# A LINE-1 Retrotransposition-Deficient Mouse Genome

> **NIH NIH R21** · CARNEGIE INSTITUTION OF WASHINGTON, D.C. · 2020 · $214,663

## Abstract

Project Summary
Transposable elements (TEs) are discrete mobile DNA sequences whose intact and mutated copies constitute a
substantial fraction of host genomes. Over the past decade, numerous studies implicated TEs in the evolution
of genomes and gene expression networks. However, whether TEs contribute to development or disease is an
open crucial question answering which might expand and even radically change our views on the genetic
foundations of human health and pathology. Of particular interest to human health is a Long Interspersed
Element 1 (LINE-1 or L1). For example, over a hundred single-gene human diseases arose from L1 insertions.
Intriguingly, recent studies implicated L1 retrotransposition in normal development (embryogenesis, oogenesis,
neurogenesis), aging and disease (autoimmune disorders, cancers). However, despite a multitude of correlative
studies, none have established a causative role of L1 retrotransposition in these processes to date. The primary
challenge of studying endogenous L1s lies in the large numbers of full-length intact L1s in mammalian genomes.
Experimental reduction of TE activity at the transcriptional or post-transcriptional levels does not provide
specific, stable and long-term L1 repression in complex tissues. This R21 proposal aims to make the first step
toward closing this gap in our understanding of the contribution of L1 to development and disease. We propose
an experimental strategy to gradually and systematically inactivate full-length L1 elements in the mouse genome
using the embryonic stem cell (ESC) model. We will monitor and quantify the extent of L1 mutagenesis and
ultimately identify candidate ESC clones whose developmental potential we will subsequently test in vivo. The
proposed research will provide the foundation for future rigorous tests for the role of L1s in development and
disease.
Relevance
Studies over the past decade implicated mobile element retrotransposon L1 in healthy development and disease.
If true, this contention will radically expand our understanding of the genetic foundations of human health and
pathology. We propose to test this hypothesis by systematically inactivating L1 elements in the genome of
mouse embryonic stem cells and characterizing the developmental potential of genomes lacking active L1
elements.

## Key facts

- **NIH application ID:** 9925240
- **Project number:** 5R21HG010512-02
- **Recipient organization:** CARNEGIE INSTITUTION OF WASHINGTON, D.C.
- **Principal Investigator:** ALEX BORTVIN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $214,663
- **Award type:** 5
- **Project period:** 2019-05-02 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925240

## Citation

> US National Institutes of Health, RePORTER application 9925240, A LINE-1 Retrotransposition-Deficient Mouse Genome (5R21HG010512-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9925240. Licensed CC0.

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