Message from Leadership
We’ve seen a lot of exciting advances and community-building at the New York Genome Center (NYGC) over the last several months.
Our faculty and staff scientists are receiving numerous grants and awards for their research, much of it done in collaboration with our institutional members and other research partners. NYGC researchers continue to advance the field of genomics with important studies published in high-impact journals and as invited speakers at events around the country.
NYGC’s sequencing and clinical labs continue to contribute to the scientific and medical community. Our NovaSeq systems, acquired this past spring, are now fully installed, enabling us to conduct large-scale genomics projects with greater speed and throughput. Our Clinical Lab is in the final stages of the approval process with New York State for its oncology whole genome and transcriptome assay — the first of its kind for the state. And our best-in-class Bioinformatics team is ensuring that investigators and clinicians have access to the highest quality data analysis.
2018 is off to a strong start. Our new Affiliate Membership program for external academic researchers is further expanding our collaborative network. We were excited to announce our new licensing and collaborative research agreement with BioLegend, a developer and manufacturer of antibodies and reagents, to further develop our CITE-seq technology — an example of our in-house innovation. We hosted the 5th Human Genetics in New York City Conference on February 2nd, which had an amazing line-up of speakers and posters and record attendance by the community. We are also recruiting for a new core faculty member to join the NYGC, with the selection process currently underway.
We are proud of our team for a remarkable period of accomplishment — showcased in this newsletter — and we thank you for your ongoing support.
Tom Maniatis, PhD
Cheryl A. Moore
In the News
Contributing to Science & More
How many DNA sequence errors does the human brain develop over a lifetime? NYGC Bioinformatics team members are contributors to a collaborative research project exploring this question by analyzing clonal cell populations from human forebrains and calculating somatic mutation rates. The study, Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis, published online in December and in print in February by Science, was heralded as a powerful technical paper providing critical new insights on this subject in a commentary article entitled “Thousands of Mutations Accumulate in the Human Brain Over a Lifetime” in The Scientist. The Science publication is more than a dozen studies with NYGC Bioinformatics co-authors in 2017.
The team also participated in the Advances in Genome Biology and Technology (AGBT) general meeting in February, with Michael Zody, PhD, Senior Director, Computational Biology, serving as co-organizer of the conference. Andre Corvelo, PhD, Senior Bioinformatics Scientist, gave a concurrent talk at the meeting, titled “Discovery and Typing of Polymorphic Non-Deletions of Ancestral Hominid Sequence in the Human Genome.”
Technology Innovation Lab
Expanding of CITE-seq™ to “Hashing,” Human Cell Atlas, BioLegend Partnership
Scientific community interest continues to grow for CITE-seq™, the novel technique for multidimensional single-cell analysis developed by the Technology Innovation Lab, in a team led by Marlon Stoeckius, PhD, Senior Research Scientist, in collaboration with the lab of NYGC Core Faculty Member Rahul Satija, PhD.
The lab team is looking forward to a long and productive relationship with BioLegend, Inc., with an exclusive worldwide license and collaborative research agreement for CITE-seq™ technology for use in the research field entered into by the NYGC and BioLegend and announced on January 11. In December, lab team members published a preprint in collaboration with BioLegend, and with the Satija Lab, on cell “hashing.” Cell “hashing” is an extension of previously published CITE-seq™ work that enables cell multiplexing, confident identification of doublets (instances when two cells are captured together) and super-loading of cells on commercial single-cell RNA-seq platforms. The team benchmarked cell “hashing” against previously described genotyping-based cell multiplexing strategies and demonstrated comparable performance and significant advantages in several contexts. Most importantly, cell “hashing” enables samples of the same genotype to be multiplexed and super-loaded, allowing a five-fold increase in cell yield compared to non-hashed samples.
Earlier, the lab, in collaboration with the Satija Lab, was awarded a grant from the Chan Zuckerberg Initiative (CZI) as part of its call for pilot projects to help build tools and technologies for the Human Cell Atlas project. The grant was awarded to fund a proposal focused on the benchmarking and optimization of CITE-seq™, which will include creating an open-source CITE-seq™ toolkit for Human Cell Atlas project researchers. Peter Smibert, PhD, Manager, Technology Innovation, and Rahul Satija, PhD, NYGC Core Faculty Member, are co-Principal Investigators on the grant, and attended the inaugural meeting for grantees at the CZI Biohub research campus in San Francisco in January. (Read the NYGC press release on the CZI grant.)
In February, Nature Communications published collaborative research by NYGC’s Technology Innovation Lab and Satija Lab detailing the development a 3D-printed, portable and low-cost microfluidic controller which was then deployed to study synovial tissue from patients with rheumatoid arthritis (RA) at the Hospital for Special Surgery. William Stephenson, PhD, Senior Research Engineer, Technology Innovation Lab, led the development of the instrument and is the lead author on the study; NYGC Core Faculty Member Rahul Satija, PhD, is the study’s senior author. (Read the NYGC press release on the study and media coverage highlights.)
Testing, Leveraging NovaSeq Sequencing
“For all you seq…,” a poster detailing a wide array of sequencing options, is featured on a wall in NYGC’s Sequencing Lab, and no wonder – the lab team is dedicated to offering investigators both best-in-class and best-fit sequencing services available for their particular research projects.
By December 2017, the team had completed key quality control and methods testing as well as run some inaugural client projects on the NovaSeq system acquired earlier in the year. The NovaSeqs, which join the lab’s lineup of Illumina sequencers, enable the team to run large-scale genomics sequencing projects with greater speed and sample capacity.
The lab has already run exome, RNA, whole genome and collaborator-prepared sample projects on the NovaSeqs. The system is able to run four different assay or flow cell types with varying amounts of data output, to cater to different project sizes. Assay types include S1, being the smallest flow cell producing up to 500Gb or 1.6 billion reads, all the way up to S4, which produces up to 3000Gb or 10 billion reads. Currently, only the S2 and S4 assays/flow cells are available, and the lab has successfully run both. Lab team members are currently also testing S1 flow cell technology. The team has also evaluated and has begun using the NovaSeq Xp workflow, which enables individual lane loading to allow for more flexibility, as opposed to loading all samples across all lanes.
Contact the Sequencing Lab’s project management team at email@example.com or 646-977-7222 for more details on service offerings.
Publishing Rare Disease Case Study, Progressing on Additional Diagnostic Offerings
In December, an early access version of a study from NYGC’s Clinical Lab in collaboration with Columbia University Medical Center (CUMC) was posted on the journal Clinical Case Reports’ website.
The study, to be published in an upcoming print edition, details a journey of genetic testing of the most heartbreaking – and challenging – kind. In 2014, the NYGC Clinical Lab was contacted by CUMC after the parents of a child who had died at 15 months without a definitive diagnosis inquired about risks to future pregnancies some two years after the child’s death. With no tissue samples available, the physician reached out to the NY State Department of Health to locate dried blood samples from the child’s newborn screening, from which the lab conducted its NY State-approved clinical whole exome sequencing (WES) testing for undiagnosed disease. The team uncovered a diagnosis – the child’s DNA revealed loss of function of the ASNS gene, which has been associated with a rare and severe neurologic disorder called Asparagine Synthetase Deficiency. The lab also discovered two novel variants to the existing ASNS gene mutation spectrum in their analysis. Asparagine Synthetase Deficiency is an autosomal recessive condition; both parents were found to carry a gene mutation in this gene and are at 25% risk of having another affected child. Based on this analysis, the parents decided to pursue preimplantation genetic testing in their next pregnancy to help them make an informed decision.
Avinash Abhyankar, PhD, Manager, Clinical Informatics, is first author on the study, and Vaidehi Jobanputra, PhD, FACMG, Director of Molecular Diagnostics is corresponding author.
In October, Dr. Abhyankar gave a talk on this study, “Exome Sequencing from Archived Residual Newborn Screening Blood Spot,” at the American Society of Human Genetics (ASHG) annual meeting as well as presented the poster “Clinical Validation of Whole Genome Sequencing Assay for Constitutional Disorders.”
In November, Dr. Jobanputra was an invited speaker at the Association of Molecular Pathologists annual meeting to speak on another lab initiative – its oncology whole genome and transcriptome (WGTS) assay validation – in a talk entitled “Integrated Genomic Profiling Using Clinical Whole Genome and Transcriptome Sequencing to Enable Precision Oncology.” The lab is currently awaiting approval from New York State (NYS) for this test; during this waiting period, physicians can request a waiver for their patient(s) from the state to order this test from the lab, with waivers granted on a case-by-case basis.
Once the lab’s Oncology WGTS test is formally approved by NYS, the lab will be able to complete its application for accreditation by the College of American Pathologists (CAP). One of the world’s leading organizations in clinical laboratory quality assurance, CAP is affiliated with the American Medical Association and authorized by the Centers for Medicare and Medicaid Services (CMS) to accredit laboratories. The lab is already certified by the Clinical Laboratory Evaluation Program, NYS’s quality assurance accreditation program, and the Federal Drug Administration’s Clinical Laboratory Improvement Amendments, which regulate laboratory testing and require clinical laboratories to be certificated by their state as well as the CMS before they can accept human samples for diagnostic testing.
The lab team is also in the process of gaining NYS approval for two other assays: WGS for oncology and Short Multiply Aggregated Sequence Homologies (SMASH) for genetic testing. SMASH is being developed in partnership with the Wigler Lab at Cold Spring Harbor Laboratory (CSHL), led by NYGC Senior Associate Core Member Mike Wigler, PhD, and Marvel Genomics, a spinout of CSHL. SMASH utilizes random fragmentation of input genomic DNAs to create chimeric sequence reads, from which multiple mappable tags can be parsed using maximal almost-unique matches (MAMs). The SMASH tags are then binned and segmented generating a profile of genomic copy number at the desired resolution. SMASH libraries can be highly multiplexed, allowing large numbers of individuals to be analyzed at low cost. SMASH is intended to replace Chromosomal Microarray (CMA) testing, which is a first-tier reimbursable clinical test performed for pediatric patients with developmental delay and/or undiagnosed disease. Usually, CMA is ordered before an exome and this can be a companion test to exome sequencing because copy number variations are not detected by exomes.
For more about the Clinical Lab’s genetic diagnostic tests, go to: http://www.nygenome.org/clinical-products/nygc-diagnostic-tests/
Neville Sanjana, PhD, Receives NIH New Innovator Award for Next-Generation Gene-Editing Research
“It’s the reason I get up in the morning: I want to go in the lab and build new gene-editing tools and try to attack new diseases.”
That’s how NYGC Core Faculty Member Neville Sanjana, PhD, described the guiding passion behind his gene-editing research in a video interview at the Swiss Re Institute Symposium held in Boston in November. In the fall, Dr. Sanjana also presented the Sanjana Lab’s recent work at the National Cancer Institute’s Surgery Branch, Columbia University’s Department of Systems Biology and as a keynote speaker at Yeshiva University’s Medical Ethics Society conference.
Dr. Sanjana and his lab also received a National Institutes of Health (NIH) Director’s New Innovator Award in October. The award of nearly $2.9 million supports the Sanjana Lab’s work in deciphering the logic of gene regulation through the development of new tools for targeted, precise modifications to the genome. (Read the NYGC press release here.)
Also in October, Molecular Cell published High-Throughput Approaches to Pinpoint Function within the Noncoding Genome, a study from the Sanjana Lab providing a review of high-throughput CRISPR-based approaches to uncover and understand functional elements within the noncoding genome and discussing practical aspects of noncoding library design and screen analysis. The paper’s co-authors are Sanjana Lab postdoctoral scientists Antonino Montalbano, PhD, and Matthew Canver, MD, PhD.
In November, Target Discovery for Precision Medicine Using High-Throughput Genome Engineering, a chapter co-authored by lab members Xinyi Guo, Research Associate, and Poonam Chitale, Graduate Student, NYU, was published in Precision Medicine, CRISPR and Genome Engineering.
Lappalainen Lab Contributes to Genotype-Tissue Express (GTEx) Project Papers in Nature, Genome Research
In October 2017, the largest analysis to date of findings from the Genotype-Tissue Expression (GTEx) project were published in several papers in Nature and many other scientific journals. The Lappalainen Lab has played an important part in this project, funded by the NIH, where a large consortium of researchers have developed a detailed atlas to document genetic variants in the human DNA that influence gene expression across 44 types of tissue, from blood vessels to 10 different brain regions. The samples were collected from 450 anonymous deceased donors. The GTEx project’s main paper, published in Nature and featured on the cover, includes Lappalainen Lab Postdoctoral Associates Stephane Castel, PhD, Postdoctoral Associate, and Pejman Mohammadi, PhD, as co-leading analysts, and NYGC Core Faculty Member Tuuli Lappalainen, PhD, as the last author of the eQTL working group. A Lappalainen Lab companion GTEx paper, Quantifying the regulatory effect size of cis-acting genetic variation using allelic fold change, was published in Genome Research. Given her lab’s strong long-term involvement with the initiative, Dr. Lappalainen was interviewed by Nature in its October 12 podcast. The GTEx project is now moving ahead with the analysis of the final data release, totaling 18,000 samples from a full set of 900 donors, with the upcoming final consortium paper being co-led by Dr. Lappalainen. She was also recently invited to join the Scientific Advisory Boards of Gene Ontology and European Variation Archive, two important genomic data resources.
Also this winter, Dr. Castel was awarded a prestigious K99/R00 fellowship by National Human Genome Research Institute to support transitioning from a postdoctoral to independent researcher. His funded project will focus on developing low-cost protocols for large-scale RNA-sequencing studies, which he will work on first in the Lappalainen Lab.
In November, Dr. Lappalainen and Margot Brandt, a PhD student working in the lab, published an invited article in Cell that provides a “Snapshot” tutorial to molecular QTL analysis (pictured; click on image to expand this infographic to its full size.)
Dan Landau, MD, PhD, Leads Genetic Monitoring Cancer Study; Team Recognized with ASH Awards
Frequent monitoring for genetic changes in chronic lymphocytic leukemia (CLL) patients during targeted treatment may allow clinicians to adjust treatments as the cancer evolves, according to a study led by NYGC Core Faculty Member Dan Landau, MD, PhD, and published in December by Nature Communications.
Sequencing cancer samples from these patients more frequently – every month or so – and using computer modeling to predict the cancer’s genetic evolution, Dr. Landau and his collaborators from the National Heart, Lung and Blood Institute of the NIH, Broad Institute, the University of Texas MD Anderson Cancer Center, among other institutions, were able to identify a subset of patients in whom cancer cells had certain genetic variations, making their cancer cells die less quickly than others. These changes were seen as early as one to three months after treatment initiation, and well before the affected patients develop any signs of cancer recurrence.
As Dr. Landau noted in an interview that ran in the Cornell Chronicle, he hopes the study has implications for other types of cancer. The emergence of liquid biopsy, which detects tiny amounts of DNA from solid tumors in the blood, makes it possible to do frequent genetic testing not only for cancers such as CLL, one of the most common types of blood cancer, but also for solid-tumors cancers such as lung cancer. “Everything else we do in medicine we do with continuous monitoring,” he said. “This would be a way to extend the precision medicine paradigm to include continuous dynamic measurements in cancer with the potential of using this for continuous optimization of therapy.”
With his Weill Cornell Medicine colleague Samuel F. Bakhoum MD, PhD, Dr. Landau was also co-author of Cancer Evolution: No Room for Negative Selection, an article in the November 15 edition of Cell that provided an overview and analysis of several cancer evolution studies included in the issue.
In December, the Landau Lab team was recognized with several awards at the 59th American Society of Hematology (ASH) Annual Meeting. Franco Izzo, PhD, a postdoc in the lab, was the recipient of the Outstanding Abstract Achievement Award, being the first author on Single-Cell Methylome and Transcriptome High-Resolution Maps Define the Effects of Epigenetic Modifiers on the Landscape of Hematopoietic Differentiation, the top-scoring abstract in the postdoctoral fellow category among ASH reviewers. Two other lab abstracts, Single-Cell Joint Methylomics and Transcriptomics Define the Epigenetic Evolution and Lineage Histories of Chronic Lymphocytic Leukemia and Integrative Epigenomics Reveals Novel Chronic Lymphocytic Leukemia-Specific Chromatin States Associated with Epigenetic and Transcriptional Heterogeneity, were also presented.
At the ASH meeting, Dr. Landau was also recognized with the Joanne Levy Memorial Award for Outstanding Achievement, given to the current ASH Scholar who has the highest-scoring abstract at the meeting. HemOnc Today also announced that Dr. Landau was on its inaugural list of Next Gen Innovators, a new initiative by the journal to help showcase the talents and expertise of rising stars in hematology and oncology.
Imielinski Lab Awarded Starr Foundation Grant to Study Mutational Signatures in Cancers
In early January, NYGC Core Faculty Member Marcin Imielinski, MD, PhD, presented “Cell-Of-Origin Footprints in Lung Cancer Genomes and Transcriptomes,” in an invited talk at the fifth annual International Joint Conference on Lung Cancer Translational Science from the Bench to the Clinic.
The “bench to clinic” theme of this conference, jointly held by the American Association for Cancer Research and the International Association for the Study of Lung Cancer, also describes the focus of the Imielinski Lab, which is committed to translating clinically relevant basic research findings into genomic diagnostics and incorporating these into precision cancer care.
In November, the lab received notice of a significant new grant to support this objective – Dr. Imielinski, working with collaborators at Memorial Sloan Kettering Cancer Center (MSKCC), was an award recipient in the Starr Foundation’s Eleventh Starr Cancer Consortium Grant Competition for a project titled “Deciphering Signatures of Broken DNA Repair Pathways in Long-Range Cancer Whole Genome Sequences.” With Dr. Imielinski as Principal Investigator and MSKCC’s Simon Powell, MD, PhD, and Jorge Reis-Filho, MD, PhD, as Co-Principal Investigators, the project team will expand the catalogue of mutational signatures associated with specific DNA repair defects through the application of 10X Chromium, a novel microfluidic-based “linked-read” whole genome technology that enables the detection of long-range patterns of mutation in cancer samples. Conducting the bulk of the 10X Chromium sequencing project at NYGC’s Sequencing Lab, the team will profile 40 samples of breast, ovarian, pancreatic, and head and neck cancers arising from patients with known defects in homologous recombination and interstrand-crosslink repair. The work will involve development of innovative computational methodologies to phase complex somatic variants and characterize recurrent mutational patterns associated with specific DNA repair defects. The proposed research has the potential for wide impact on the basic understanding of the mutational signatures associated with DNA repair defects and genomically informed management of patients with both inherited and non-inherited forms of cancer.
CGND’s ALS Research, Consortium Continues to Expand
In December, the New York Community Trust announced a new $125,000 gift to the Center for Genomics of Neurodegenerative Disease (CGND) at the New York Genome Center, led by Hemali Phatnani, PhD, Director. The CGND has firmly established itself as an organizing global hub of ALS data collection and analysis, thanks to fostering an ever-growing array of important collaborative partnerships within the ALS research community.
The new gift is specifically targeted to help fund further development of MetroNome, the interactive clinical/genomics database developed in collaboration with NYGC’s Bioinformatics and Software Engineering teams, that provides the ALS research community with tools to store their data, compare their data to other datasets, and compile information with the goal of helping to identify causes of ALS disease.
The CGND’s ALS Consortium, the international collaboration formed by the CGND just over three years ago to advance study of the disease, continues to expand rapidly. The Brigham and Women’s Hospital and the NIH’s National Institute of Neurological Disorders and Stroke (NIH NINDS) joined as the 26th and 27th institutional member, respectively, by year-end 2017 (for list of Consortium members, click here.) To date, over 1,450 whole genome sequencing samples from ALS patients have been made available to ALS researchers around the globe through MetroNome.
The Retroelements working group, another initiative at CGND in collaboration with CSHL and NIH NINDS, is exploring transposon copies, those elements of the region of so-called “junk” DNA which can “jump” into DNA sequences. Specifically, the group is focused on the retrotransponson elements of HERV-K and LINE, ancient viral DNA copies that long ago integrated into the human genome, and how these seem to become reactivated in ALS. The CGND has implemented a protocol that captures both transposon and gene transcripts from ALS post-mortem tissues, with some 350 RNA-seq samples, originating from several regions of the central nervous system, being analyzed by this group as part of the research study. This analysis has expanded to the study of all classes of transposons, whether ancient or recent.
Satija Lab Holds 2nd Annual Single Cell Genomics Day Workshop
In January, the Satija Lab hosted its second annual Single Cell Genomics Day, a workshop offering attendees an overview of the exciting developments in the field over the past year, followed by in-depth presentations with an emphasis on practical details and considerations. The workshop featured speakers from NYU and NYGC, keynote speakers from the Broad Institute and Harvard Medical School, and scientists from 10X Genomics. Thanks to support from the NYU Center for Genomics and Systems Biology and the Chan Zuckerberg Initiative, the event was free of charge to 150 attendees and openly live streamed to more than 2,000 viewers online. Additional resources, slides, and video of selected talks are available at www.satijalab.org/scgd.
During the fall of 2018, the lab contributed to publications related to the Human Cell Atlas project (Regev et al., eLife 2017) and the GTEx Consortium initiative (Tukiainen et al., Nature, 2017) and a review of single cell genomics for immunology (Papalexi and Satija, Nature Reviews Immunology, 2017). The lab also published two collaborative preprints, a single cell atlas of the Drosophila optic lobe with the Desplan Lab at NYU (Konstantindes et al, bioRxiv, 2017) and an exciting method for sample multiplexing and doublet detection deemed cell “hashing” with the Technology Innovation Lab (Stoeckius*, Zheng* et al, bioRxiv, 2017).
The lab also celebrated being awarded a Human Cell Atlas pilot project grant from the Chan Zuckerberg Initiative, with NYGC Core Faculty Member Rahul Satija, PhD, attending the inaugural meeting for grantees, with co-Principal Investigator Peter Smibert, PhD, Manager, Technology Innovation, NYGC, at the CZI Biohub research campus in San Francisco in January.
In February, Nature Communications published collaborative research by NYGC’s Technology Innovation Lab and Satija Lab detailing the development a 3D-printed, portable and low-cost microfluidic controller which was then deployed to study synovial tissue from patients with rheumatoid arthritis (RA) at the Hospital for Special Surgery. William Stephenson, PhD, Senior Research Engineer, Technology Innovation Lab, led the development of the instrument and is the lead author on the study; Dr. Satija is the study’s senior author. (Read the NYGC press release on the study and media coverage highlights.)
Publications & Preprints
For an up-to-date listing of the NYGC publications and preprints by NYGC faculty and staff, visit the Publications section of the NYGC website.
Education & Outreach
Information Sharing on Cancer Genomics, Longevity Research and More
As part of our educational mission, the NYGC continues to host many scientific meetings, workshops, conferences and lectures. There include:
Cancer Genomics Research Network Meetings
To advance collaborative efforts on cancer genomics, Cancer Genomics Research Network Meetings are held at the NYGC on the first Tuesday of every month during the academic year to bring together leading cancer researchers, clinicians and postdocs from the NYGC’s Institutional Founding Members and other key academic institutions. The organizers include Drs. Harold Varmus (NYGC and Weill Cornell Medicine), Marcin Imielinski (NYGC and Weill Cornell Medicine), Ross Levine (MSKCC) and Sohail Tavazoie (The Rockefeller University).
These meetings are organized by NYGC’s Genome Center Cancer Group, which is composed of clinicians and cancer researchers representing all NYGC member institutions, including all six of New York City’s NCI-designated Cancer Centers. The group is led by NYGC Senior Associate Member Harold Varmus, MD, Lewis Thomas University Professor of Medicine at Weill Cornell Medicine, and Charles Sawyers, MD, Chair, Human Oncology and Pathogenesis Program; Marie-Josée and Henry R. Kravis Chair, MSKCC. Drs. Varmus and Sawyers serve as moderators at the monthly meetings.
Five Points Lecture Series
NYGC’s faculty members and scientists also continue to serve as moderators/hosts for the NYGC’s Five Points Lecture Series, which feature presentations from leading researchers from around the country.
The NYGC’s Evening Talks events are intended to showcase and explain genomic science to the non-scientific community. The Evening Talks Series is sponsored by The New York Community Trust – Pyewacket Fund.
For more on all upcoming events, including our March 20 Five Points Lecture featuring Sekar Kathiresan, MD, from Massachusetts General Hospital, Broad Institute and Harvard Medical School and moderated by NYGC Core Faculty Member Tuuli Lappalainen, PhD, visit the Events section of the NYGC website.
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