skin from the back of a cadaver; right, skin surrounding a basal cell car\ cinoma. b, Expression profiles :105)/F 4/H/N/Rect[57.9287 162.77 65.7662 152.59]/Subtype/Link/Type/Annot>> endobj 48 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:18. Petljak, M. etal. Characterizing mutational signatures in human cancer cell lines\ reveals episodic APOBEC mutagenesis. Cell 176, 1282 1294.e20 \(2019\).\r:106)/F 4/H/N/Rect[111.833 55.2704 116.769 45.0899]/Subtype/Link/Type/Annot>> endobj 49 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:19. Talevich, E., Shain, A. H., Botton, T. & Bastian, B. C. CNVkit: genome-wide copy n\ umber detection and visualization from targeted DNA sequencing. PLOS Comput. Biol. 12, e1004873 \(2016\).\r:107)/F 4/H/N/Rect[505.31 227.27 509.688 217.09]/Subtype/Link/Type/Annot>> endobj 50 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:20. Talevich, E. & Shain, A. H. CNVkit-RNA: copy number inference from RNA-sequencing dat\ a. Preprint at https://www.biorxiv.org/content/10.1101/408534v1 \(2018\).\r:108)/F 4/H/N/Rect[511.051 227.27 516.898 217.09]/Subtype/Link/Type/Annot>> endobj 51 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 1 | A workflow to genotype individual skin cells. a, Examples of healt\ hy skin from which we genotyped individual cells. Left, skin from the back of a cadaver; right, skin surrounding a basal cell ca\ rcinoma. b, Expression profiles:109)/F 4/H/N/Rect[549.48 205.77 556.18 195.59]/Subtype/Link/Type/Annot>> endobj 52 0 obj <>/BS<>/Border[0 0 0]/F 4/H/N/Rect[415.801 130.52 561.26 120.34]/Subtype/Link/Type/Annot>> endobj 53 0 obj <>/BS<>/Border[0 0 0]/F 4/H/N/Rect[306.142 119.77 350.295 109.59]/Subtype/Link/Type/Annot>> endobj 54 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:21. Fewings, E., Tang, J., Chang, D. & Shain, A. H. 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Elwood, J. M. & Gallagher, R. P. Body site distribution of cutaneous malignant mel\ anoma in relationship to patterns of sun exposure. Int. J. Cancer 78, 276 280 \(1998\).\r:114)/F 4/H/N/Rect[371.047 528.27 376.413 518.09]/Subtype/Link/Type/Annot>> endobj 72 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:23. Nehal, K. S. & Bichakjian, C. K. Update on keratinocyte carcinomas. N. Engl. J. 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Roerink, S. F. etal. Intra-tumour diversification in colorectal cancer at the sin\ gle-cell level. Nature 556, 457 462 \(2018\).\r:118)/F 4/H/N/Rect[392.401 732.52 397.93 722.34]/Subtype/Link/Type/Annot>> endobj 133 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 2 | The genomic landscape of individual melanocytes from physiologically nor\ mal human skin. a, Top, mutation burden of melanocytes from physiologically normal skin of six donors across different ana\ tomic sites \(adj, adjacent; BCC,:119)/F 4/H/N/Rect[323.729 711.02 332.28 700.84]/Subtype/Link/Type/Annot>> endobj 134 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:25. Machiela, M. J. etal. Female chromosome X mosaicism is age-related and preferenti\ ally affects the inactivated X chromosome. Nat. Commun. 7, 11843 \(2016\).\r:120)/F 4/H/N/Rect[487.411 678.77 492.446 668.59]/Subtype/Link/Type/Annot>> endobj 135 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:26. Forsberg, L. A. etal. Mosaic loss of chromosome Y in peripheral blood is associat\ ed with shorter survival and higher risk of cancer. Nat. Genet. 46, 624 628 \(2014\).\r:121)/F 4/H/N/Rect[493.808 678.77 499.322 668.59]/Subtype/Link/Type/Annot>> endobj 136 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:27. Shain, A. H. etal. Genomic and transcriptomic analysis reveals incremental disrup\ tion of key signaling pathways during melanoma evolution. Cancer Cell 34, 45 55.e4 \(2018\).\r:122)/F 4/H/N/Rect[456.646 625.02 461.263 614.84]/Subtype/Link/Type/Annot>> endobj 137 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:28. Bastian, B. C., Olshen, A. B., LeBoit, P. E. & Pinkel, D. Classifying melanocytic \ tumors based on DNA copy number changes. Am. J. Pathol. 163, 1765 1770 \(2003\).\r:123)/F 4/H/N/Rect[462.624 625.02 468.173 614.84]/Subtype/Link/Type/Annot>> endobj 138 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Table 1 | Pathogenic mutations in melanocytes from normal human skin\r\r\ A curated list of pathogenic mutations in melanocytes found in this study \(see Methods for details on how these were defined\)\ .\naNonsense mutations.:124)/F 4/H/N/Rect[423.157 560.52 426.523 550.34]/Subtype/Link/Type/Annot>> endobj 139 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:29. Hodis, E. etal. A landscape of driver mutations in melanoma. Cell 150, 251 26\ 3 \(2012\).\r:125)/F 4/H/N/Rect[347.111 485.27 352.122 475.09]/Subtype/Link/Type/Annot>> endobj 140 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:30. Pollock, P. M. etal. High frequency of BRAF mutations in nevi. Nat. 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Arafeh, R. etal. Recurrent inactivating RASA2 mutations in melanoma. Nat. Genet\ . 47, 1408 1410 \(2015\).\r:130)/F 4/H/N/Rect[413.009 377.77 418.261 367.59]/Subtype/Link/Type/Annot>> endobj 145 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 3 | Distinct trajectories of melanoma evolution. 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Med\ . 374, 995 996 \(2016\).\r:133)/F 4/H/N/Rect[321.577 281.02 327.24 270.84]/Subtype/Link/Type/Annot>> endobj 148 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 3 | Distinct trajectories of melanoma evolution. On the basis of the data sh\ own here and previously, we propose that melanomas can evolve via distinct trajectories depending upon the order in which mutati\ ons occur.:134)/F 4/H/N/Rect[346.913 281.02 351.426 270.84]/Subtype/Link/Type/Annot>> endobj 149 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:37. Kelly, J. W., Chamberlain, A. J., Staples, M. P. & McAvoy, B. Nodular melanoma. No\ longer as simple as ABC. Aust. Fam. Physician 32, 706 709 \(2003\).\r:135)/F 4/H/N/Rect[415.419 259.52 420.275 249.34]/Subtype/Link/Type/Annot>> endobj 150 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:38. Huang, F. W. etal. Highly recurrent TERT promoter mutations in human melanoma. 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Zeng, H. etal. Bi-allelic loss of CDKN2A initiates melanoma invasion via BRN2 act\ ivation. Cancer Cell 34, 56 68.e9 \(2018\).\r:151)/F 4/H/N/Rect[287.055 259.553 292.553 249.34]/Subtype/Link/Type/Annot>> endobj 176 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:14. Macaulay, I. C. etal. Separation and parallel sequencing of the genomes and tran\ scriptomes of single cells using G&T-seq. Nat. Protocols 11, 2081 2103 \(2016\).\r:152)/F 4/H/N/Rect[447.045 453.02 451.862 442.84]/Subtype/Link/Type/Annot>> endobj 177 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:15. Macaulay, I. C. etal. G&T-seq: parallel sequencing of single-cell genomes and tr\ anscriptomes. Nat. Methods 12, 519 522 \(2015\).\r:153)/F 4/H/N/Rect[453.223 453.02 457.752 442.84]/Subtype/Link/Type/Annot>> endobj 178 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:14. Macaulay, I. C. etal. Separation and parallel sequencing of the genomes and tra\ nscriptomes of single cells using G&T-seq. Nat. Protocols 11, 2081 2103 \(2016\).\r:154)/F 4/H/N/Rect[493.512 442.27 498.229 432.09]/Subtype/Link/Type/Annot>> endobj 179 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:15. Macaulay, I. C. etal. G&T-seq: parallel sequencing of single-cell genomes and t\ ranscriptomes. Nat. 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Shain, A. H. etal. Genomic and transcriptomic analysis reveals incremental disru\ ption of key signaling pathways during melanoma evolution. Cancer Cell 34, 45 55.e4 \(2018\).\r:156)/F 4/H/N/Rect[98.9111 377.77 103.792 367.59]/Subtype/Link/Type/Annot>> endobj 185 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 1 | A workflow to genotype individual skin cells. a, Examples of he\ althy skin from which we genotyped individual cells. Left, skin from the back of a cadaver; right, skin surrounding a basal cell\ carcinoma. b, Expression profi:157)/F 4/H/N/Rect[79.6131 205.77 87.2443 195.59]/Subtype/Link/Type/Annot>> endobj 186 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:44. Reinius, B. etal. Analysis of allelic expression patterns in clonal somatic cells\ by single-cell RNA-seq. Nat. Genet. 48, 1430 1435 \(2016\).\r:158)/F 4/H/N/Rect[496.189 678.77 501.956 668.59]/Subtype/Link/Type/Annot>> endobj 187 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 1 | A workflow to genotype individual skin cells. a, Examples of h\ ealthy skin from which we genotyped individual cells. Left, skin from the back of a cadaver; right, skin surrounding a basal cel\ l carcinoma. b, Expression prof:159)/F 4/H/N/Rect[403.196 474.52 411.718 464.34]/Subtype/Link/Type/Annot>> endobj 188 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 1 | A workflow to genotype individual skin cells. a, Examples of \ healthy skin from which we genotyped individual cells. Left, skin from the back of a cadaver; right, skin surrounding a basal ce\ ll carcinoma. b, Expression pro:160)/F 4/H/N/Rect[444.561 453.02 453.084 442.84]/Subtype/Link/Type/Annot>> endobj 189 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<>>> endobj 190 0 obj <>stream x]ےFr}o؇zوIՒZw]rp$؄88gşʬ[fٵ&D6B]z(>X<wy%Wᄌ7X~B=&D]9⥮]bxʡ6e7"q&0\z1D|&7}]l;R6tfUt[nôEz߾Xl.] Vu,ѓNVj +e>*nF3-6X>dG;h/NtOQTm5[9/B,dwސ˶ {&Woݷ|FIU ݟxղGK=>ޗ'Ϳ˞ z.'I>o7߱>e|X.d?_`QOttroE tg*D&W'*fK0 QqK `z>_$e?a[X($ed'dxmt0]S?vwf-˛[L2I&!#Yh9}t+cي{rGxۖ k;iIcGz:KbۅbƺV;'%o;Gv^%v\(-nv\<ݍCA1 Z?liϊu*7h^@̰nmɯ.j8aQ"[:K'(8^+ـ 5tspl@HjJn5rh71Ը9%)=hFjo_M*x " ,OY3^LnyWm,zH⩅HR3*X [H^437Yh57G^x1݀W{خkGG_g7@n4uX`qK,VckA!kȸjEPKnua./zǟZ9PՐZG@IPvA!oՃ?ẇ[0+ͪkmvi -2! ؽ:%aJ.Ş"WfWUtz:Kuim3f#c W>|O;BӍ[eݵ^O~YBш5"%g-VP,2O+P3ƚ`fbC_԰zW-)2#o]$^)np{fy ]QN/R_ *H6Ѓ1J;(ԗFЅolpup8=_L !_KåWS'ȼċ'&EPJak.]ѕξ;#[r9vB*O虽oKǡKJ%ι^cz!O!a۟mGؙfL "_X]kV~!4 I<3WjrH (onŷ f$Qh,U \)l=TLX1l9_^@אra8'j<U1;jlV!;J2A8O _ :(EdP(Mhz 򕷹n弎U ZؠzzԝX_x+(6bo4s==$:^s9hoZ 1HuH\ Ę6HEK;S oQk@!]N 4$i+~kIȭb;k8]Qw=uZyDAeq-5jT,`~ 5^8*XP)Vai|g.~Qn%Y4#Wͫj߂7)5΍bOWr&=~TNTo?XPnx9US:B39rK?7`W e kS5 t(m.ue=x_Ղxd)롮S&]kif'jky!zD*|J1jR UA.6pWuOe;34TA\)f>=BY{ $g,!?iXҙ]ܕ v[v¦Lj'đ5!)&]+&]7?(AEFh,]3nڦs<4]k*]}y6s[(Fou[$ DM7$C(go=X6Y/=;[?,Xك+}ՑdK=|Xe*Hv0rnE޺<K#MAeWh)EMy?7 fWHǢkWU(r]D{gRFZ[r1#70A՚=>̇4bAn*.HM0{%"Y.h'O(3P6r"a3z'\Ќ"BZ=v,8 *JCisrW*Ǒ%.q8ueJBvsXDIr4@DbG罒G -M{nӞhNKb6,)z0^DĠ*2zFu7)Q+}Uokl 4+zخ(UAUyPC6vcOr\/J.k2I'Vq.՞ȏ@E0rH+_-+f%{uRD]m7B*^j9yXΗJ/* K U2!giz-B&LR0=}Ǫ?&I)Aaŋy'u$#纔]VC!_Ύծ;IЃ:tXZ]b 珯tXfr Hݝ AX5wFMw=y"uTmy+Iv(p]ӳ,[B&?}pV{@rWb׵ݹo<'(Zܠ8=`^1r+$GذqZ FD'ó^dmE!~He泇kڹ#ś;hX!)h4R"d2 "8EN:AQ Ӗ >2AcZޭ8Ep꤮E(6tad-{<s 7Cȡ'574-:iVo9ƁZtW5poEQJ91ҸXK^EfnTܬj2x\^,1t!8GEV!:vKgM.:K $zӃO;J㟔ՄƾK]9gs]O.iޅAZ []$T@ ibfrPUq;'Krq :c'  T&a.;Faao\HsǎGiƃ-Ah8ʁE.`2? akv*()KZ=R9q`jS00ɱz;UǍ*XChNv❒N9Ys; ,n/.hy7iwڻJ+aPƏzgpԈ~x;=>\:V|d 8Eֲw)Q}{\MUR`J2ٴm+6#+&2e6"t.7{KqJ㿵䢦zZin]iOf49 ߛ}`^MTivҼX(٘V\9: /ݛy҉#ӬbVUkItQ?5 9IŰI`3o/f7K1 f*6O{0 Lꋏ9AS׼I2cȜYn\V&mAP?H0kԋuDI\mX΃ဨACBbqp{FH5 F. <ӎ+m+oA TȅgK(,o`V@\QY5vI{iyyMQ[t|؈OB_}', ~P~Mqe\ea9}/uZ3]l=m.Ll;$؁+KUPҩǮ*M` [M4SB ГORnT+hccC&>y,de#Z&%QAb&˺e <9Z2ƗTQC7`+c%ad0Zɏ4]h]: 8b*)kA+J@-D'pn3'~"==8{DG9]-9Zbz I{?T4ۓTn[۔22MQ o!0i)"0-oz+؝z*;)5 qvj3\-[0(ސ1[MPHmK.mSã3~Ľ+q&DkS:úi Y+}-V6&dJ ʊ` n! imYM8PH+ʋ_LB`{ɳb`=xAl?ҐޅXkV$[>`xKj֣Z>kҥoeLm t{`QFQnei_LW|c{s/m~k+"P(w*%ͨ?mN! 3k!ozcc+3R |xl6w"2텇K4ƣ(~anR SB`$O=eɔ&~I4-3: !'6iRsTY-*r@Gi!l^ޠK{ x4vB!OG.gZ? j'a~Z[0NaZW0VTgIQ>;Dy Q&@+N2ɶw1 f#2:@q  4Q?M?$|[Y% L2t5B&YTaR`$mRp;7_4Pa<9QqpٜG{|UJ*$КoA>1 'TPlJ ^1Ɇ oVCcg8ї,4,M.ry3?M)+'z1 / G5Vl3Ҭ.(p(YkL.nhjV@VRT4L<|݂Ӏ}G8w9&& j'M& t+mK@>Cu2dk:jd#bnHOvj0hYz&~j2~V: Jkivg@(XzwItn־,\pđ0{i }ʞ|G: 8r9!!Epv^ nJ 5vt.ry9-<'xzm T'Qq{$rDUy⓬OVf:>9a쟃3 3Zx .KsBvE> t`3y45IlڮJ9)4Te0铧2c'YDf=AJ?0KLiIZ{Z Q1 s6}t( ou6|{y53 ZYȦ0Z"fy: mmqa:Aᷡa)j tPQ\zMv=r e8֧#})W-R'RMa-p^g}R G~ Ur}{пl¹4M+RVIv?ӮNzdfhG |bfVaQ w̽1W~cB'vX˕I x*aO`8pSyIRTv` Hpf!0:0δ VS?3JaWwrp endstream endobj 191 0 obj <> endobj 192 0 obj [193 0 R 194 0 R 195 0 R 196 0 R 197 0 R 198 0 R 199 0 R 200 0 R 201 0 R 202 0 R 203 0 R 204 0 R] endobj 193 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 1 | A workflow to genotype individual skin cells. a, Examples of\ healthy skin from which we genotyped individual cells. Left, skin from the back of a cadaver; right, skin surrounding a basal c\ ell carcinoma. b, Expression pr:161)/F 4/H/N/Rect[226.355 700.27 234.417 690.09]/Subtype/Link/Type/Annot>> endobj 194 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 1 | A workflow to genotype individual skin cells. a, Examples o\ f healthy skin from which we genotyped individual cells. Left, skin from the back of a cadaver; right, skin surrounding a basal \ cell carcinoma. b, Expression p:162)/F 4/H/N/Rect[284.843 571.27 292.562 561.09]/Subtype/Link/Type/Annot>> endobj 195 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:19. Talevich, E., Shain, A. H., Botton, T. & Bastian, B. C. CNVkit: genome-wide copy \ number detection and visualization from targeted DNA sequencing. PLOS Comput. Biol. 12, e1004873 \(2016\).\r:163)/F 4/H/N/Rect[209.341 227.27 213.742 217.09]/Subtype/Link/Type/Annot>> endobj 196 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:20. 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Genetics 155, 945 959 \(2000\).\r:166)/F 4/H/N/Rect[502.968 281.02 508.214 270.84]/Subtype/Link/Type/Annot>> endobj 200 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:46. Sudmant, P. H. etal. An integrated map of structural variation in 2,504 human gen\ omes. Nature 526, 75 81 \(2015\).\r:167)/F 4/H/N/Rect[481.621 248.77 487.661 238.59]/Subtype/Link/Type/Annot>> endobj 201 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:46. Sudmant, P. H. etal. An integrated map of structural variation in 2,504 human ge\ nomes. Nature 526, 75 81 \(2015\).\r:168)/F 4/H/N/Rect[497.917 162.77 503.669 152.59]/Subtype/Link/Type/Annot>> endobj 202 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:Fig. 1 | A workflow to genotype individual skin cells. a, Examples \ of healthy skin from which we genotyped individual cells. Left, skin from the back of a cadaver; right, skin surrounding a basal\ cell carcinoma. b, Expression :169)/F 4/H/N/Rect[362.704 130.52 371.377 120.34]/Subtype/Link/Type/Annot>> endobj 203 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:47. Dobin, A. etal. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29,\ 15 21 \(2013\).\r:170)/F 4/H/N/Rect[444.888 109.02 450.064 98.8399]/Subtype/Link/Type/Annot>> endobj 204 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:48. Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data w\ ith or without a reference genome. BMC Bioinformatics 12, 323 \(2011\).\r:171)/F 4/H/N/Rect[539.431 98.2704 545.305 88.0899]/Subtype/Link/Type/Annot>> endobj 205 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<>>> endobj 206 0 obj <>stream x]ݓq!xqڥM":dٖNt. wo_$ve fzfW_}cݏzwoWW_Q8%&8JW׫8N-*IיZsUZDY*7E':Zg*+е}0v<Gը=G}=*zLUx{].St7t-j4dCSәWy=,xQں?W#|k[ifonOr]4.r;l3t-bݲ+мУJyƖl5$[mobo3:g3|q O`X),ʈAuw9{>٨ߣb ǂ$T4@gsַ'u;Q&jJuvT41/±]«D|S3gD,~̦2;C=F2q;fVӛ]yVNvȺ= ~ 7˪[Vw`~Ikhڡ7\~6c]YRC>Gk.xޯ i54]% L fj4˛-IO莚,}ۿaϵO6U2MqEb\|HoբTufD#W1EFR.Z"Qw_^'lՁ9Lmfc,+^fv X9ES{P{nٍ'8@Q96'qQFW5hNW0MOLc}ך6mk!4].'_}8v7nF{7HOJ0{rUww';PL3?)کbJ&<NK2x')&+K(S5"9|`km3rpH qzSmhv(ՉFY0ym89ZdU3tLi q*^b r2%SUޮH_G.lpjH\@FzvFd4:f̏xU&pZk[p\'054IEUoeRJ4*A9.o. 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Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and disper\ sion for RNA-seq data with DESeq2. 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Petljak, M. etal. Characterizing mutational signatures in human cancer cell l\ ines reveals episodic APOBEC mutagenesis. 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Moderated estimation of fold change and dispe\ rsion for RNA-seq data with DESeq2. Genome Biol. 15, 550 \(2014\).\r:184)/F 4/H/N/Rect[496.632 474.52 502.111 464.34]/Subtype/Link/Type/Annot>> endobj 222 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:18. Petljak, M. etal. Characterizing mutational signatures in human cancer cell \ lines reveals episodic APOBEC mutagenesis. Cell 176, 1282 1294.e20 \(2019\).\r:185)/F 4/H/N/Rect[339.241 281.02 344.068 270.84]/Subtype/Link/Type/Annot>> endobj 223 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_2785.indd:18. Petljak, M. etal. Characterizing mutational signatures in human cancer cell\ lines reveals episodic APOBEC mutagenesis. 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