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In-vitro Mutagenesis

In-vitro Mutagenesis

To learn more about the function of a gene, researchers can observe what happens when the gene is inactivated or “knocked out,” by creating genetically engineered knockout animals. Knockout mice have been particularly useful as models for human diseases such as cancer, Parkinson’s disease, and diabetes.

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Related Experiment Video

Updated: Sep 30, 2025

Surgical Method for Virally Mediated Gene Delivery to the Mouse Inner Ear through the Round Window Membrane

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Published on: March 16, 2015

Identification and characterisation of spontaneous mutations causing deafness from a targeted knockout programme.

Morag A Lewis^1,2, Neil J Ingham^3,4, Jing Chen^3,4

¹Wolfson Centre for Age-Related Diseases, King's College London, London, SE1 1UL, England. Morag.lewis@kcl.ac.uk.

|March 17, 2022

Summary

Spontaneous mutations frequently arise during mouse breeding programs, impacting genetic studies. Careful record-keeping and pedigree analysis are crucial to distinguish these from targeted mutations and ensure accurate research findings.

Keywords:

Deafness Large-scale mutagenesis programme Non-segregating phenotypes Progressive hearing loss Spontaneous mutations

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Last Updated: Sep 30, 2025

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Area of Science:

Genetics
Genomics
Developmental Biology

Background:

Targeted mutation programs in mice are essential for studying gene function and disease.
Generating targeted alleles and culturing embryonic stem cells can introduce spontaneous mutations.
Identifying spontaneous mutations is challenging as they may not segregate with targeted alleles and phenotypes can be subtle.

Purpose of the Study:

To assess the frequency and impact of spontaneous mutations in a large-scale targeted mouse knockout program.
To identify the origins of spontaneous mutations occurring during breeding and stem cell procedures.
To emphasize the importance of rigorous record-keeping and pedigree management in genetic research.

Main Methods:

Analysis of 1311 mouse lines generated through a targeted knockout program.
Phenotypic assessment using Auditory Brainstem Response (ABR) and behavioral tests to detect hearing and vestibular dysfunction.
Genetic analysis to identify causative mutations, including deletions, insertions, and point mutations.
Investigation of embryonic stem cells to determine mutation origin.

Main Results:

25 out of 1311 lines exhibited deafness phenotypes unlinked to the targeted allele.
Eight lines with various progressive or complete hearing loss and vestibular dysfunction were isolated.
Causative mutations included novel genes and new alleles of known hearing loss genes.
Most spontaneous mutations arose during breeding, not in embryonic stem cells, with one occurring in a wildtype colony.

Conclusions:

Spontaneous mutations are a common occurrence in intensive mouse breeding programs, including targeted mutation efforts.
These mutations can confound phenotypic analyses of targeted alleles.
Accurate record-keeping and pedigree maintenance are critical for reliable genetic research.