Sequencing / Production Lab
On April 7, the tweet went out – Production Lab team members pictured with a NovaSeq sequencing system, the first of five NovaSeqs that the New York Genome Center (NYGC) will receive before the end of the year. With this upgrade, the NYGC becomes one of only a handful of sites in the world to offer NovaSeq technology.
The NovaSeq system, released by Illumina earlier this year, represents the newest, cutting-edge technology in next-generation sequencing. One NovaSeq can run 48 genomes in 2.5 days as compared with Illumina’s previous HiSeqX technology, which can sequence 16 genomes in three days. Besides increased throughput, another advantage of the NovaSeq system compared to the HiSeqX system is that it is not restricted to whole genomes, and can inexpensively sequence whole exomes and RNA samples. NovaSeqs also run different-sized flow cells, with its largest having more than three times the data output compared to HiSeqX systems and at 20 percent less cost.
The NYGC’s HiSeqX systems will continue to be fully utilized for the short term, with the Production Lab gradually transitioning projects from HiSeqX to NovaSeqs. (The upgrade to NovaSeq included trading in five of the NYGC’s current 16 HiSeqX systems for the five new NovaSeq machines.)
During the last week in April, the Bioinformatics team at the New York Genome Center (NYGC) hosted its second Sequencing Informatics Workshop, organized and overseen by Mike Zody, PhD, Senior Director, Computational Biology, and taught by Dr. Zody and members of the Computational Biology team. Participants from multiple research institutions from the New York area and around the country learned the basics of sequence data alignment, data analysis and identifying somatic variation in cancer samples; how to read and understand common file formats; how to analyze ChIP-Seq data; and how to analyze RNA-Seq data for expression and differential expression. The week-long popular workshop was funded through the support of the Alfred P. Sloan Foundation. It is designed for graduate students and postdocs, as well as faculty and core and research lab staff, to build next-generation sequencing and computational expertise. The next workshop is planned for the fall.
The Bioinformatics team also continues to publish its own research and is credited as contributing co-authors on many publications with its collaborative researchers. On May 5, team members posted the preprint taxMaps – Ultra-comprehensive and highly accurate taxonomic classification of short-read data in reasonable time on bioRxiv, describing a novel computational tool capable of delivering high classification accuracy within comprehensive genomic databases at greater speed and less computational cost than existing tools. The tool’s performance and comprehensiveness makes it highly suitable for unbiased contamination detection in large-scale sequencing operations, microbiome studies comprising a large number of samples and for applications where delivery time and accuracy are both critical factors, such as pathogen identification from clinical or environmental samples.
Technology Innovation Lab
This past spring, the Technology Innovation Lab team at the New York Genome Center launched its own Twitter handle – @NYGCtech – and shared news of its latest invention: Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), a new method to simultaneously measure immunophenotypes and transcriptomes in single cells on a massively parallel scale.
The method, developed with contributions from the NYGC’s Satija Lab, is detailed in the preprint Large-scale simultaneous measurement of epitopes and transcriptomes in single cells.
As the NYGC authors note, recent high-throughput single-cell sequencing approaches have been transformative for understanding complex cell populations, but have been unable to provide additional phenotypic information such as protein levels of well-established cell-surface markers. Using oligonucleotide-labeled antibodies, the Technology Innovation Lab team integrated measurements of cellular proteins and transcriptomes, linking detection of surface proteins and mRNA while maintaining full compatibility with pre-existing high-throughput single-cell RNA-seq (scRNA-seq) approaches. CITE-seq enable analysis of cellular phenotypes with unprecedented detail and readily scales as throughput of scRNA-seq increases.
The team’s proof-of-principle experiments, outlined in the preprint, involved using five protein markers in 2,600 single cells. The Lab team is now analyzing data from 8,700 single-cord blood mononuclear cells with 10 antibodies.
Marlon Stoeckius, Research Scientist, Technology Innovation Lab, presented CITE-seq at the 2017 Association of Biomolecular Research Facilities annual meeting in March and the 10x Genomics New York User Group Meeting held at the Alexandria Center in NYC in May.
Tuuli Lappalainen, PhD, Core Faculty Member at the New York Genome Center (NYGC) and Assistant Professor in the Department of Systems Biology at Columbia University, has been awarded a five-year, $1.7 million R01 grant from the National Institute of General Medical Sciences of the National Institutes of Health. The project is to study how genetic interactions affect penetrance of genetic variants. Penetrance is a widespread but poorly understood phenomenon where individuals carrying the same genetic variant – for example, one causing severe disease or cancer – demonstrate varying severity or symptoms of the disease, typically for unknown reasons. This project will explore how regulatory variants affect the penetrance of coding mutations in their target gene, using population genetics, medical genetics and experimental techniques. The project will be driven by the Lappalainen Lab, in collaboration with Dr. Daniel MacArthur’s lab at Massachusetts General Hospital and the Broad Institute. Read the press release here.
Preprints and Publications
The preprint Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations, a study led by Sarah Kim-Hellmuth, MD, PhD, a postdoctoral fellow in the Lappalainen Lab, was submitted to bioRxiv in March. This work shows how genetic regulatory variants in monocytes respond to diverse immunological stimuli, thus mapping genetic variants that may underlie differences in immune responses between different individuals. Importantly, the study also shows that genetic variants modified by immunological stimuli play a major role in common diseases, especially autoimmune disorders. This work is a collaboration with the Veit Hornung and Johannes Schumacher labs in Germany.
A Nature Reviews Genetics perspective article by Dr. Lappalainen and Dr. John Greally from the Albert Einstein College of Medicine was published on May 30. The paper, Associating cellular epigenetic models with human phenotypes, discusses epigenome-wide association studies (EWAS) that aim to capture how environmental exposures affect long-term disease risk. The authors point out that traditional EWAS have several shortcomings, often producing results that are biologically and medically uninterpretable. In the paper, the authors propose a redirection towards second-generation EWAS, a study design founded on biological mechanisms of how environmental exposures affect cells. With integration of multiple genetics and functional genomics assays, the field can move towards joint characterization of both genetic and environmental factors underlying human traits and diseases.
Honors and Awards
Dr. Lappalainen has been selected as an Associate Editor of PLoS Genetics and was a section editor of the “Genomics and Epigenomics” issue of Current Opinion in Systems Biology published in February. She has also been invited to be a member of the steering committee of Common Disease Forum, an international forum launched by Drs. Sek Kathiresan and Eric Lander at the Broad Institute to advance research and translational efforts in common diseases.
April was an exciting month for the Sanjana Lab, with Neville Sanjana, PhD, Core Faculty Member at the New York Genome Center (NYGC) and Assistant Professor in the Departments of Biology, Neuroscience and Physiology at New York University (NYU), recognized with both a Sidney Kimmel Scholar Award and a Young Investigator Award from the Melanoma Research Alliance. These awards will help fund the Lab’s work in leveraging gene-editing tools including CRISPR (Clustered regularly interspaced short palindromic repeats) to comprehensively survey mutations that allow cancer cells to resist immunotherapy treatment. Read more about these awards here.
Support of this research comes at a critical time with melanoma rates in particular rising dramatically, outpacing almost all other cancers. Today, it is one of the most common cancers found among young women of ages 25 to 29. Melanoma is a tremendously mutagenic cancer, which makes effective treatment challenging. Immunotherapy, which supplements and encourages the body’s own immune system to attack cancer, was the first treatment of any kind ever to extend survival in metastatic melanoma. In some cases, however, melanoma cancer cells do not respond at all to immunotherapy and in others develop resistance to the treatment due to melanoma’s high rate of mutation.
Using high-throughput CRISPR screens, the Sanjana Lab will explore and study thousands of genetic mutations related to melanoma tumor resistance in a fraction of the time it would take to do this individually. Targeted DNA manipulation will allow for parallel editing of each individual gene in a genome, non-coding regions around a single gene of interest or a subset of genes. The resulting pool of engineered cells can be tested for virtually any biological phenotype to enable functional discoveries.
Explaining CRISPR in “5 Levels of Difficulty”
On May 24, Wired posted a video on its website featuring Dr. Sanjana in its new science video series. His challenge was to talk about CRISPR, and explain gene editing in a way that could be comprehended on five levels of understanding: by a seven-year-old, a 14-year-old, a college student, a grad student and a CRISPR expert. Just one of many engaging moments in this interview is Dr. Sanjana guiding the seven-year-old through a “eureka” moment about how his allergies may related to a genetic mutation. Click here to watch the video.
Additionally, in March, a segment in which Dr. Sanjana was interviewed by host Donna Hanover for CUNY-TV’s “Science & U” about his work on CRISPR was aired. Click here to watch the video.
Early this year, Rahul Satija, PhD, Core Faculty Member at the New York Genome Center (NYGC) and Assistant Professor at the Center for Genomics and Systems Biology at New York University (NYU), and his Lab team posted its first preprint working at the NYGC. Titled Inhibitory neuron diversity originates from cardinal classes shared across germinal zones, the study is a collaboration with the Fishell Laboratory at NYU Medical Center. The preprint drew strong positive response from researchers, with fellow NYGC Core Faculty Member Neville Sanjana, PhD, describing it as a “tour de force” of droplet sequencing and one commentator on bioRxiv noting that the study probes the “inner lives of 36,000 cells.”
Satija Lab members are also co-authors of the preprint Large-scale simultaneous measurement of epitopes and transcriptomes in single cells, which describes CITE-seq, a newly invented analysis tool developed in collaboration with the NYGC’s Technology Innovation Lab.
2017 has also marked publications of the following studies from the Satija Lab on NYGC-affiliated research:
- A multi-step transcriptional and chromatin state cascade underlies motor neuron programming from embryonic stem cells in Cell on February 2.
- Seq-Well: portable, low-cost RNA sequencing of single cells at high throughput in Nature Methods on April 4.
In March, Dr. Satija gave a talk at the ZENCODE/DevCom Conference in Carmona, Spain, discussing Drop-seq analysis of early fate decisions in human hematopoiesis. He was an invited speaker at the Human Cell Atlas Meeting at Stanford University in February, which was hosted by the Chan Zuckerberg Biohub and Chan Zuckerberg Science. Also in 2017, Dr. Satija gave the inaugural lecture at the Computational Single Cell Analysis seminar series sponsored by the National Institutes of Health (NIH) in Bethesda, MD, attended the NIH’s Accelerated Medicines Partnership’s Network Leadership Committee Meeting in Houston and was a presenter at the Weizmann Institute of Science’s “R based advanced methods for deep sequencing analysis” workshop.
Marcin Imielinski, MD, PhD, Core Faculty Member at the New York Genome Center (NYGC) and Assistant Professor of Computational Genomics and Assistant Professor of Pathology and Laboratory Medicine at Weill Cornell Medicine (WCM) and John Maciejowski, PhD, a postdoctoral researcher working in the Imielinski Lab and The Rockefeller University, have published Modeling cancer rearrangement landscapes in Current Opinion in Systems Biology. Asserting that “the biggest challenges and opportunities for interactions between computationalists and experimentalists lie in the analysis of DNA rearrangements,” the paper proposes a “biology first” approach to probe the genomic consequences of these perturbations by using model systems of cultured cells and/or widely used organism models such as mice or worms. This new experimental framework is what the authors see as “the seeds of an emerging field of systems biology of cancer genome integrity,” necessary since DNA rearrangement data are sparse, comprising many fewer events per sample than for single nucleotide variants (SNVs), which has been the most mature area of research.
In Prostate cancer: Clinical hallmarks in whole cancer genomes, published online by Nature Reviews Clinical Oncology on April 4, Dr. Imielinski and Dr. Mark A. Rubin, a colleague and collaborator at WCM’s Englander Institute for Precision Medicine, explore the possible use of whole genome sequencing in the field of precision medicine for prostate cancer.
Dr. Imielinski has also been working closely with Nico Robine, PhD, Assistant Director, Computational Biology, NYGC and fellow NYGC Core Faculty Member Dan Landau, MD, PhD, on the new biweekly “CBGB” (cancer biology, genomics and bioinformatics) meetings being held at the NYGC. The goal of this meeting, which is open to all cancer researchers and clinicians, is to highlight and stimulate collaborative work in cancer genomics between the NYGC faculty, NYGC staff and Institutional Founding Members. It is part of a larger effort to organize cancer activities at the NYGC as guided by Harold Varmus, MD, Senior Associate Core Faculty Member, NYGC and Lewis Thomas University Professor of Medicine, WCM, and members of the Genome Center Cancer Group, and also includes New York Cancer Genomics Research Network meetings, held on the first Tuesday of each month.
“Game of Clones” is the catchy title often put on presentations to describe the complex work of the Landau Lab, led by Dan Landau, MD, PhD, Core Faculty Member at the New York Genome Center (NYGC) and Assistant Professor of Medicine in the Division of Hematology and Medical Oncology and the Department of Physiology and Biophysics at Weill Cornell Medicine (WCM). The Lab’s research does indeed focus on “clones” – studying the dynamics of cancer at the cellular level, specifically the body’s monoclonal cells that are produced from a single ancestral cell by repeated cellular replication. The Lab team develops computational and experimental tools to study cancer evolution, using both patient-derived samples and experimental models. The overall goal is to apply this knowledge to designing the next generation of precision medicine tools to overcome cancer evolution, which is a central challenge in the treatment of cancer.
The Lab’s research was recently part of the study Genomic complexity of multiple myeloma and its clinical implications, which was published in Nature Reviews Clinical Oncology earlier this year with Dr. Landau as co-author along with collaborators from the Broad Institute, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts General Hospital and WCM. Multiple myeloma, a cancer formed by malignant plasma cells, is a genetically complex disease that evolves from pre-malignant stages, such as monoclonal gammaopathy, in which an abnormal protein — known as monoclonal protein or M protein — appears in the blood but has underdetermined significance, and smouldering multiple myeloma, in which slightly increased levels of M protein and a slightly increased number of plasma cells are present in the bone marrow. The analysis of these stages in relation to symptomatic multiple myeloma is a continuum that provides a unique framework to study the sequential genomic evolution of cancer.
In March, Dr. Landau discussed his Lab’s data-science approach to cancer study and precision medicine in “Smart with Heart: The Human Face of the Fourth Industrial Revolution,” the inaugural installment of a planned science documentary series produced by Arirang TV, South Korea’s only global network broadcast in English, reaching nearly 90 million households in 188 countries around the world and available on DirecTV in the U.S. Watch the segment here.
On April 18, the Center for Genomics of Neurodegenerative Disease (CGND) at the New York Genome Center (NYGC), led by Hemali Phatnani, PhD, Director, CGND and Adjunct Assistant Professor of Neurogenetics in the Department of Neurology and the Institute for Genomic Medicine at Columbia University, announced some exciting news: a high-quality whole genome sequenced dataset of 132 post-mortem tissue samples from ALS patients now available to the research community via MetroNome, the NYGC’s newly launched clinical genomics database.
The samples were collected by Target ALS, a member of CGND’s ALS Consortium, and primarily drawn from Columbia University, Johns Hopkins University, University of California at San Diego, Georgetown University and Barrows Neurological Institute with some contributions from other entities that met Target ALS’s criteria of high quality and no embargo on use. The samples are also being RNA sequenced and are clinically annotated, with more samples to be added to MetroNome in the future. To look at the dataset, go to: https://metronome.nygenome.org/TargetALS/.
Target ALS is a nonprofit organization with the overall goal of accelerating development of new treatments for ALS. This organization also recently awarded the CGND a grant for a project to study the initiation and spread of ALS pathology in mouse models of the disease and in post-mortem spinal cords of ALS patients using the novel Spatial Transcriptomics (ST) system, a gene expression visualization technology for tissue sample sections. The Lab will analyze the datasets generated using state-of-the-art computational methods, providing a previously unavailable view of genotype-phenotype interactions and intercellular dynamics as the disease unfolds.
The CGND Lab team is also continuing its work on a project, funded with a Project ALS grant, to explore how genetic mutations affect autophagy/cellular defects in the development of the disease. Members of the Project ALS team visited the CGND early this year and tweeted out an announcement of the partnership (see picture above).
Dr. Phatnani presented an overview of the CGND’s work at the ALS Association’s Greater New York Chapter walk kickoff event, held at the NYGC, for the NYC Walk to Defeat ALS, which took place in May.
In June, the ALS Association announced that three large research organizations — Project MinE, Answer ALS and the NYGC — will be working collaboratively toward its mission for treatments and a cure for ALS. Through this new collaboration, Answer ALS is partnering with Project MinE and the NYGC’s ALS Consortium to share their well characterized cohort of whole genomic sequencing data to further Project MinE’s international efforts in genetics. In return, Project MinE will contribute results from its global genetic studies to further Answer ALS’s objectives, in addition to lending its technical expertise in analyzing sequence data. This adds to the sequencing expertise already provided by the NYGC, which provides whole genome data on Answer ALS participants. Learn more about this collaboration here.
Education & Outreach
A new interdisciplinary course called Genomic Innovation will be launching this fall semester at the New York Genome Center (NYGC). The project-focused course will bring together students from multiple universities in New York at the NYGC to learn about the current landscape of genomic science from prominent leaders in the field. The course will be led by NYGC Core Faculty Members Tuuli Lappalainen, PhD, and Neville Sanjana, PhD, and feature guest speakers from the New York City area genomics community. During the semester, the students will develop their own genomic ventures, which could be the basis for a research project, a non-profit or a startup. For eligibility and application information, email email@example.com.
The NYGC hosted its first-ever Genomics Hackathon in collaboration with the National Center for Biotechnology Information (NCBI) June 19 – 21. Read more about this initiative, which includes the GitHub link that will be a repository for hackathon projects, here.
Throughout this past winter and spring, the NYGC also hosted a series of educational events. On April 5, the NYGC’s Mike Zody, PhD, Senior Director, Computational Biology, and Brian Houck-Loomis, PhD, Manager, Technology Innovation, were the informative and engaging speakers at The ABCs of DNA: A Genomic Revolution, the well-received spring installment of NYGC’s Evening Talks lecture series for the general public. This popular lecture series on advances in genomic science is sponsored by the New York Community Trust–Pyewacket Fund. The talk covered both basic information about DNA and the human genome and how the newest discoveries are advancing precision medicine and other areas of research. The lecture was moderated by CBS Medical Correspondent Dr. Max Gomez, pictured at right with Drs. Houck-Loomis and Zody. Watch the archive of the video here.
The video of the event was launched on the NYGC’s website and YouTube channel on April 25 in honor of National DNA Day, the annual celebration sponsored by the National Human Genome Research Institute that commemorates the discovery of DNA’s double helix in 1953 and the completion of the Human Genome Project in 2003.
Scientific Meetings and Lectures
To advance collaborative efforts on cancer genomics, Harold Varmus, MD, Senior Associate Core Faculty Member, NYGC and Lewis Thomas University Professor of Medicine, Weill Cornell Medicine, continues to convene monthly New York Cancer Genomics Research Network meetings at the NYGC. These meetings bring together leading cancer researchers and clinicians from our Institutional Founding Members and other key academic institutions around the world.
NYGC faculty also serve as moderators/hosts for the Five Points lecture series, featuring presentations from leading researchers from around the country. Recent scientific presentations included:
- Itai Yanai, PhD, Director of the Institute for Computational Medicine and Professor of Biochemistry and Molecular Pharmacology at the New York University School of Medicine, discussed his work dissecting the embryo with single-cell RNA-Seq as well as The Society of Genes, a book he co-authored with Dr. Martin Lercher, Professor of Bioinformatics at Heinrich Heine University, Düsseldorf. (A memorable takeaway: there are apparently “Kramer” type genes that freeload off another gene’s activity, just like the character from Seinfeld.) NYGC Core Faculty Member Dan Landau, MD, PhD, was Dr. Yanai’s host and event moderator.
- Nancy J. Cox, PhD, Director, Vanderbilt Genetics Institute; Director, Division of Genetic Medicine; and Mary Phillips Edmonds Gray Professor of Genetics, described the variety of data integration strategies that her lab is using at Vanderbilt University Medical Center, including drawing on the center’s electronic health records of 2.6 million people and, in particular, the 225,000-member subset on which her lab has DNA to study genome variation. NYGC Core Faculty Member Tuuli Lappalainen, PhD, was Dr. Cox’s host and event moderator.
- Jin Billy Li, PhD, Assistant Professor of Genetics at Stanford University, spoke about new insights into RNA editing regulation and how RNA modifications affect gene regulation and beyond. NYGC Core Faculty Member Neville Sanjana, PhD, was Dr. Li’s host and event moderator.
- Ben Raphael, PhD, Professor in the Department of Computer Science at Princeton University, discussed interpretation and evolution of cancer genomes. He described computational approaches to translate cancer sequencing data into deeper insights about the processes that drive cancer development, including techniques to infer patterns of tumor evolution and metastasis. Nico Robine, PhD, Assistant Director, Computational Biology, NYGC, was Dr. Raphael’s host and event moderator.
Development & Communications
The NYGC’s A Year in Review – 2016 was completed earlier this year and is now available on the NYGC website. Also newly posted on the website is an updated 2017 At A Glance document, a one-sheet summary of key facts (mission, leadership research team structure, etc.) about the NYGC.
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