Request for Information: Challenges and Opportunities in Improving our Understanding of Transposable Elements and Somatic Mosaicism
Notice Number:
NOT-RM-20-020

Key Dates

Release Date:

June 17, 2020

Response Date:
July 17, 2020

Related Announcements

None

Issued by

Office of Strategic Coordination (Common Fund)

Purpose

Background

A significant percentage of the human genome contains signatures of mobile genetic elements, though few of these elements remain active. The elements that are active are thought to play an important role in introducing genetic diversity into the human population, by modifying the progression of different diseases and conditions as well as playing a role in tissue development, including embryogenesis and wound healing. The discovery of different classes of transposons, that 1-10% of individuals have unique insertions from birth, that more than 100 genetic diseases are associated with retrotransposon insertions, and that the activity of elements in tissues can be influenced by exogenous signals have led to a growing need to better understand the relationship between mobile element activity and tissue function.

Somatic mosaicism includes both small- and large-scale chromosomal aberrations and can arise through many different mechanisms including retrotransposon activity. Somatic mutations are thought to occur in nearly all human cell replication and as a consequence of endogenous and exogenous mutagens. While mosaicism can emerge throughout the lifespan, mutations arising during development can have particularly profound effects. Reanalysis of Genome-Wide Association Studies indicated that the number of detectable mosaic events increases in older adults. To date, the most commonly studied mutations have visible phenotypes. Mutations often occur in a cell type-specific manner and are known to have cell-specific effects. A deeper study of how mutations influence important biological processes across the lifespan may provide new insights into human development, gene regulation, and additional genetic factors that may influence disease progression and treatment.

The recent development of cellular resolution, multiplexed imaging technologies, and high throughput single cell sequencing platforms provides the research community with unprecedented insight into the molecular organization of human tissues and facilitates characterization of the nuclear architecture, transcriptome, and proteome of millions of individual cells across hundreds of people. In spite of these and other advances, there remain many challenges in detecting, characterizing, and functionally describing the role of transposable elements and somatic mosaicism in tissues, across the human body, and across the lifespan. In order to help identify the needs and priorities in this area of science, and plan future activities and initiatives that can most significantly impact biomedical research, the Somatic Mosaicism and Retrotransposition Working Group of the NIH Common Fund is seeking comments from the global community regarding conceptual, technical or methodological barriers limiting progress and to help prioritize research activities or community resources that are most likely to propel this field forward for the greater benefit of the biomedical research community.

Information Requested

The NIH is considering the possibility of developing a Common Fund program to better understand the relationship between transposable elements, somatic mosaicism and human tissue function. Recognizing on-going work to detect and characterize mobile elements, to study the potential of mobile elements and somatic mosaicism to modify functional tissue units, and the emergence of new imaging and sequencing technologies and computational approaches, the Working Group is requesting input from the scientific community on the challenges and opportunities in this area that could best be addressed through a concerted and coordinated effort. Specifically, we welcome responses in the following domains:

  1. Methods, tools, or community resources needed to study DNA mobile element activity in human tissues at the single cell level, including the potential to integrate molecular and functional assays to study gene regulation, characterize cell type and state sensitivity, and study permissive and repressive factors.
  2. Methods, tools, or community resources needed to reproducibly characterize somatic mosaicism in human tissues arising from mutagenic events, erroneous DNA replication / mitosis or transposable element activity across the lifespan, including the opportunity for large-scale mapping of variants based on cell lineage, studying tissue and cell type specific mosaicism, and new computational tools needed to visualize, model and interpret data.
  3. Methods, tools, or community resources needed to improve manipulation, induction and monitoring of mobile DNA elements in model systems for study of changes in biological processes, signaling and tissue function during development and across the lifespan.
  4. Emerging technologies for characterizing the drivers and interactions between somatic mosaicism and transposable elements in vivo or in situ, including imaging tools for identifying regions of transposable element activity and mosaicism, techniques for mapping cell lineage and real-time monitoring of a small subset of cells within a living model system composed of billions or trillions of cells.
  5. Characterizing health consequences of DNA mobile element activity and accumulation of somatic variants during development and aging.
  6. Characterizing health consequences of changes in DNA mobile element activity in response to environmental challenges, including understanding the rate of accumulation of extent of heterogeneity in specific cell types, different tissues, and different people across the lifespan.
  7. Methods, tools, or community resources that would be required to define and validate human biomarkers of retrotransposon activity or specific somatic variants relevant to multiple diseases, dysfunctions and contexts, including neurodegenerative disorders, cancer and any response of the immune system.
  8. Approaches to screen for therapies that interfere with transposable element expression or activity, and whether these might play a role in modifying the outcomes of different diseases and conditions.

How to Submit a Response

Responses to this RFI will be accepted through July 17, 2020. All comments will be anonymous and must be submitted via email to SMART@od.nih.gov. Please include the Notice number (NOT-RM-20-020) in the subject line.

In your email, please include the bullet you are addressing (or if you are proposing a novel topic), and justification for your suggestion. Please note that we are interested in better understanding both the beneficial as well as the deleterious effects of transposable elements and somatic mosaicism, and that feedback would be most beneficial if focused on areas where a consortium working together to create community-accessible resources such as reagents, model systems, datasets, validated workflows, or analytical tools could deliver results that would be difficult from a similar number of individual labs.

Responses to this RFI are voluntary. The Government is under no obligation to acknowledge receipt of the information provided and respondents will not receive individualized feedback. This RFI is for planning purposes only and should not be construed as a solicitation or as an obligation on the part of the United States Government. NIH will use the information submitted in response to this RFI at its discretion. NIH does not intend to make any type of award based on responses to this RFI or to pay for either the preparation of information submitted or the United States Government's use of such information. The information submitted will be analyzed and may be shared internally, appear in reports or be reflected in future solicitations, as appropriate and at the Government's discretion. Proprietary, classified, confidential, or sensitive information should not be included in your response. The Government reserves the right to use any non-proprietary technical information in any resultant solicitation(s) or other activities. No basis for claims against the U.S. Government shall arise as a result of a response to this request for information or from the Government's use of such information.

Inquiries

Please direct all inquiries to:

Amy Lossie, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301- 827-6092
Email: amy.lossie@nih.gov

Richard Conroy, Ph.D.
Office of the Director (OD)
Telephone: 301-402-1486
Email: Richard.Conroy@nih.gov


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