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Multiplex Detection of Bacteria in Complex Clinical and Environmental Samples using Oligonucleotide-coupled Fluorescent Microspheres

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Multiplexed in vivo base editing identifies functional gene-variant-context interactions.

Jonuelle Acosta^1,2, Grace A Johnson^1,2, Samuel I Gould^1,2

¹Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Biorxiv : the Preprint Server for Biology

|March 10, 2025

Summary

This summary is machine-generated.

This study introduces a new in vivo platform using base editing to analyze cancer-associated genetic variants in mice. The findings reveal the crucial role of the in vivo environment and highlight limitations of standard CRISPR-Cas9 approaches for variant functional analysis.

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Area of Science:

Genomics
Cancer Biology
Genetic Engineering

Background:

Human genome sequencing identifies numerous genetic variants linked to cancer predisposition, progression, and treatment outcomes.
Understanding the functional impact and relative importance of these variants in their native context is crucial for clinical applications.
Current methods for studying genetic variants in vivo are limited, hindering comprehensive analysis of their physiological roles.

Purpose of the Study:

To develop a multiplexed in vivo platform for systematic functional analysis of endogenous genetic variants in cancer.
To investigate the impact of the physiological in vivo environment and cellular organotropism on gene-variant phenotypes.
To compare the efficacy of base editing with standard CRISPR-Cas9 nuclease approaches for variant analysis.

Main Methods:

Integration of cross-species base editing sensor libraries with syngeneic cancer mouse models.
Development of a multiplexed in vivo platform for high-throughput screening of genetic variants.
Engineering and phenotyping of 7,783 human cancer-associated mutations across 489 genes using 13,840 guide RNAs.

Main Results:

Construction of a comprehensive compendium of gene-mutation-context interactions in vivo.
Demonstration that the in vivo environment and organotropism significantly influence gene-variant phenotypes.
Identification of mutations and their in vivo effects missed by standard CRISPR-Cas9 approaches, revealing potential site-specific mechanisms.

Conclusions:

The developed in vivo platform enables systematic functional interrogation of genetic variants in their native physiological context.
The study underscores the importance of the in vivo microenvironment in determining the phenotypic consequences of genetic variations.
This versatile platform offers a powerful tool for investigating genetic variation in cancer and other diseases, potentially uncovering new therapeutic strategies.