# Leveraging natural and directed evolution to dissect the functional consequences of sequence variation in human L1 retrotransposons

> **NIH NIH R35** · PACIFIC NORTHWEST RESEARCH INSTITUTE · 2024 · $109,451

## Abstract

PROJECT SUMMARY
Transposable elements have generated the majority of the sequence in the human genome, and all of human
biology has evolved in the ever-present DNA, RNA, and protein made by these self-replicating pieces of
selfish DNA. The replication of transposable elements constitutes a major source of new mutations in humans
which drive genome instability and a variety of genetic diseases. Our group previously discovered the rapid
evolution of several restriction factors of Long Interspersed Element-1 (L1), the endogenous retroelements most
active in humans. This pattern of evolution suggests that L1s have evolved to evade these restriction factors,
driving rapid host evolution to keep pace. However, it is unknown how sequence variation in L1s impacts
their ability to evade and replicate in the presence of host restriction factors.
We are specifically interested in understanding – have transposable elements evolved to evade the defense
mechanisms of the human genome? What are the mechanisms of transposable element evasion? What are the
consequences to human health of evasive transposable elements replicating at times and places they are
normally repressed? To answer these questions, our lab employs non-traditional combinations of approaches
including retrospective analyses of genomes to understand what has happened and prospective experiments to
ask what could happen. We propose to leverage the lab’s recently generated, diverse panel of more than 130
young human L1s to search for variation in the ability of L1s to replicate in the presence of otherwise effective
host restriction factors. This variation could indicate adaptation of an L1 to evade host restriction or adaptation
of the host to restrict evasive L1s. In addition to this retrospective analysis of evolutionary history, we propose to
‘speed up’ evolution by building an in vitro evolution system to select for L1s that evade a defined restriction
factor. Comparison of these historical and prospective evolutionary approaches will help us decode the
selective pressures that drove L1 and human evolution. This research will address a fascinating basic
science question about the mechanisms of L1 evolution in the face of the host innate immune system with impact
on our understanding of sporadic autoimmune diseases without a clear genetic contribution.
Our lab combines a dedication to mentorship and scientific outreach with effort to build a communicative
and accommodating space to enable creative, daring science. Our diverse and experienced team of scientists
integrates expertise in comparative genomics, genome evolution, L1 biology, in vitro evolution, and protein
evolution and function to bring an evolution-driven approach to the proposed projects. With our record of pushing
conceptual and technical boundaries to bring new understanding to the fields of protein evolution and
restriction factor biology, our team is uniquely poised to bring about a new understanding of L1 evolution and
biolo...

## Key facts

- **NIH application ID:** 11097399
- **Project number:** 3R35GM142773-04S1
- **Recipient organization:** PACIFIC NORTHWEST RESEARCH INSTITUTE
- **Principal Investigator:** Richard Noel McLaughlin
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $109,451
- **Award type:** 3
- **Project period:** 2021-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11097399

## Citation

> US National Institutes of Health, RePORTER application 11097399, Leveraging natural and directed evolution to dissect the functional consequences of sequence variation in human L1 retrotransposons (3R35GM142773-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11097399. Licensed CC0.

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