bioRxiv preprint doi: https://doi.org/10.1101/388611; this version posted August 12, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Genomic landscape and chronological reconstruction of driver events in multiple myeloma

Francesco Maura1,2,3*, Niccoló Bolli1,2,3*, Nicos Angelopoulos3, Kevin J. Dawson3, Daniel Leongamornlert3, Inigo Martincorena3, Thomas J. Mitchell3, Anthony Fullam3, Santiago Gonzalez4, Raphael Szalat5, Bernardo Rodriguez-Martin6, Mehmet Kemal Samur5, Dominik Glodzik3, Marco Roncador3, Mariateresa Fulciniti5, Yu Tzu Tai5, Stephane Minvielle7, Florence Magrangeas7, Philippe Moreau7, Paolo Corradini1,2, Kenneth C. Anderson5, Jose M. C. Tubio3,6, David C. Wedge8, Moritz Gerstung4, Herve Avet-Loiseau9, Nikhil Munshi5,10 # and Peter J. Campbell3 #

*These authors contributed equally to this work; # Co-corresponding authors

1 Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy 2 Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 3 The Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom 4 European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL- EBI) 5 Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA; 6 CIMUS - Molecular Medicine and Chronic Diseases Research Centre University of Santiago de Compostela, Spain 7 CRCINA, INSERM, CNRS, Université d’Angers, Université de Nantes, Nantes, France 8 University of Oxford, Big Data Institute 9 IUC-Oncopole, and CRCT INSERM U1037, 31100, Toulouse, France. 10 Veterans Administration Boston Healthcare System, West Roxbury, MA;

Running Title: Multiple Myeloma Driver Events

Key words: Multiple Myeloma, Whole Genome Sequencing, Driver Events, Structural Variations, Chromothripsis

Corresponding Authors:

Dr Peter J Campbell, Dr Nikhil C. Munshi Cancer Genome Project, Dana-Farber Cancer Institute Wellcome Sanger Institute, 450 Brookline Avenue, Dana B106 Hinxton CB10 1SA, Boston, MA 02215, USA United Kingdom. Phone: +1-617-632-4218 Phone: +44 1223 494745 Fax +1-617-582-8608 e-mail: [email protected] e-mail: [email protected]

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Abstract

Multiple myeloma (MM) has a heterogeneous genome, evolving through both

pre-clinical and post-diagnosis phases. Here, using sequences from 67 MM

genomes serially collected from 30 patients together with public datasets, we

establish a hierarchy of driver lesions. Point mutations, structural variants and copy

number aberrations define at least 7 genomic subgroups of MM, each with distinct

sets of co-operating driver mutations. Complex structural events are major drivers of

MM, including chromothripsis, chromoplexy and a replication-based mechanism of

templated insertions: these typically occur early. Hyperdiploidy also occurs early,

with individual chromosomes often gained in more than one chronological epoch of

MM evolution, showing a preferred order of acquisition. Positively selected point

mutations frequently occur in later phases of disease development, as do structural

variants involving MYC. Thus, initiating driver events of MM, drawn from a limited

repertoire of structural and numerical chromosomal changes, shape preferred

trajectories of subsequent evolution.

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The genome of multiple myeloma (MM) is complex and heterogeneous, with a

high frequency of structural variants (SVs) and copy-number abnormalities (CNAs)1-

3. Translocations between the immunoglobulin heavy chain (IGH) locus and

recurrent oncogenes are found in ~40% of patients. Cases without IGH

translocations often have a distinctive pattern of hyperdiploidy affecting odd-

numbered chromosomes, where the underlying target genes remain mysterious.

These SVs and recurrent CNAs are considered early drivers, being detectable also

in pre-malignant stages of the disease1,2,4. Cancer genes are also frequently altered

by driver point mutations, with MAPK and NF-κB signaling as major targets5-8.

Many blood cancers develop along preferred evolutionary trajectories. Early

driver events, drawn from a restricted set of possible events, differ in which

subsequent cancer genes confer clonal advantage, leading to considerable

substructures of co-operativity and mutual exclusivity among cancer genes. These

subtypes vary in chemosensitivity and survival, suggesting that although patients

share a common histological and clinical phenotype, the underlying biology is

distinctly heterogeneous. Preliminary studies have suggested that these patterns

exist in MM as well5,7,9-12, but have not yet been systematically defined in large

cohorts with broad sequencing coverage.

We performed whole genome sequencing (WGS) of 67 tumor samples

collected at different time points from 30 MM patients, together with matched

germline controls (Supplementary Fig. 1, Supplementary Table 1, Methods). We

also included in our analyses published whole exome data from 804 patients13,14. To

discover significant cancer genes, we analyzed the ratio of non-synonymous to

synonymous mutations, correcting for mutational spectrum and covariates of

mutation density across the genome using a published algorithm15,16. Overall, 55

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genes were significantly mutated with a false discovery rate of 1% (Fig. 1a,

Supplementary Table 2). A significant fraction of these driver mutations was

detected at subclonal level, suggesting a major role in late phases of cancer

development (Supplementary Fig. 2a). Beyond well-known myeloma genes such as

KRAS, NRAS, DIS3 and FAM46C5-8, several other interesting candidate genes

emerged. The linker histones HIST1H1B, HIST1H1D, HIST1H1E and HIST1H2BK

all showed a distinctive pattern of missense mutations clustered in the highly

conserved globular domain (Supplementary Figure 2b-e), as reported in follicular

lymphoma17. Many of the mutations were nearby, or directly affected, conserved

positively charged residues critical for nucleosome binding, suggesting that they

disrupt the histones’ role in regulating higher order chromatin structure. FUBP1, an

important regulator of MYC transcription18, showed an excess of splice site and

nonsense mutations, suggesting it may be a tumor suppressor gene in MM

(Supplementary Figure 2f). MAX, a DNA-binding partner of MYC, showed an

interesting pattern of start-lost mutations, nonsense and splice site mutations,

together with hotspot missense mutations at residues Arg35, Arg36 and Arg60,

known to abrogate DNA binding7 (Supplementary Fig. 2g). Genes with rather more

mysterious function were also significant: the zinc finger ZNF292, recently described

as mutated in chronic lymphocytic leukemia and diffuse large B-cell lymphoma19,20,

showed an excess of protein-truncating variants (Supplementary Fig. 2h); the

uncharacterized TBC1D29 gene showed two hotspots of missense mutations21

(Supplementary Fig. 2i).

In pairwise comparisons, these cancer genes showed distinct patterns of co-

mutation and mutual exclusivity (Supplementary Fig. 2j). To define the logic rules

underpinning the conditional dependencies of driver events, we employed Bayesian

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networks and the hierarchical Dirichlet process (Fig. 1b-c, Supplementary Fig. 3).

This confirmed that the strongest determinants of genomic substructure in myeloma

are IGH translocations and recurrent CNAs. Some co-operating genetic lesions were

non-randomly distributed across these main groups: a significant fraction of patients

without IGH translocations were generally enriched for 1q gain and deletions on

1p13, 1p32, 13q, TRAF3 and CYLD (Cluster 1). RAS signaling mutations, especially

NRAS and KRAS, were associated with hyperdiploidy and MYC translocations

(Cluster 2). A significant fraction (33%) of patients with t(11;14) were characterized

by low genomic complexity and high prevalence of IRF4 and CCDN1 mutations

(Cluster 3). Patients harboring TP53 bi-allelic inactivation were clustered in an

independent sub group (Cluster 4). A significant fraction of MMSET (51%) and

CCND1 (19%) translocated patients were characterized by multiple cytogenetic

aberrations, with low prevalence of CYLD/FAM46C deletions and TRAF3 deletion

respectively (Cluster 5). A second fraction of patients with MMSET translocation

(46%) were grouped with deletion of 13q14, gain of 1q21, DIS3 and FGFR3

mutations (Cluster 6); finally, patients with either MAF/MAFB translocations or no

IGH translocations was characterized by a high driver mutation rate (Cluster 7).

Thus, there is evidence for at least 7 distinct genomic subtypes of myeloma, each

with distinct combinations of driver mutations and recurrent SVs (Figure 1c).

Straightforward reciprocal translocations such as the canonical IGH-oncogene

translocations only accounted for 6% (127/2113) of SVs in the 67 samples from 30

patients studied by WGS (Figure 2a, Supplementary Fig. 4a-b). Other structural

variants included many unbalanced translocations and complex events

(Supplementary Fig. 4c-f, Methods)22. Most (24/30; 80%) patients had at least one

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complex SV, of which chromothripsis was the most frequent (11/30; 36%) (Fig. 2b-

c)22-26. Chromoplexy occurred in 3 patients (Fig. 2b, Supplementary Fig. 5a-c)22,27.

In 6/30 (20%) patients, we found a novel complex pattern characterized by

cycles of templated insertions. Here, several low-amplitude copy number gains on

different chromosomes were linked together through SVs demarcating the region of

duplication (Fig. 2b,d; Supplementary Fig. 5d-h). The most plausible explanation

for this pattern is that the templates are strung together into a single chain, hosted

within one of the chromosomes. We have observed such events in some solid

cancers22, where the copy number gains suggest a mutational process that is

replication-based, rather than the break-and-ligate processes generating

chromothripsis and chromoplexy23.

This complex landscape of SVs in myeloma often involved known driver

genes: MYC (14/30 cases; 46%), CCND1 (7/30; 23%) and MMSET (3/30; 10%) were

common targets (Supplementary Fig. 4b) of these non-canonical events. The

juxtaposition of CCND1 to the IGH locus was caused by either unbalanced

translocations or insertional events in 5/8 patients (Supplementary Fig. 6). Similarly,

MYC translocations showed unanticipated complexity, with four cases of templated

insertions involving MYC or its regulatory regions (Supplementary Fig. 7). Such

events are the structural basis of oncogene amplification observed by FISH in many

cases of t(11;14) and t(8;14)28,29. Interestingly, many of the MYC SVs involved the

immunoglobulin light chain loci, IGK or IGL, rather than the heavy chain IGH locus,

and were seen in patients with hyperdiploidy (Supplementary Fig. 4b). Although

sometimes occurring late, these events were under strong selective pressure: we

identified a striking case of convergent evolution where a subclone bearing an

IGL:MYC translocation was lost and one bearing an IGH:MYC was acquired at

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relapse (Supplementary Fig. 8). SVs also led to loss of tumor suppressor genes

such as BIRC2/3, CDKN2A/B, CDKN2C, TRAF330 and FAM46C, either within focal

deletions or more complex events. These data confirm that SVs, accessing both

simple and complex mechanisms of genome rearrangement, is a major force

shaping the myeloma genome.

In our cohort of serial WGS samples we could evaluate the temporal evolution

of the disease, integrating SVs, CNAs and point mutations. This included not only

defining clonal and subclonal mutations and CNAs, but also timing the relative order

of acquisition of clonal chromosomal gains, which we estimated with “molecular time”

analysis based on the fraction of duplicated to single-copy point mutations

(Methods)31.

Hyperdiploidy was found in 18/30 patients. Applying our “molecular time”

analysis, we found that chromosomal gains were not necessarily acquired

simultaneously (Fig. 3a). In 11/18 cases, we found evidence of several independent

gains over time, although the other 7 patients acquired all chromosome gains in a

much narrower time window (Fig. 3b). As might be expected if gains occur as

independent events, subclonal evolution within the myeloma cells between diagnosis

and relapse could lead to considerable diversification of chromosome complements.

In fact, we observed significant karyotype changes within the same patient over time,

including loss of some trisomies in hyperdiploid patients (Supplementary Fig. 9a-

b)32. At the extreme end of this cytogenetic dynamism, we found 4 patients acquiring

a whole genome duplication at relapse, suggesting its potential role in

relapsed/refractory stages (Supplementary Fig. 9c-g).

By pairwise comparison of the relative timings of copy number alterations we

reconstructed the preferred chronological order of CNAs acquisition (Methods).

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Gains of chromosomes 19, 11, 9 and 1q were amongst the earliest in our series

(Fig. 3c) and recurrent chromosome losses were generally acquired later than

trisomies, consistent with the proposition that hyperdiploidy is an early driver event in

MM.

Translocations involving CCND1 and MMSET were always fully clonal,

similarly confirming their early driver role in MM pathogenesis. Most chromothripsis

events were clonal and conserved during evolution (17/22; 77%), suggesting they

occurred early in MM pathogenesis. However, a small fraction of patients showed

some evidence of subclonal or late chromothripsis (5/22; 23%), implying a potential

involvement in drug resistance and late cancer progression (Supplementary Fig.

9h).

We integrated all extracted chronological data on SVs, hyperdiploidy and

point mutations to generate phylogenetic trees for each sample (Methods and

Supplementary Fig. 10)5,33. The methodology is worked through for one illustrative

patient carrying i) several chromosome gains, ii) 3 separate chromothripsis events

and iii) a whole genome duplication (Fig. 3d-f). One chromothripsis involved

chromosomes 8 and 15, duplicating the long arm of chromosome 15. Because few

mutations were present on chromosome 15 at the time it duplicated, this must have

occurred early in molecular time (Fig. 3e). Gain of chromosome 3 and copy-neutral

loss-of-heterozygosity of small arm of chromosome 1 (chr1p) occurred not long after,

and were followed by a second chromosomal crisis involving chromosomes 3, 5, 13

and 22. This chromothripsis must have occurred in one of the two duplicated alleles

of chromosome 3 (and therefore after the acquisition of a chromosome 3 trisomy)

because losses within the chromothripsis region had copy number 2 and SNPs were

heterozygous. Within the same time window, a separate chromothripsis event

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occurred on chr1p after copy-neutral loss-of-heterozygosity. Finally, this patient

underwent whole genome duplication after two therapy lines (Supplementary Fig.

9f).

Applying this approach to all patients, we observed that the trunks of the

phylogenetic trees of 29/30 (97%) patients were characterized by few genomic

events generally acquired during different time windows of the MM life history before

emergence of the most recent common ancestor (Fig. 4). Overall, chromothripsis,

cycles of templated insertions, chromosomal gains and other SVs accounted for

most of the earliest events, emerging as key early drivers of the disease and paving

the way for subsequent driver mutations that would confer further selective

advantage to the clone.

Taken together, these data suggest that MM development follows preferred

evolutionary trajectories, with stuttering accumulation of driver events in keeping with

its insidiously progressive but unpredictable clinical course. Critical early events

include immunoglobulin translocation with MMSET and CCND1; hyperdiploidy and

focal complex structural variation processes hitting key myeloma genes. These early

driver mutations shape the subsequent evolution of myeloma, each with preferred

sets of co-operating cancer genes.

Acknowledgements:

FM is supported by A.I.L. (Associazione Italiana Contro le Leucemie-Linfomi e

Mieloma ONLUS) and by S.I.E.S. (Società Italiana di Ematologia Sperimentale).

NB is funded by AIRC (Associazione Italiana per la Ricerca sul Cancro) through a

MFAG (n.17658).

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This work was supported by: Department of Veterans Affairs Merit Review Award

I01BX001584-01 (NCM), NIH grants P01-155258 (N.C.M., H.A.L., M.F., P.J.C., K.

C.A.) and 5P50CA100707-13 (N.C.M., H.A.L., K.C.A).

Authorship Contributions:

F.M., N.B., and P.J.C. designed the study, collected and analyzed the data and

wrote the paper; H.A.L., N.C.M. designed the study and collected the data; K.J.D.,

D.L., N.A., I.M., T.J.M., A.F., D.G., S.G., M.G., M.R., F.A., B.R.M., J.M.C.T. and

D.W. analyzed the data; S.M., R.S., M.K.S., M.F., Y.T.T., M.F., P.M., P.C., K.C.A.,

collected the data.

Disclosure of Conflicts of Interest:

No conflict of interests to declare.

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Figure Legend

Figure 1. a) Landscape of Driver Mutations in Multiple Myeloma (MM). Each bar

represents a distinct driver gene and each bar’s colour indicate its prevalence across

the main MM cytogenetic sub-groups. b) We built the optimal Bayesian network by

considering the recurrent SVs/ CNAs (n 14) and driver SNVs (n 55) across 724 MM

patients where the final list of 69 variables was assessed. To further investigate the

type of recurrence patterns we fitted logic gates between parent and child nodes in

the network. The gate combination with the highest Fisher exact test p value was

selected. The line width is proportional to the log hazard ratio of the test. Dashed

lines represent non-significant associations (p>0.05). CNAs and translocations were

coloured by red and light blue respectively. The width of the boundary line of each

drawn box is proportional to its prevalence across the entire series. c) Heat map

showing the main MM genomic subgroups across 724 MM patients. The genomic

profile of each cluster was generated by integrating the hierarchical Dirichlet process

and Bayesian network data. Rows in the graph represent individual genomic lesions,

and the columns represent patients.

Figure 2. a) SVs prevalence across the entire series. b) Heatmap representing the

distribution and prevalence of the main complex SVs: chromothripsis, chromoplexy

and templated insertion. c) Three examples of chromothripsis. d) Example of

templated insertion. In the middle, the genome plot of patient PD26422 represents all

main genomic events: mutations (external circle), indels (middle circle; dark green

and brown lines represent insertion and deletion respectively), copy number variants

(red = deletions, green = gain) and rearrangements (blue = inversion, red =

deletions, green = ITD, black = translocation). Externally, a copy

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number/rearrangement plot of each chromosome involved by the templated insertion

is provided, highlighting a focal CNA around each breakpoint. This case represents a

clear example of how templated insertion may involve critical driver oncogenes, like

CCND1 in this case. A schematic representation of this sample templated insertion is

reported on the right.

Figure 3. a-b) Molecular time estimation on all chromosomal gains observed in 2

hyperdiploid MMs. On the left the copy number profile is reported, where gold line =

total copy number, grey = copy number of the minor allele. The presence of more

than 1 cytogenetic segment is compatible with the existence of a subclonal CNA

whose CCF is proportional to the segment thickness [see for example the gain on 4q

in PD26410d (a)]. On the right, the molecular time (blue dots) estimated for each

clonal gain and copy neutral loss of heterozygosity (Methods). Red dots represent

the molecular time of a second extra gain occurred on a previous one. Dashed green

lines separate multi gain events occurring at different time windows c) Bradley Terry

model based on the integration between the CCF and molecular time of each

recurrent MM CNAs (gains and deletions). Segments were ordered from the earliest

(top) to the latest (bottom) occurring in relative time from sampling (X-axis). d)

Genome plot of patient PD26419a where the three chromothripsis events [(8;15),

(3;5;13;22) and 1p] were highlighted with different colored dashed lines connected to

specific rearrangements/copy number plots. In these plots, the red arch represents a

deletion, the green arch represents an ITD and the blue arch represents an

inversion. e) Molecular time of the main clonal gains and LOH in the PD26419a

sample. This data suggested the existence of at least 2 different and independent

time windows: the first involving alterations on chromosome 3, 15 and 1p and the

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second on chromosome 1q. f) The driver events of patient PD26419 are

reconstructed in chronological order.

Figure 4. The most likely phylogenetic trees generated from the Dirichlet process

analysis (Methods). The root (always colored in red) and branch length is

proportional to the (sub)clone mutational load. All main drivers (CNAs, SNVs and

SVs) were annotated according to their chronological occurrence. Early clonal

events (root), where it was possible to establish a specific time window, were

chronologically annotated on the right. All different “root” time windows were

separated by a green line; conversely, early drivers without a clear timing were

grouped together on the left of the root. All driver events that occurred in the root

were reported with larger font size. Patients were grouped according to the genomic

clustering showed in Figure 1c. Templated insertion is abbreviated with TI.

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References

1 Corre, J., Munshi, N. & Avet-Loiseau, H. Genetics of multiple myeloma: another heterogeneity level? Blood 125, 1870-1876, doi:10.1182/blood-2014- 10-567370 (2015).

2 Manier, S. et al. Genomic complexity of multiple myeloma and its clinical implications. Nat Rev Clin Oncol 14, 100-113, doi:10.1038/nrclinonc.2016.122 (2017).

3 Morgan, G. J., Walker, B. A. & Davies, F. E. The genetic architecture of multiple myeloma. Nat Rev Cancer 12, 335-348, doi:10.1038/nrc3257 (2012).

4 Walker, B. A. et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun 6, 6997, doi:10.1038/ncomms7997 (2015).

5 Bolli, N. et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun 5, 2997, doi:10.1038/ncomms3997 (2014).

6 Chapman, M. A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467-472, doi:10.1038/nature09837 (2011).

7 Lohr, J. G. et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 25, 91-101, doi:10.1016/j.ccr.2013.12.015 (2014).

8 Walker, B. A. et al. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma. J Clin Oncol 33, 3911-3920, doi:10.1200/JCO.2014.59.1503 (2015).

9 Bolli, N. et al. Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups. Leukemia, doi:10.1038/leu.2017.344 (2017).

10 Keats, J. J. et al. Clonal competition with alternating dominance in multiple myeloma. Blood 120, 1067-1076, doi:10.1182/blood-2012-01-405985 (2012).

11 Magrangeas, F. et al. Minor clone provides a reservoir for relapse in multiple myeloma. Leukemia 27, 473-481, doi:10.1038/leu.2012.226 (2013).

14 bioRxiv preprint doi: https://doi.org/10.1101/388611; this version posted August 12, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

12 Walker, B. A. et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia 28, 384-390, doi:10.1038/leu.2013.199 (2014).

13 Maura, F. et al. Biological and prognostic impact of APOBEC-induced mutations in the spectrum of plasma cell dyscrasias and multiple myeloma cell lines. Leukemia, doi:10.1038/leu.2017.345 (2017).

14 Miller, A. et al. High somatic mutation and neoantigen burden are correlated with decreased progression-free survival in multiple myeloma. Blood Cancer J 7, e612, doi:10.1038/bcj.2017.94 (2017).

15 Martincorena, I. & Campbell, P. J. Somatic mutation in cancer and normal cells. Science 349, 1483-1489, doi:10.1126/science.aab4082 (2015).

16 Martincorena, I. et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880-886, doi:10.1126/science.aaa6806 (2015).

17 Krysiak, K. et al. Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma. Blood 129, 473-483, doi:10.1182/blood-2016-07-729954 (2017).

18 Seiler, M. et al. Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types. Cell Rep 23, 282- 296 e284, doi:10.1016/j.celrep.2018.01.088 (2018).

19 Puente, X. S. et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519-524, doi:10.1038/nature14666 (2015).

20 Reddy, A. et al. Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell 171, 481-494 e415, doi:10.1016/j.cell.2017.09.027 (2017).

21 Hoang, P. H. et al. Whole-genome sequencing of multiple myeloma reveals oncogenic pathways are targeted somatically through multiple mechanisms. Leukemia, doi:10.1038/s41375-018-0103-3 (2018).

22 Li Y, R. N., Weischenfeldt j, Wala JA, Shapira O, Schumacher SE, Khurana W, & Korbel J, I. M., Beroukhim R, Campbell PJon behalf of the PCAWG- Structural Variation Working Group ^ and the PCAWG Network. Patterns of structural variation in human cancer. bioRxiv, doi:http://dx.doi.org/10.1101/181339. (2017).

15 bioRxiv preprint doi: https://doi.org/10.1101/388611; this version posted August 12, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

23 Korbel, J. O. & Campbell, P. J. Criteria for inference of chromothripsis in cancer genomes. Cell 152, 1226-1236, doi:10.1016/j.cell.2013.02.023 (2013).

24 Li, Y. et al. Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature 508, 98-102, doi:10.1038/nature13115 (2014).

25 Maciejowski, J., Li, Y., Bosco, N., Campbell, P. J. & de Lange, T. Chromothripsis and Kataegis Induced by Telomere Crisis. Cell 163, 1641- 1654, doi:10.1016/j.cell.2015.11.054 (2015).

26 Magrangeas, F., Avet-Loiseau, H., Munshi, N. C. & Minvielle, S. Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients. Blood 118, 675-678, doi:10.1182/blood- 2011-03-344069 (2011).

27 Korde, N. et al. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol 1, 746-754, doi:10.1001/jamaoncol.2015.2010 (2015).

28 Affer, M. et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia 28, 1725-1735, doi:10.1038/leu.2014.70 (2014).

29 Fabris, S. et al. Characterization of oncogene dysregulation in multiple myeloma by combined FISH and DNA microarray analyses. Genes Chromosomes Cancer 42, 117-127, doi:10.1002/gcc.20123 (2005).

30 Chavan, S. S. et al. Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker. Blood Cancer J 7, e535, doi:10.1038/bcj.2017.12 (2017).

31 Gerstung, G. et al. The evolutionary history of 2,658 cancers. bioRxiv, doi:http://dx.doi.org/10.1101/161562. (2018).

32 Rasche, L. et al. Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. Nat Commun 8, 268, doi:10.1038/s41467-017- 00296-y (2017).

33 Nik-Zainal, S. et al. The life history of 21 breast cancers. Cell 149, 994-1007, doi:10.1016/j.cell.2012.04.023 (2012).

16 bioRxiv preprint doi: https://doi.org/10.1101/388611; this version posted August 12, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

34 Walker, B. A. et al. Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells. Blood 121, 3413-3419, doi:10.1182/blood-2012-12-471888 (2013).

17 bioRxiv preprint doi: https://doi.org/10.1101/388611; this version posted August 12, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

a b Fisher test odds Hyperdiploid CCND1 ACTG1 BCL7AMut.excl (shownBHLHE41 odds=0.25) BTG1 Co-occur (shown odds=4) 150 t(11;14) 0.05 < q.val t(14;16) # events (shown med=15,max=382) t(14;20) t_11_14 AND gate t(4;14) OR gate None XOR gate NOT gate

analysed) NFKBIA 100 (of 834

delTRAF3 t_14_16 50

TRAF3 Number of of patients Number

0 HIST1H1B delCYLD HDR EGR1

LTB RB1 DIS3 MAX IRF4 PIM1 IRF1 BRAF TP53 CYLD BTG1 POT1 DTX1 RPL5 XBP1 KRAS NRAS IGLL5 EGR1 SP140 TGDS TRAF3 ACTG1 FGFR3 KLHL6 SETD2 NFKB2 RPL10 TCL1A TRAF2RFTN1 BCL7A RPS3A FUBP1 RASA2 LCE1D DUSP2 PRKD2 KMT2B PRDM1 CCND1 ZNF292 NFKBIA FAM46C PABPC1 PTPN11 CDKN1BRPRD1B SAMHD1 TBC1D29 BHLHE41 HIST1H1E HIST1H1B HIST1H1D HIST1H2BK MAX ampMYC c del17p13 CYLD t_4_14 RPRD1B cluster cluster cluster HyperdiploidHyperdiploid t.11.14.t.11.14. t.4.14.Hyperdiploidt.4.14. t.14.16.t.14.16. t.14.20.t.14.20. ampMYCampMYC TP53 KRAS delCDKN2C FGFR3 del13q14t.11.14.del13q14 del17p13del17p13 delCDKN2CdelCDKN2C delCYLDdelCYLD delFAM46Ct.4.14.delFAM46C delTRAF2delTRAF2 delTRAF3delTRAF3 gain1q21t.14.16.gain1q21 del13q14 FUBP1 KRASKRAS NRASNRAS IGLL5IGLL5 DIS3t.14.20.DIS3 BRAFBRAF TRAF3TRAF3 TP53ampMYCTP53 FAM46CFAM46C DIS3 NRAS TCL1A HIST1H1E BRAF delFAM46C DUSP2DUSP2 ACTG1ACTG1 HIST1H1Edel13q14HIST1H1E KLHL6KLHL6 CYLDCYLD CCND1CCND1 IRF4del17p13IRF4 gain1q21 PABPC1PABPC1 PIM1PIM1 TCL1AdelCDKN2CTCL1A FGFR3FGFR3 SP140SP140 PRDM1PRDM1 SETD2delCYLDSETD2 TRAF2TRAF2 SAMHD1 TGDS RPS3A XBP1 IRF4 NFKB2NFKB2 RB1delFAM46CRB1 BTG1BTG1 RFTN1RFTN1 1.4 TBC1D29TBC1D29 wt HIST1H1BdelTRAF2HIST1H1B Cluster 1 RASA2RASA2 KMT2B CNA/SV DTX1DTX1 Cluster 2 HIST1H2BKHIST1H2BK Missense HIST1H1DdelTRAF3HIST1H1D Cluster 3 BCL7ABCL7A Nonsense FUBP1FUBP1 Cluster 4 CDKN1Bgain1q21CDKN1B Stop/Loss XBP1XBP1 Cluster 5 RPL5RPL5 PTPN11 IGLL5 Essential Splice LCE1DLCE1D Cluster 6 RPRD1BKRASRPRD1B BHLHE41BHLHE41 Cluster 7 POT1POT1 1.4 RPS3ANRASRPS3A IRF1IRF1 TGDSTGDS wt Cluster 1 RPL10RPL10 ZNF292IGLL5ZNF292 CNA/SV Cluster 2 PTPN11PTPN11 NFKBIANFKBIA Missense Cluster 3 SAMHD1SAMHD1

1.2 Nonsense Cluster 4 KMT2BDIS3KMT2B LTBLTB Stop/Loss Cluster 5 PRKD2PRKD2 RB1 EGR1BRAFEGR1 Essential Splice Cluster 6 MAXMAX Cluster 7 TRAF3 TP53 FAM46C 1.2 DUSP2 ACTG1

1 ● 1.0 HIST1H1E KLHL6 CYLD CCND1

1 ● 1.0 IRF4 PABPC1

0.8 PIM1 TCL1A FGFR3 SP140

0.8 PRDM1 SETD2 TRAF2 0.6 NFKB2 0.6 0.8 RB11.0 1.2 1.4 IndexBTG1 RFTN1 0.6 TBC1D29

0.6 HIST1H1B 0.8 1.0 1.2 1.4 RASA2 Index DTX1 HIST1H2BK HIST1H1D BCL7A FUBP1 CDKN1B XBP1 RPL5 LCE1D RPRD1B BHLHE41 POT1 RPS3A IRF1 TGDS RPL10 ZNF292 PTPN11 NFKBIA SAMHD1 KMT2B LTB PRKD2 EGR1 MAX a c Number of SVs 100 120 140 100 120 140 20 40 60 80 20 40 60 80

Copy number Copy number 0 Copy number 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0 1 2 3 4 5 6 7 bioRxiv preprint 0 0 0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 19 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Translocation ITD Inversion Deletion ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 19 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Translocation ITD Inversion Deletion ● ● ● ● ● ● ● ● ● ●

● PD26400a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26400c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26401a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26401c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26400a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26402a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 10 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26402c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26400c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26403a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26403c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26401a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26403d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 20 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ● PD26404a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● doi: ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26404c ● ● ● ●

● PD26401c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 50 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26405a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26405c ● ● ● ● ● ● ● ● ● ● certified bypeerreview)istheauthor/funder.Allrightsreserved.Noreuseallowedwithoutpermission. ● ● ● ● ● ● ● ● ● ● ● ●

● PD26402a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 20 ● ● https://doi.org/10.1101/388611 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26406a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26406c ● ● ● ● ● ● ● ● ● ● ● ● ● 8 ● ● ● ● ● ● ● ● ● ● ●

● PD26402c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26408a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 14 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26408c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 21 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Chr ● ● ● ● ● ● ● ● ● PD26425e PD26414a PD26424a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26403a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Chr Chr ● ● ● ● ● 8 8 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26409a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● chr19 position (Mb) chr17 position(Mb) ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● chr6 position(Mb) ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26409c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26425e PD26414e PD26424a ● PD26403c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 17 (Mb)17 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26410d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 9 (Mb)9 6 (Mb)6 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 40 ● ● ● ● PD26411a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26403d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 30 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26411c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26411d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 21 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26404a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26412a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26412c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 100 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26412d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26404c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26414a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26414b ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26405a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26414e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26414f ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 40 ● ● ● ● ● ● ● ● ●

● PD26414g ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26405c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26415c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26415g ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26406a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 60 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26416d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26416e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26406c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26418a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26418c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26418d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26408a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ; ● ● ●

● PD26418e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 50 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● this versionpostedAugust12,2018. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26419a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26408c ● ● ● ● ● ● ● ● ● ● ● ● ● ● 150 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26419c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26419d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26409a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26420a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26420c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26409c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26422d ● ● ● ● ● ● 14 14 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26422e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 80 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26422f ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 14 ● ● ● ● ● 14 14 ● ● ● ● ● ● ● ● ● PD26410d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26423e PD26423g PD26411a PD26423h PD26424a PD26411c PD26424c PD26425e PD26411d PD26425f PD26426e PD26412a PD26427a PD26427c PD26412c PD26428a PD26428c

Copy number PD26412dCopy number d PD26429a PD26432c 0 1 2 3 4 PD26414a0 1 2 3 4 PD26432e 0 0 PD26434c PD26414b PD26435c PD26435e PD26414e Templated

● PD26414f The copyrightholderforthispreprint(whichwasnot ● 20 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 20 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● b ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26414g● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

Copy number ● Copy number ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26415c● ● ● ● ● ● ● ● ● ● ● ● ● ● Chromothripsis ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26415g ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Chromoplexy ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 40 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Chr Chr ● ● ● ● 40 ● ● ● ● ● ● ● ● ● ● ● ● ● Complex SV ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26416d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● chr14 position(Mb) ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● chr15 position(Mb) ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26422e ● ● ● 20 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26420c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26416e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 14 (Mb) 15 (Mb) ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 10 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26418a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Insertion ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 60 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26418c● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 1 ● ● ● ● 60 ● ● 20 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 22 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 40 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26418d● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26418e● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 20 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Chr ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Chr ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● chr12 position(Mb) chr22 position(Mb) ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 80 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26419a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 60 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 12 ● ● ● ● ● ● 14 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26422e PD26422e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 22 (Mb) ● ● ● ● ● 80 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 12 (Mb) ● ● ● ● Chromoplexy Cyclo_Temp_more_chr Chromotripsis Other Complex ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26419c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26419d● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 30 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 80 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 100 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26420a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26429a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26425f ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 1 ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 11 ● ● ● ● ● ● ● ● ● ● ● ● ● 100 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26420c● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26435e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 11 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26435c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26422d ● ● ● PD26400c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 1 0 1 1 ● ● 100 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26400a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 1 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 40 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26401a ● ● ● ● ● ● ● PD26422e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26401c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26425e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26422f ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26419d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 120 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26411a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 1 1 1 ●

● PD26423e ● ● ● ● ● ● ● 15 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26411c ● ● ● ● ● ● ● ● ● ● ● ● ● ● 22 ● ● ● ● ● ● ● ● 0 1 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26411d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 1 1 1 ● ● ● ● ● ● ● ● ● ● ●

● PD26423g ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 50 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26408a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26408c 0 0 1 1 PD26423h PD26422e PD26422d 0 2 0 1 Copy number PD26422e PD26424a 0 2 0 1 PD26422f 0 1 2 3 4 Copy number 0 2 0 1 PD26423g 0 0 1 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26424c ● ● 0 1 2 3 4 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26423h ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 1 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26404a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26425e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26404c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26410d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26425f ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26419a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26419c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 20 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26426e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26405a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● 50 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26405c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26427a ● ● ● ● ● ● ● ● ● ● ● ● ● PD26420a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26420c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26424a ● ● ● ● ● ●

● PD26427c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26424c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 40 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26409a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26428a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 1 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26409c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 1 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 100 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26416d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Chr ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26428c ● ● 0 1 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● chr1 position(Mb) ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26423e ● ● ● ● ● Chr ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 1 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26422e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● chr11 position(Mb) ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26432c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 1 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26429a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 60 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26422e ● ● 1 (Mb) ● PD26432e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 1 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 11 (Mb) ● ● ● ● ● ● ● ● PD26416e ● ● ● ● ● ● ● ● ● ● ● ● ● 14 ● ● ● 1 1 0 2 ● ● ● ● ● ● ● ● ● ● ●

● PD26432c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26403d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 1 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 14 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26403a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

PD26432e ● ● ● ● ● ● ● ● ● ● ● ● ● ● 150 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 14 ● ● ● PD26403c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 80 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26415c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 14 ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26434c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26415g ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26418a ● ● ● ● ● ● ● ● ● ● ●

● ● Chr ● ● ● ● ● ● ● ● ● ●

● Chr ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● PD26435c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26418c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26418d ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● 15 ● ● ● ● ● ● ●

● 22 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26435e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 100 ● ● ● ● ● ● PD26418e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 200 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26427a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26427c ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● X ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26414a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● X ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26414b ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26414e ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 120 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26414f ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26414g ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 1 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26426e ● ● ● ● ● ●

● ● Chr ● ●

● Chr ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 1 0 1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26402a ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 0 0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PD26402c

0 0 0 0

12 14 PD26406a 0 0 0 0 PD26406c 0 0 0 0 IGH PD26407a 0 0 0 0

PD26407c Chr 0 0 0 0 PD26412a 0 0 0 0 PD26412c

0 0 0 0 1 PD26412d 0 0 0 0 PD26428a 0 0 0 0

PD26428c Chr 0 0 0 0 PD26434c 0 0 0 0

CCND1 11 bioRxiv preprint doi: https://doi.org/10.1101/388611; this version posted August 12, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

a c PD26410d - Molecular Time PD26410d Late PD26410d 19 gain ● n=14 5 1q gain ● n=12 4 9 gain ● n=14 3 2nd MG ● ● 2 ● ● 11 gain n=10 Ploidy 1 ● ● 1st MG ● Early ● 15 gain n=12 ● 0 ● 5 gain ● n=10 b 3 gain ● n=13 ● n=4

chr3 gain chr5 gain chr7 gain chr8 gain chr9 gain 21 gain chr11 gain chr21 gain 7 gain ● n=10 PD26404aPD26404a - Molecular Time PD26404a 16 del ● n=5 5 Late 13 del ● n=11 4 3 6q del ● n=5 2 14 del ● n=8 ● Ploidy ● ● ● ● 1st MG 1 ● 1p del ● n=6 0 Early 17p del ● n=2 −2 0 Relative2 4Order 6Time 8 10 chr3 gain chr5 gain chr7 gain chr11 gain chr19 gain chr10 LOH d PD26419a PD26419a 3

5 7 4 6 ● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ●●● ● ●● ●● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ●●● ● ● ●● ●●● ●●●● ● ●●● ●●● ● ● ●●●●● ● ● ● ● ●●●●●● ●●● ● ● ●●●●●● ●●●●● ●● ● ●●● ● ● ●●● ● ●●●●● ●●●● ●●● ●● 5 ● ●●●●● ●●●●●●●●●●● ●●●●●●●●●● ●●●●●●● ● ●●●●● ● ●● ●●●●●●● ● ●●●●●●● ● ●● ●●●●●● ●●●● ● ●●● ● ●●●● ● ●●●●●●●●●● ●●●●●● ● ● ●●● ● ●●● ● ●● ●●●●● ●●●●● ●●●●●●●●● ●●●●●●● ● ●●●●●●●●● ●● ●● ● ●●● ●●●●● ●●●●●●●●●●● ●●●●●●●●●● ●●●● ●●●● ●●●●●●●● ●●●● ●●●●●● ●● ● ● ●●●●●●●●● ●● ●● ●● ●●●● ● ● ● ●●●●●●●●●●●●●●●●● ●● ●●●●●●●●● ● ●●●● ●●● ●●● ● ●●●● ●●●●●●●●●●●●●●●● ●●●●●●●●● ● ●●●●●●●●●●● ●● ●● ●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●●●●●●●● ●● ● ●●●●●●●●● ●●●●●●● ●●●●●●●●●●●●●●●●●●●●●●● ●●●●●●●●●●●●●●● ● ●●● ●●● ●●●●●●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●●● ● ● ● ● ●●●● ●● ● ●●●●●● ●●●●●●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●● 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●●●●●● ● ●● ● ●● ●●●● ● ● ● ● ● ● ● ●● ● ● ● ●●● ●●● ● ● ● ● ● ● ●●● ●● ●●●●● ● ● ● ●● ● ● ●● ● ● ●●●● ● ●●●●● ●● ●●●●● ●●● ●● ● ● ●●● ● ● ●● ●● 4 ● ● ● ● ● ● ● ● ● ● ●●● ● ●●● ● ● ● ●●● ● ●● ●● ● ● ● ●● ●● ●● ●● ● ● ● ● ● ● ●●● ●● ● ● ●●● ●●● ● ● ● ●●●● ● ● ●● ●●●●●● ● ●●●●●●●●●● ●● ● ● ● ●● ●●● ●●● ● ● ● ● ●●● ● ● ● ●●● ● ● ● ●● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ● ●● ● ● ● ●● ● ●● ● ●● ● ● ●●● ● ● ● ●● ● ●● ● ● ● ● 2 ● ● ● ● ● ●●●●●●●●●●●●● ●● ●●●● ●●● ● ●●● ●●● ●●● ●●●●●●●● ●● ●●● ●●●●●●●● ●●● ● ●● ● ● ● ● ●● ● ● ● ● ● ●●● ● ●● ● ● ● ● ● ● ● ● ●● ● 3 ● ●● ●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ● ●●●●●●●●●● ●●●●●●●● ●●●●● ●●●●●●●● ●● ●●●●● ●● ●● ● ●● ●● ●●● ●● ● ● ● ●● ● ● ●●●● ● ●● ●● ● ● ●●●●●● ●● ●●● ●●●● ●● ● ● ● ● ●● ● ● ● ● ● ● ●●●● ● ●● ●● ●●●●●●●●●● ●●●● ●●●●● ●●●●●●●●●● ●●●●●●●●●●●●●● ● ●●●●●●●●●●●●●●●●●●● ● ●● ●●●●●● ●●●●●●● ●●● ● ●●● ● ● ●●● ●● ●●●●●● ●●●● ● ●●● ● ● ●●● ●●● ●● ●● ● ●● ●●●● ● ●● ●●●●● ● 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● ● ● ● ●● ●● ●●●● ●●●● ● ● ●● ● ●●●●●● ●●●● ●●● ●●● ●● ● ●● ●● ● ●● ● ● ●● ●● ●● ● ●● ●●●● ●● ●● ● ●● ● ● ● ● ●● ● ●●●●●● ● ● ● ●●●●● ●● ● ● ●●●●●●●●●●●●●●●●● ●● ●●●●●●●●●●●●●●●●●● ●●●●● ●●●●●●●●● ●●●●●● ●●●●●● ●●●●●●●●●●●●●●●●●●●●● ●●● ●●●●●●●●●●●●●●●●●●●●●●●●●● ●●●●●●●●●●● ●●● ●●●●●● ● ●●●●● ●●●●●●●● ●●●●●● ●●●●●●●●●●●●●● ●●● ●●● ●●●●●● ●●●●●●●●●●●● ● ● ● ● ●●● ●● ●● ● ● ●●●●● ● ●●●●●●● ● ●●● ●● ●●● ●●●●●● ●●●●●●● ●●●●● ●● ●● ● ● ● ●●●●● ● ●●● ●●● ●●●●●●●●●●●● ●●● ●● ● ●●●●● ● ● ● ● ● ● ● ● ●● ● ● ●● ●●● ● ●●●● ●●●●●●●●● ●●●●●●●●●●●●● ●●●●●●●●● ●●●●●●●● ●●●●●● ●●● ●● ●● ●●●●● ●●● ●●●●● ● ● ● ●●● ●● ● ● ● ● ● ● ●●●● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●●●●● ● ● ●● ●●●● ● ●●●● ● ●● ●● ● ●●● ● ● ●●●● ●● ●●● ● ●●●●● ● ●● ● ●● ● ● ●●● ● ● ●● ● ● ●● ● ● ● ● ●● ●●● ● ● ● 2 ● ● ● ● ● ●● ● ● ● ●● ● ● ●●●● ● ● ●● 1 ● ● ● ●●●●●●●●●● ●●●● ●●●●●● ● ● ●● ●●●●●●●●●●●●●●● ●●●●●●●● ●● ● ● ● ●●● ●●●●●●●●●●●●●●●●●●● ● ● ● ●● ● ● ● ● ●●●●●●● ● ● ● ●● ● ● ● ●● ●● ●● 1 ● ● ● ● PD26419a ● ●● 0 ● ● ● ● 0 ●

0 10 20 30 40 50 0 50 100 150 200 Chrchr2222 position (Mb) (Mb) chr1 position (Mb) PD26419a ChrPD26419a1 (Mb) 8 8 8 8 8 13 2 8 888 8 8 8 8 2213 2

6 6 5 5 ● ● ●●●● ● ● ●● ● ● ● ● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●●●●● ● ● ● ● ●● ● ● 4 ● ● ● ●●●● ●●●●●● ● ● ●●● ●● ●●●● ● ●● ●●● ● ● ● ●●● ● ● ● ● ● ● ●●●●●● ● ●● ●● ● ● ● ● ● ●●● ● ●● ●● ● ● ●●●● ●●●●●● ● ●●● ●● ●●● ● ●● ● ● ● ●● ● ●●● ● ● ● ● ●● ●●● ●● ● ●● ●● ● 4 ● ● ● ●● ●● ● ● ● ● ● ●●●● ● ● ● ● ● ●●● ●● ● ●● ●● ● ● ●●● ● ● ●● ● ● ● ●● ● ● ● ● ● ●●● ●● ● ● ● ●● ●●● ● ● ● ● ●●● ● ●● ● ● ● ● ●●● ● ● ●●● ● ● ● ●● ●● ● ●● ● ●● ● ● ● ●●● ●●● ● ● ●●●● ● ● ● ● ●●●●● ● ● ●● ●●● ● ● ● ● ● ● ● ●● ● ● ● ●●● ● ● ●●●●●●●● ● ● ● ●●● ●● ●●●●●●● ●●● ● ●● ●● ●●●● ●● ● ● ● ● ● ● ●●●●● ●● ●●● ●●●●●●●● ●● ● ●●●●●● ● ● ●●●● ●●●●●● ● ●●● ●●● ●●● ● ●●●●●●●●●● ● ●● ● ●●●●● ●●●●●●●●●●●● ●● ● ●●●●●●● ●●●● ●● ● ●●● ● ●●●●●●● ●●●● ●●● ● ●● ●●●● ●●● ●●●●●●●●● ●●●●●●●● ●●●●●●● ●● ● ●●●● ●●● ● ● ●●● ● ● ●● ●●● ●● ● ●●●● ● ●● ● ● ● ●●●●●●● ●● ● ●●● ●●●● ●●● ●●●●● ●●●●●●●●●●● ●●●● ● ●●●●●●●●● ●●● ●●●●●●●●●● ● ●● ●● ●●●●●●●●●●● ●●●●●●●●●● ●● ● ●●●●●● ●●● ●●●● ●●● ●● ● ●● ● ● Copy number Copy ● ● ●● ●●●● ●● 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0 20 40 60 80 100 0 50 100 150 chr15 position (Mb) chr3 position (Mb) Chr PD26419a15 (Mb) ChrPD26419a3 (Mb) 3 5 13 5 3 13

4 5 3 4 ● ● ● ● ●● ●● ●●● ● ● ●●● ● ● ●● ●● ● ●● ● ●●●● ●● ● ●●●● ● ● ● ●●●● ● ● ● ● ● ●●●●● ●● ●●●●●● ●● ● ● ● ● ● ●● ●●●●● ● ● ●●●●●● ● ●● ● ● ●● ●●● ●●● ●● ● ● ●●●●● ●●●●●●●●●●●● ●● ●● ●●●●●● ● ● ●● ●● ●● ● Copy number Copy ● ● ● number Copy ● ● ●●●●●●●●●●● ● ●●●●● ●● ● ●● ● ● ●● ● ●●● ● ● ● ● ●●●●●●●● ● ●●● ● ●● ● ● ●●●●●● 3 ● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ●● ●● ● ●●●● ●● ● ●● ●●●●● ● ● ● ●●●●● ●● ● ●●●● ● ● ●● ●●●● ●● ●● ●●●●●● ● ● ●●●●●●●● ● ●●● ●● ● ● ● ● ●● ●●●● ● ●● ● ● ●● ●● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ●● ● ● ● ●●● ●● ● ●● ●● ●●● ●● ●●●●●● ● ●●●●●●●●●●●●●●●● ●●●●●●● ●● ● ● ●● ●●● ●● ●●●●● ●● ● ● ● ● ●●●●●●●● ● ●● ●●●● ●● ● ●● ● ●●● ●● ●● ●● ● ●● ●●● ●● ● ● ●● ● ●● ● ●●● ● ● ●●●●●●●●●● ● ●● ●● ●● ● ● ●● ● ●●● ● ● ● ● ●●● ● ● ●●●● ●●●●●● ●● ●●●● ●●●● ● ● ● ●● ● ● ● ●●●● ●● ●●●●●●● ●● ●●●●●●● ●●●● ● ● ●●●●● ● ● ● ● ●●●●●● ● ●●● ● ●●● ●● ●●● ●●● ● ● ● ● ●●●●●● ● ● ● ● ● ●●● ●● ● ● ●●●●●● ● ● ●●● ●●● ● ●● ●●● ●●● ●●●● ●●● ●●● ● ●● ● ● 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0 20 40 60 80 100 PD26419a 0 50 100 150 chr13 position (Mb) chr5 position (Mb) 15 151515 1515 15 14 Chr 13 (Mb) 15 15 1515 14 Chr 5 (Mb)

5

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0 20 40 60 80 100 120 140 chr8 position (Mb) Chr 8 (Mb) e f PD26419aPD26419a – Molecular Time st nd Late Chromothripsis 1 2 (3,5,13,22) Chromothripsis Gain 3, 15, Chromothripsis Whole ● ● 2nd MG on (8;15) LOH 1p on 1p Genome ● ● Duplication ● 1st MG Early 1q gain Treatments chr1 gain chr3 gain chr1 LOH chr15 gain PD26408 PD26415 PD26426 gain 15 PD26407 PD26420 PD26427 del 6q PD26403 del 14q del Xq27 ● ● del 13q34 ● bi-del RB1 del Xq25 x 3 ● ● ● nd ● nd ● 2 MG events ● Chromoplexy t(3;8;18;X) Chromothripsis 4 2 gain 1q21-23 ● t(4p16.1;18q21) ● ● 2nd gain 8q24 del 6q, 9p, 19 gain 3 ● gain 18q t(8q24;20q11) ● Chromothripsis 16 del 16 gain 3 ● Complex 11 gain 9q 2st MG LOH Xq ● ● Complex t(15;20) ● NRAS del 17 t(12q21;15q21) del 8p ● ● t(3q11;20p11) ● PRDM1 del 3q del 6q16 Complex 19 t(6q14;Xq21) st bi-del CDKN2C del 6q27 Complex 6p FAM46c 1 MG (1,8) NRAS del 1p 1st MG (3,4,5,6,7, del 13 BRAF t(7p21;8q21) del 13 1st MG 11,19) 1st MG t(1q23;12q23) 1st MG (1,9,11,15) del CDKN2C 1st MG (3,5,7,10,11,19) 1nd MG (3,5,9,11) (3,5,6,9,11,15) Complex 3p del13 (1,5,9,11,15) TI t(1;5;7;8;9;11;15;22) t(11q13;14q32) t(11q13;14q32) NRAS ● ● ● ● ● t(6q13;7p12) ● ● Complex 16p

PD26410 PD26423 PD26435 PD26404 PD26416 PD26412 PD26409 rd ● 3 MG event (4, ● Complex t(4;21) del 4p Chromothripsis 20 ● ● ● 3rd rd 11 ) extra gain 5q22 WGA t(16p12;17p11) 3 MG (1,3) ● TI t(1;6;8;22) ● amp MYC t(4q31;8q23) t(11q21;16q23) del 13 ● ● ● del 9p ● ● ● ● Chromoplexy (10;12;19) nd 2nd Complex 3p th t(1q32;15q15) ● 4 MG 2 MG (7,8,11 ) ● Complex 12q t(3p22;9p21) Complex 12q del 3p t(6p24;8q24) t(9q22;15q23) Complex 20,14q, X Complex 1q Focal MYC amp gain 9 and 15 NRAS nd 2nd Chromothripsis 1p nd 2 MG (2,7,18 ) del 6q BRAF ● ● 2 MG del 1p CYLD t(7p21;Xq21) ● t(8q24;14q32) ● t(8q24;22q11) nd ● nd Chromothripsis 8 (1,3,11) 2 MG (7) t(8q24;22) ● del 1p del 8p t(8q24;14q32) 3 MG t(2p14;19p13) del 1p del 13 KRAS del 5p del 1p t(2p24;21q22) del 17p TI t(2;10;11;12;20) NRAS 1st MG (3,5,7, t(9q21;17q21) PRDM1 Complex 14q 1st MG ITD FAM46c WGD – 2nd MG (14) 10,11,19) t(11p11;20q13) nd 1st MG (3,5,9, (5,7,15) 1 MG (3,5,9,11,21) RASA2 st TI t(2;8;16) Complex 14q 1st MG (1,2,3,4,6) 1 MG (9, 19) 1st MG (1,18) ● ● ● ● 11,19) ● ● del 13 ●

PD26401 PD26419 PD26411 PD26400 PD26429 PD26406 PD26425 2nd del 14q Complex t(4;18) st Complex 5 ● ● 2 Chromothripsis t(11;16) ● del 12p ● Del13q ● del 17p del 8p ● ● ● Complex 20q WGD del 6q ● ● t(6q14;16p11) ● bi-del CDKN2A/B IRF4 ● Complex 1p gain 2 ● del 14q ● st bi-del BIRC2/BIRC3 1 Chromothripsis t(11;16) Chromothripsis 1p ● del 11q ● ● bi-del 13q11- Complex 5q ● Chromothripsis 7p del 20q gain 9 (extra) Complex t(6;8) q21 bi-del BIRC2/YAP1 Chromothripsis 16 Complex t(2;14) del 13q14-q21 ● BRAF Complex 2 bi-del TRAF3 Complex 10q Chromoplexy t(16q21;Xq27) 3rd Chromothripsis 1p 2nd MG (12nd,16) TP53 2nd MG (5,9,11, ● t(2;8) gain 1q nd 2nd MG (6,9) ● 2 Chromothripsis t(3;5;13;21) Complex 6q FAM46c 15,16) t(8q24; 14q32) gain 1q TI t(3;7;8;22) del 6q PTPRD del Chromothripsis 16 Complex 5 Complex 18 ITD FAM46c del 13 del 13 Complex 4p t(1q32;19p13) del 14q Chromothripsis 12 Complex 19q Chromothripsis x 4 inv (1p22;1q21) del 14 inv(Xp22;Xq25) 1nd MG (1p,3,15) Complex 7q Chromothripsis 1st MG (1,3,5,6,9, (2, 11, 18, 19) del 13 DIS3 t(1;6,13,16) 16,18,19) 1st MG (5,19) nd Complex 15 ● t(4p16;14q32) t(11q13;14q32) ● ● 1 Chromothripsis t(8;15) ● ● ● ● 1nd MG (1,3,7,10,15)

PD26402 PD26424 PD26414 del 12p PD26405 PD26432 PD26434 PD26428 del 6q 2nd MG even del 1q and 14q del 8p amp MYC ● ● ● ● ● ● del 5q ● t(1q22;7q32) nd DIS3 gain 15, 16 del 13q22-31 2 gain 8 ● ●● PRKD2 t(2p25;6q15) del 12p ● LOH 3q22 nd 2 MG (5) nd Chromothripsis t(7p15;14q32) gain 21 del14q 2 WGD t(8q24;16q21) ● Complex 2p Complex t(5;10;19) Complex 6p 18q ● st 1st gain 8 gain 9 and 19 Complex t(2;9;16) 1 MG (3,5,7,19) gain 18 inv 1q Chromothripsis 4 KRAS 1st MG (6,7,9,14,18, inv(2p22;2p13) st 19,21) 1 WGD gain 1q NRAS BRAF ● ● Chromothripsis 17p del 13 LOH 4p TI t(8;11;15; 17;20) Chromothripsis t(6;8; 1st MG t(1p36;17q21) 14;21) ● del 13, 1p and 6q t(4p16;14q32) t(11q13;14q32) t(11q13;14q32) t(11q13;14q32) ● t(2p25;9p24) ● ● ● ● t(4p16;14q32) ● ●

PD26418 PD26422 Clusters Driver Events Focal 5q31 del ● del17p del4p ● LOH 13 ●

● Cluster 1 Cluster 5 SV with CNA Driver SNV ● ● t(11q23;14q24) ● ● ● Focal 5q14 del ● Complex 14q 2nd MG t(3p24;17q22) ● Cluster 2 Cluster 6 Complex Event Chromothripsis st 1 MG (5,11) Complex 6 TI t(1;11;12;14; Complex TI t(3;6;16) 15;22) Cluster 3 Cluster 7 Multi Gain Event (MG)/ t(17;22) del 17q11-q21 TP53 del 13 Whole Genome Duplication t(16p13;Xq21) t(11q13;14q32) del 1p Cluster 4 ● ● t(11q13;14q32)