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Dr Peter Lansdorp — MD, PhD, FRS(C)

Distinguished Scientist

Overview
Research Interest
Lab Members
Career Highlights

Education:
MD, Erasmus University Rotterdam, 1976
PhD, Experimental Hematology, University of Amsterdam, 1985

  • DNA replication, epigenetics and stem cells
  • Telomeres, genomic instability, aging and cancer
  • Genetic analysis using single cell Strand-seq

Asymmetric cell divisions are essential for the development of all multicellular organisms. Many mechanisms are known to help secure differences in cell fate between daughter cells following the division of a parental stem cell. We are interested in possibility that programmed epigenetic differences between sister chromatids contribute to gene expression differences during development [1]. Such differences may arise when the deposition of parental nucleosomes onto replicated DNA following replication is asymmetric because replication of one of the DNA template strands is delayed because the replisome encounters a problem on one of the template strands. Strand-specific DNA replication problems are not theoretical. We showed in 2002 that the replication of guanine-rich DNA requires a specialized helicase, which we called Dog-1 for Deletion of guanine-rich DNA [2]. We subsequently identified RTEL1 in the mouse as a major regulator of telomere length [3]. DOG-1 (aka FANCJ) and RTEL1 are iron-sulfur cluster helicase proteins that can unwind secondary structures of guanine-rich DNA called guanine quadruplex (G4) structures [4]. G4 structures were recently shown to regulate gene expression [5]. The presence and role of G4 structures at specific genomic locations as well as the enzymes required for resolving G4 structures in genome stability, gene expression and differentiation are areas of special interest. For such studies we recently developed techniques to identify and study sister chromatids in single cells [6, 7]. Current studies in the Lansdorp lab focus on three questions that can only (!) be answered using our single cell sequencing technique called Strand-seq [8]:

1)     Investigate the molecular mechanisms that regulate stem cell self-renewal and differentiation. By combining single cell Strand-seq with the analysis of transcripts in the same cell we are addressing an aspect of stem cell biology that has not been subject to experimentation before.

2)     Elucidate molecular mechanisms involved in DNA repair and epigenetic asymmetry between sister chromatids. By mapping the location of sister chromatid exchange events [9], genome copy number variations [10], polymorphic inversions [11] and loss of heterozygosity (LOH) events [12], we have a unique capability to study DNA events at the level of single cells.  Studies with cells before and after specific genetic alterations are providing new insight in cancer, specific diseases and aging.

3)     Map polymorphic inversions in human chromosomes [11] and combine this information with haplotype information [12] to generate completely phased “personalized genomes” for “precision medicine”. Ongoing studies have revealed that Strand-seq by itself, but especially in combination with other sequencing approaches, yields unprecedented precise information about individual genomes. Apart from proof of principle studies we are exploring better ways to increase the throughput and decrease the cost of our methods.

Reference: 

  1. Lansdorp, P.M., Immortal strands? Give me a break. Cell, 2007. 129(7): p. 1244-7.
  2. Cheung, I., et al., Disruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA. Nat Genet, 2002. 31(4): p. 405-9.
  3. Ding, H., et al., Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein. Cell, 2004. 117(7): p. 873-86.
  4. Bharti, S.K., et al., Specialization among iron-sulfur cluster helicases to resolve G-quadruplex DNA structures that threaten genomic stability. J Biol Chem, 2013. 288(39): p. 28217-29.
  5. Papadopoulou, C., et al., Nucleotide Pool Depletion Induces G-Quadruplex-Dependent Perturbation of Gene Expression. Cell Rep, 2015. 13(11): p. 2491-503.
  6. Falconer, E., et al., Identification of sister chromatids by DNA template strand sequences. Nature, 2010. 463(7277): p. 93-7.
  7. Falconer, E., et al., DNA template strand sequencing of single-cells maps genomic rearrangements at high resolution. Nat Methods, 2012. 9(11): p. 1107-12.
  8. Falconer, E. and P.M. Lansdorp, Strand-seq: a unifying tool for studies of chromosome segregation. Semin Cell Dev Biol, 2013. 24(8-9): p. 643-52.
  9. van Wietmarschen, N. and P.M. Lansdorp, Bromodeoxyuridine does not contribute to sister chromatid exchange events in normal or Bloom syndrome cells. Nucleic Acids Res, 2016. 44(14): p. 6787-93.
  10. Bakker, B., et al., Single-cell sequencing reveals karyotype heterogeneity in murine and human malignancies. Genome Biol, 2016. 17(1): p. 115.
  11. Sanders, A.D., et al., Characterizing polymorphic inversions in human genomes by single-cell sequencing. Genome Res, 2016. 26(11): p. 1575-1587.
  12. Porubsky, D., et al., Direct chromosome-length haplotyping by single-cell sequencing. Genome Res, 2016. 26(11): p. 1565-1574.

 

Carl-Adam Mattson

Amy Yu

PMP
Research Projects Manager

Michael Yuen

Graduate Student

Degrees and Positions

1976                      MD Erasmus University, Rotterdam, the Netherlands

1985                      PhD University of Amsterdam, the Netherlands

1986-2011           Scientist, Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada

2005-2011           Professor, Department of Medicine, UBC, Vancouver, BC, Canada

2011-2016           Professor and Founding Scientific Director, European Research Institute for the Biology of Ageing, University Medical Center Groningen, the Netherlands

2016-                     Distinguished Scientist, Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada

2016-                     Professor, Medical Genetics, UBC, Vancouver, BC, Canada

 

Scientific highlights, supported by >250 publication of which 100 were cited > 100 times (h-index 104)

  1. Developed B9, an IL-6-dependent cell line that is and has been instrumental in the IL-6 field.
  2. Discovered tetrameric antibody complexes, reagents that are key to the success of the Canadian biotech firm StemCell Technologies in Vancouver.
  3. Produced several widely used monoclonal antibodies for stem cell research (e.g. CD34, CD90).
  4. Developed serum-free culture medium and novel assays for hematopoietic stem cells.
  5. Discovered that self-renewal properties of stem cells are developmentally controlled.
  6. Discovered that blood-forming stem cells lose telomeric DNA with each division.
  7. Developed quantitative fluorescence in situ hybridization (Q-FISH) techniques.
  8. Reported that telomerase KO mice lose around 5kb of telomeric DNA per generation.
  9. Described variation in telomere length at individual human chromosome ends.
  10. Reported that DOG-1, a specialized helicase, is required to maintain guanine-rich DNA in C.elegans.
  11. Cloned and described the function of RTEL1, a helicase required for telomere maintenance.
  12. Founded Repeat Diagnostics, a company that provides clinical telomere length results.
  13. Proposed the “silent sister” hypothesis.
  14. Discovered that sister chromatids can be distinguished by parental DNA template strands.
  15. Developed the single cell Strand-seq method.
  16. Generated the first comprehensive maps of polymorphic inversions in human genomes.
  17. Developed novel ways to establish haplotypes along entire chromosomes.
  18. First to map the genomic location of sister chromatid exchange events in Bloom syndrome.

Ad 1. Following my training as MD, I worked for 2 years as a research fellow in the laboratory of experimental surgery at the Erasmus University in Rotterdam on a tumor immunology project (1,2). During this time I reproduced the hybridoma work described by Kohler and Milstein (3) for which they got the Nobel prize in 1984. Based on my self-acquired hybridoma expertise, I was hired as a research fellow in 1979 to set up monoclonal antibody (Mab) technology in the Central Laboratory of the Blood Transfusion Service in Amsterdam, the premier immunology laboratory in the Netherlands. There I developed novel immunoperoxidase assays to detect cell surface antigens (4,5) and made several monoclonal antibodies which were used in the International Workshops to define common Clusters of Differentiation (CD) antigens. For this workshop we had to submit large amounts of antibodies, which was not a problem except for one hybridoma that could only be expanded in the presence of tissue culture medium conditioned by endothelial cells (6). We later found that this hybridoma (B9) maintained a strict requirement for IL-6 for growth (7-9). This line has been instrumental in the IL-6 field ( >1200 citations). A Canadian twist to this story is that I could convince Jack Gauldie from McMaster University that the hepatocyte stimulating factor he was working on most likely was IL-6, a prediction which turned out to be correct (10) resulting in US patent No. 4,973,478.

Ad 2. In Amsterdam I made monoclonal antibodies to peroxidise to link peroxidase to cell surface antigens via monoclonal mouse antibodies and polyclonal antibodies specific for mouse IgG (4,5). Based on the bivalency of IgG antibodies and the presence of two identical heavy chains in antibody molecules, I predicted that selected monoclonal antibodies specific for epitopes present on the heavy chain of immunoglobulin molecules might be able to cross-link two monoclonal antibodies into a stable tetrameric antibody complex. To test this hypothesis, which turned out to be correct, I made (rat) monoclonal antibodies specific for mouse IgG1 (11). See Figure 1.

Figure 1. Tetrameric complexes of monoclonal rat and mouse antibodies (from (11). A. Enzyme blot using enzymes and their substrates following agar electrophoresis of mouse IgG1 anti-enzyme antibodies before and after addition of monoclonal rat anti-mouse IgG1. Lane 1: mouse IgG1 anti-peroxidase (a). Lane 2: mouse IgG1 anti- alkaline phosphatase (b). Lane 3: (a) plus an equimolar amount of rat anti-mouse IgG1 . Note: no free mouse antibody. Lane 4: (b) plus rat anti-mouse IgG1. Lane 5: equimolar amounts of (a) and (b) mixed before addition of an equimolar amount of rat anti-mouse IgG1. Note middle band with bispecific monoclonal tetrameric antibody complexes. Lane 6:  A mixture of the complexes shown in lane 3 and 4. Note the absence of bispecific complexes. Lane 7. As lane 5 with a limiting amount of rat anti-mouse IgG1. From top to bottom: free (b), (bxb), (axb), (axa), free (a). B. Scanning electron microscopy of purified tetramolecular antibody complexes. Scale bar 10 nm.

The ability to easily crosslink two different monoclonal antibodies into very stable tetrameric antibody complexes (US patent No. 4,868,109) has found numerous applications in biotechnology. For example, we described applications in cell separation (12,13) and fluorescent labeling of cell surface antigens (14). Importantly, tetrameric antibody complexes are at the heart of the cell separation technology commercialized by StemCell Technologies in Vancouver and currently employs hundreds of Canadians.

Ad 3. During my work in Amsterdam my research interest shifted from immunology to stem cell biology and purification of blood-forming stem cells using monoclonal antibodies was a key research objective. At the time, it was believed that purified stem cells, together with defined culture conditions, would allow unlimited expansion (self-renewal) of stem cells for clinical purposes such as gene therapy and transplantation. At a meeting in London I met with Allen Eaves, the director of the Terry Fox Laboratory in Vancouver at the time. Allen convinced me to visit Vancouver and, eventually, to do postdoctoral work there. I started to make monoclonal antibodies relevant for stem cell research including antibodies to CD34 and CD90. Our antibodies proved to be superior reagents to detect e.g. CD34 cells in peripheral blood (15) and identify and isolate stem cells in combination with antibodies to CD38 (16). We licensed our hybridomas to Becton Dickenson and our CD34 antibodies have become part of clinical care around the world, for example to monitor the mobilization of CD34 cells for stem cell transplantation.

Ad 4. Before the use of xeno-transplants, hematopoietic stem cell activity was primarily measured by the ability of cells to produce colony forming cells in long-term “Dexter” cultures (17). Together with Connie Eaves and Heather Sutherland we established an assay for human cells capable of initiating long-term cultures (18) using the limiting dilution principles routinely used for production of monoclonal antibodies. This assay was used to purify “candidate” stem cells and to develop a serum-free culture medium for stem cells (19). Our medium is commercialized, essentially unchanged, as “StemSpan” by StemCell, another example of a useful product coming from my laboratory.

Ad 5. Despite our novel antibodies, innovative cell purification techniques, improved culture media and assays for stem cells, our attempts to expand adult blood-forming stem cells in culture were a dismal failure. While it was possible to keep CD34+ cells alive for long periods in cultures supplemented with various cytokines, we could not markedly increase the number of CD34+ cells when cultures were initiated with purified “candidate” stem cells from adult bone marrow (20).  A breakthrough came when we finally tested “candidate” stem cells from fetal liver and umbilical cord blood in our cultures. CD34 cell numbers increased several thousand-fold in fetal liver cell cultures and several hundred-fold in cord blood cultures. We concluded that the self-renewal properties of stem cells are developmentally controlled (21). Despite our report of similar findings with purified murine stem cell candidates (22), our findings were essentially ignored only to be “rediscovered” about a decade later (23,24).

Ad 6. The failure to significantly expand adult bone marrow hematopoietic stem cells in tissue culture was a set-back for therapeutic strategies that would require significant production of stem cells. The situation did not improve when we found that hematopoietic stem cells also lost telomeric DNA with each cell divisions (25), similar to observations with cultured human fibroblasts (26).

Ad 7. My questions about the role of telomeres in biology were frustrated by the Southern analysis technique used to measure of telomere length which was laborious and required millions of cells. During a sabbatical in the laboratory of Hans Tanke in Leiden, I started to explore fluorescence in situ hybridization (FISH) techniques to measure telomere length. The breakthrough came when I could get my hands on novel, synthetic “peptide nucleic acid” probes (27,28). Briefly, I found that FISH could be made quantitative (Q-FISH) using PNA probes under stringent, low ionic strength conditions, that allow PNA, but not competing single stranded DNA, to anneal to the selected target sequences (29) and US Patent No 6,514,693.

Ad 8. With PNA and Q-FISH tools, we performed a number of important studies, the most cited being our contribution to the study of the telomerase KO mouse (30) ( > 2000 citations, including the 2009 Nobel Prize in Physiology or Medicine - Advanced Information Report). This paper was already under review at Cell when we got involved. Our findings significantly changed the message, essentially  from “telomerase is not as important as we believed: it can be knocked out without consequences” to “telomerase KO mice lose 5 kb of telomeric DNA with each generation and uncapped telomeres at late generations cause fusions and genome instability”. See Figure 2.

Figure 2. Telomerase KO mice lose about 5 kb of telomere repeats per generation. Q-FISH analysis of embryonic fibroblasts of the indicated, subsequent generations of telomerase KO mice. 1 TFU corresponds to 1kb of telomere repeats. Note that in WT animals all chromosomes are “capped” with readily detectable telomere repeats, whereas at generation 6 (left and right panel) many chromosome ends have no telomere repeats and dicentric chromosomes with no telomere repeats at the fusion point are seen. A clear fusion is seen at 9 pm, right.

Ad 9. See Reference (31). We found that the average number of telomeric DNA sequence (TTAGGG) repeats on specific human chromosome arms is similar in different tissues from the same donor but can vary markedly between donors. In all individuals studied, telomeres on chromosome 17p were shorter than the median telomere length, a finding we confirmed by analysis of terminal restriction fragments from sorted chromosomes and by an independent study (32).

Ad 10. Intrigued by the large variation in the average telomere length between cells of individuals of the same age, I became intrigued by the genetic factors that regulate average telomere length. We focused on studies of mice in collaboration with Richard Hodes at NIH and identified a region on mouse chromosome 2 that is required to elongate the sort telomeres on chromosomes of M. spretus in crosses with M.musculus that have very long telomeres (33). However, this region was too large (>10 Mb) to knock out all the “candidate” genes in this region. Instead, we focussed further studies of one candidate gene, “Novel Helicase Like” in C.elegans, for no good reason other than that a knock-out strain of a very similar gene was already available in the lab of Ann Rose at UBC. This turned out to be a very fortunate choice as we found that the KO animal had a striking genome instability phenotype: deletions throughout the genome that invariable started at the 3’ end of poly-guanine tracks longer than 18 nucleotides (34). We renamed the gene Dog-1 (for deletions of guanine rich-DNA) and we postulated that the helicase encoded by Dog-1 might be required to resolve guanine quadruplex (G4) structures during replication. This pioneering work allowed us to deduce the function of a helicase protein from the very specific “deletion signature phenotype” observed in its absence. This work has stood the test of time and others have shown since that the human homolog of DOG-1 (FANCJ) also is required to prevent instability at G-rich DNA (35,36).

Ad 11. Encouraged by our findings in C.elegans we decided to knock-out “Novel Helicase Like” in the mouse in collaboration with Andras Nagy and Hao Ding in Toronto. We could demonstrate that this gene is indeed a major regulator of telomere length and we named the gene accordingly: Regulator of telomere length (37). This work has also stood the test of time and recently patients with mutations in RTEL1 have been described by several groups (38,39). Such patients have very short telomeres and often show bone marrow failure similar to patients with mutations in telomerase genes such as TERT or TERC.

Ad 12. We developed and perfected a method to measure the average length of telomeres in specific nucleated cell types in peripheral blood using PNA probes, fluorescence in situ hybridization (FISH) and flow cytometry, a technique we called Flow FISH (38,39). With this method, we showed that there is a large variation in the average telomere length between individuals of the same age and that the most dramatic decline in telomere length occurs in the first few years of life (Figure 3).  Interestingly, at birth and throughout life the average telomere length was found to be longer in females than in males (40) and Figure 3, left). In collaboration with hematologists and geneticists at NIH, we established that the telomere length in patients with genetic defects in telomere pathway genes, such as TERT, TERC, RTEL1 and others could readily be distinguished from patients with other causes for their bone marrow failure (reviewed in (41). Because our flow FISH measurements could also distinguish carriers from telomerase mutations from siblings without such genetic defect (Figure 3, right), we were soon overwhelmed by requests from clinicians to perform diagnostic Flow FISH experiments in our research lab. This clearly was not ideal and I decided to set up a company, Repeat Diagnostics Inc., to provide clinical telomere length measurements. This company was not set up to generate a profit and has seen steady growth over the years. Currently Repeat Diagnostics employs 5 people and is processing 10-20 samples/day for clinicians around the world looking after patients suspected of inherited or acquired “telomeropathies”.

Figure 3. Telomere length decline with age in human lymphocytes in peripheral blood measured using flow FISH. The left panel shows that a difference in average telomere length between females (pink) and males (blue) persist throughout life. The right panel shows the telomere length in heterozygous carriers of a mutation in either the TERC or the TERT gene (red) and their unaffected siblings (black). Blue line: bottom 1 percent of normal telomere length at indicated age. Figure adapted from (40).

Ad 13. In our hunt for genes that regulate telomere length we had discovered two genes encoding similar helicases, Dog-1 (34)  or FANCJ in humans and RTEL (37). For both helicases, we proposed a role in the replication of guanine-rich DNA: the unwinding of single stranded DNA folded into guanine quadruplex (G4) structures. Long poly-guanine tracts in the C.elegans  genome are much more abundant than would be predicted by chance (42), raising questions about the biological role of G4 structures and G4 motifs in biology. One possibility is that G4 structures, arising stochastically during replication at G4 motifs in the genome and at telomeres, result in epigenetic differences between sister chromatids as delayed replication of one sister chromatid with a G4 motif in the DNA template strand could perturb the distribution of parental nucleosomes over both sister chromatids. I proposed the possibility of epigenetic differences between sister chromatids as the “silent sister hypothesis” in a review for Cell (43).

Ad 14. In order to test the silent sister hypothesis (Ad 13), we needed to distinguish sister chromatids in paired daughter cells. The solution we found was based on the Chromosome Orientation (CO-FISH) technique developed by Ed Goodwin and colleagues in the 90’s (44). Specifically, we found that sister chromatids of mouse chromosomes could be distinguished using PNA probes specific for the large unidirectional arrays of major satellite sequences in such chromosomes (45).

Ad 15. Based on the Nature paper described under Ad 14, we mustered the courage to develop a single cell DNA template strand sequencing technique (46). At the time, we could not have predicted the wide range of applications that this new technique would have outside our initial goal: to reliably distinguish sister chromatids in order to test the “silent sister” hypothesis. These applications include haplotyping and the mapping of polymorphic inversions (reviewed in (47) and several other papers that are now either in press, under review or to be submitted soon. These include papers describing Strand-seq for a) haplotyping in combination with other sequence modalities (Nature Communications, in press), b) studies of DNA repair in yeast (bioRxiv 164756; doi: https://doi.org/10.1101/164756) c) improving vertebrate reference genome assemblies (Nature Communications, under review) and d) studies of structural variation in human genomes by the 1000 Genome Structural Variation Consortium (bioRxiv 193144; doi: https://doi.org/10.1101/193144).  All these papers highlight the value of Strand-seq as a tool for genetic discovery and analysis and underscore the use of single cells as the ultimate unit for genetic analysis. Examples of Strand-seq analysis are shown in Figures 4, 5 and 6.

Figure 4. a) Strand-seq allows identification and analysis of sister chromatids. The two daughter cells of a single parental CD34+ cell show perfect, complementary segregation of parental DNA template strands and only a single sister chromatid exchange event (arrow, bottom chr 1). Note that all chromosomes showing reads mapping to both strands of the reference genome (Chr 2, 5, 6, 7, 9, 11, 14, 16, 17 and 18 in this cell pair) can be used to map SNPs to parental genomes along entire chromosomes and assemble complete physical maps of parental haplotypes. b) Sister chromatid exchange events are very common in cells from patients with Bloom’s syndrome. In this cell 56 SCE events are detected (arrows).

Ad 16. My lab generated the first comprehensive map of polymorphic inversions in the human genome. This work by Ashley Sanders when she was a graduate student in my lab, was published in 2016 (48). The principle of the method and an example of results are shown in Figure 5. By combining haplotyping, discussed under Ad 15, with the characterization of polymorphic inversions, genetic variation of individual humans can be mapped with unprecedented precision. This type of information cannot easily be obtained by other techniques and Strand-seq is expected to become a routine method in medical genetics.

Figure 5. Sequence reads generated by Strand-seq map either concordant with the human reference genome sequence (a, left) or map to both strands of the reference genome (reflecting a heterozygous inversion (a, middle panel) or completely to the opposite strand of the reference genome reflecting a homozygous inversion (a, right panel). Polymorpic inversions in the human genome generate a large amount of genetic diversity between individuals (48) as is shown in b for a 20Mb segment of chr 7 (red box) for 6 individuals. Note that the role of this type of genetic diversity is largely unexplored because of the difficulty to generate genome-wide information about polymorphic inversions using other sequence modalities.

Ad 17. The diploid nature of the genome is neglected in many analyses done today, where a genome is perceived as a set of unphased variants with respect to a reference genome. However, important biological phenomena such as compound heterozygosity and epistatic effects between enhancers and target genes can only be studied when haplotype-resolved genomes are available. Hence a method that can produce dense and accurate chromosome-length haplotypes at reasonable costs is highly desirable. Using a well-studied trio from the HapMap consortium we recently showed that Strand-seq allows for accurate phasing along entire chromosomes (49). The principle of this method and results of phasing of the trio family members are shown in Figure 6. When combined with other type of sequencing data, Strand-seq allows near complete phasing (>99% of SNP’s) of human genomes (Fig 7 from Nature Comm., in press).

Ad 18. Strand-seq can be used to map the location of sister chromatid exchange events (SCEs) with a resolution that is orders of magnitude better than is possible using the conventional cytogenetic technique (50). We applied Strand-seq to map the genomic locations of SCEs in human and murine cells (Figure 4 and bioRxiv 17325, https://doi.org/10.1101/173252). Our results show that in the absence of BLM, SCEs in human and murine cells do not occur randomly throughout the genome but are strikingly enriched at coding regions, specifically at sites of guanine quadruplex (G4) motifs in transcribed genes. We propose that BLM protects against genome instability by suppressing recombination at sites of G4 structures, particularly in transcribed regions of the genome (submitted).

Figure 6. a) Strand-seq provides a physical haplotype map of SNP’s along entire chromosomes. Multiple cells with Strand-seq sequence reads mapping to both strands of the reference genome for a given chromosome (orange and blue) are used to assemble haplotype backbones (49). Such chromosome-long haplotypes correspond accurately (>99%) with HapMap reference data for a child (b, yellow) but not her parents (father blue , mother red), where Strand-seq reveals the location of parental meiotic recombination events (resp. red and blue dots). The haplotype backbones generated by Strand-seq allow complete phasing of human genomes when combined with other type of sequence data (e.g. 10X or PacBio data, Nat Comm., in press).

Figure 7. A) Two homologous chromosomes are shown (blue and black). Experimental phasing approaches like Strand-seq can connect heterozygous alleles along whole chromosomes, however, at higher costs (time and labor) and lower density of captured alleles. In contrast, read-based phasing can deliver high-density haplotypes, but only short haplotype segments are assembled with an unknown phase between them. B) Barplot showing the percentage of phased variants, for each sequencing technology, from the total number of reference SNVs (Illumina platinum haplotypes). C) Graphical summary of phased haplotype segments for Illumina, PacBio, 10X Genomics and Strand-seq phasing shown for chromosome 1. Each haplotype segment is colored in a different color with the longest haplotype colored in red. Side bargraph reports the percentage of SNVs phased in the longest haplotype segment. D) Accuracy of each independent phasing approach measured as percentage short switch errors in comparison to benchmark haplotypes.

REFERENCES

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  3. Kohler, G. and Milstein, C. (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature, 256, 495-497. View Abstract
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