Center for Genomics of Neurodegenerative Disease, New York Genome Center – By Dr. Hemali Phatnani
Through donations from the ALS Ice Bucket Challenge, The ALS Association is supporting strategic initiatives that emphasize collaboration, data sharing and state-of-the-art scientific methods. Here we feature the Center for Genomics of Neurodegenerative Disease (CGND) at the New York Genome Center (NYGC). Meet Dr. Hemali Phatnani and learn about how the CGND at the NYGC is making a huge impact on ALS research.
My name is Hemali Phatnani and I direct the Center for Genomics of Neurodegenerative Disease (CGND) at the New York Genome Center (NYGC). I am also Adjunct Assistant Professor of Neurogenetics in the Department of Neurology and the Institute for Genomic Medicine at Columbia University Medical Center. My research program is centered on building a framework to study the causes and mechanisms of ALS.
Just about two years ago today, The ALS Association in partnership with the Greater New York Chapter of The Association, announced its commitment to the CGND at NYGC. The CGND’s vision is to establish a framework to apply state-of-the-art genomics and bioinformatics to the study of disease mechanisms in ALS and by building partnerships with clinicians, basic scientists, geneticists and computational biologists.
The CGND’s partners include not only NYGC’s founding members such as Columbia and Rockefeller, but also ALS centers throughout the northeast, such as the University of Pennsylvania, Massachusetts General Hospital and Johns Hopkins School of Medicine, among others.
Through the support of The ALS Association, our efforts also synergize with other ALS Association-funded consortia, such as ALS ACT and the GTAC (“Genomic Translation for ALS Care”) consortium. Through a multidisciplinary collaborative effort that spans multiple ALS centers and bridges ALS clinicians and scientists, we are using whole genome sequencing to discover and study mutations and mechanisms underlying ALS. Broadly stated, the goals of this consortium are the following:
- Integrate whole genome sequencing with RNA sequencing to interrogate relationships between mutations, gene expression and disease mechanisms
- RNA sequencing analyses combined with whole genome sequencing will help us to identify how changes in DNA are expressed in the brain and spinal cord and how this affects the presentation and course of disease
- Integrate genomic and clinical data to identify genetic modifiers of disease onset/progression/presentation
-Our partners’ clinical phenotyping efforts will enable us to sequence well-stratified patient cohorts, so that we can eventually identify mutations that are associated with different forms of the disease, or gene variants that can modify the presentation of the disease and could be further studied to identify pathways for the targeted development of therapies.
- Create and maintain a data warehouse for genomic data that can be broadly accessed by the academic community
-Our sequencing data will be made freely available to the research community. Resource and data sharing is an integral aspect of our efforts, because we want the data that we generate to be as useful as possible to as many researchers as possible. Broad sharing will only accelerate the pace of discovery and therapeutics, which are crucially needed in ALS.
-Such broad sharing and collaborative efforts are ultimately geared towards making the best use of sequencing data. For example, comparing clinical profiles to genomic profiles can enable us to determine whether specific mutations are associated with specific clinical outcomes – this may ultimately make truly “personalized” medicine possible.
- Design and create ALS models to test effects of mutations in stem cell derived neurons and in mouse models using state-of-the-art genomic manipulation methods
-To study the function of any sequence variants that we identify and to understand how they affect disease mechanisms, we will collaborate with our research partners to make new models of disease such as induced pluripotent stem cells (iPS cells) and mouse models. We can use these models to study, for example, how mutations affect the different cell types that are known to play a role in ALS, such as astrocytes, microglia and oligodendrocytes, all of which are known to affect motor neurons in ALS. Using these models, we will be able to examine regulatory mechanisms affecting the transcriptome (i.e. all the messenger RNA (mRNA) in a cell or in a population of cells), as well as mechanisms underlying intercellular interactions in disease.
-To further these analyses, we are developing tools to integrate the experimental and computational analysis of large-scale data that includes transcriptomes of specific cell types in the Central Nervous System, profiles of RNA-binding proteins implicated in disease and high-resolution imaging. The combination of new deep sequencing methods, sample acquisition, data analysis pipelines and molecular and phenotypic characterizations using new mouse models will provide mechanistic insights that were previously not possible.
-Any models that we develop through our collaborative efforts will be made freely available to the research community – this is in fact a condition of any partnerships that we undertake. In addition, the conceptual framework and infrastructure should be widely applicable to other neurodegenerative diseases.
The CGND at NYGC occupies a unique position at the confluence of science, technology and medicine. By building this framework to understand the causes and mechanisms underlying ALS, the CGND’s efforts will ultimately help us to translate genomics research into clinical solutions.
Since our inception two years ago, we have made significant progress, including:
- The Consortium has rapidly grown to now formally include thirteen member institutions and several more sites have requested to participate.
- The NYGC ALS Consortium also partners synergistically with Target ALS, to sequence autopsy samples from its post mortem core and iPS samples from its stem cell core.
- NYGC, The ALS Association and Target ALS have formed a partnership to create a valuable resource of RNA sequence data generated from tissue samples and induced pluripotent stem cells (iPSCs). This resource will help advance a project examining how Human Endogenous Retrovirus (HERV) RNA sequences may play an important role in a proportion of ALS cases. Read more here.
- The Consortium has received almost 1000 samples so far, and whole genome sequence data from these samples will be distributed to all Consortium members later this year. Genomic data from these samples will be also shared with the International Consortium on Amyotrophic Lateral Sclerosis Genetics (ALSGEN) collaboration – also supported by The ALS Association for joint analysis with all existing ALS data, greatly increasing the power of these analyses.
- Genomic and clinical data from these samples can be visualized and explored in NYGC’s database, also scheduled to be released to the community later this year.
To learn more about the CGND at NYGC visit the NYGC Strategic Initiative page.