Germ Cell Mutagenesis Testing in Transgenic Models

Assessing mutagenic effects in the germ line is essential for understanding reproductive risks, heritable genetic disorders and long-term population health. Transgenic models, especially rodents engineered to carry reporter genes, have become central to these evaluations. Such models integrate bacterial or viral reporter sequences into the genome, permitting quantification and sequencing of induced mutations in sperm or early embryos. Beyond conventional plaque or selection assays, modern applications pair these reporter systems with high-accuracy, error-corrected sequencing, enabling detection of ultra-rare base substitutions, insertions and deletions. These methods reveal dose-dependent mutation frequencies, trinucleotide substitution patterns and regional susceptibility across genome contexts. They also facilitate direct measurement of de novo mutations transmitted to offspring following chemical or environmental exposure. Insights from transgenic germ cell mutagenesis testing inform regulatory safety frameworks, mechanistic understanding of mutational processes, and the identification of environmental agents that contribute to human disease signatures.

Research from Nature Portfolio

Recent studies have harnessed duplex sequencing to refine measurement of de novo mutation frequencies and spectra in human sperm, achieving error rates below one per billion base pairs and uncovering a mutation spectrum closely matching trio-based whole-genome analyses. The approach revealed an unexpected abundance of small insertions and deletions in sperm, attributed to extrachromosomal circular DNA elements, highlighting novel mutational sources in the male germ line. Another investigation applied next-generation sequencing to lacZ reporter mutations in the bone marrow of transgenic mice exposed to diverse chemical mutagens, revealing distinct substitution signatures that parallel those found in human cancers and offering a powerful platform for environmental carcinogen assessment.

Research from all publishers

In transgenic MutaMouse models, duplex sequencing has been applied to assess bone marrow mutations following procarbazine exposure, demonstrating lower variability and higher sensitivity than classical reporter assays, and enabling the detection of mutational increases at previously undetectable doses. A separate study in transgenic rodents exposed to benzo[a]pyrene mapped mutation induction across genic and intergenic targets, revealing heightened susceptibility in heterochromatic regions and distinct C:G→A:T transversion patterns tied to trinucleotide contexts. Additionally, whole-exome sequencing of offspring from ethyl nitrosourea-treated gpt delta mice quantified inherited germline mutations, confirming a marked increase in de novo single-nucleotide variants and establishing direct sequencing of transgenic models as a robust tool for transgenerational mutagenesis assessment.

Germ Cell Mutagenesis Testing in Transgenic Models publication trend

The graph below shows the total number of articles in germ cell mutagenesis testing in transgenic models across all publications each year (not limited to Nature Index journals).

Technical terms

Duplex Sequencing: An error-corrected sequencing method that independently tags and compares both DNA strands to eliminate artefacts and detect ultra-rare mutations.

Transgenic rodent mutation reporter assay: An in vivo test using rodents carrying an exogenous reporter gene to quantify induced mutations in somatic or germ cells.

De novo mutation: A genetic alteration that arises spontaneously in a gamete or early embryo and is transmitted to offspring but absent in parental genomes.

Mutation spectrum: The distribution of mutation types and nucleotide changes observed within a genomic region, often classified by base substitution categories and sequence context.

References

1. Duplex sequencing provides detailed characterization of mutation frequencies and spectra in the bone marrow of MutaMouse males exposed to procarbazine hydrochloride. Archives of Toxicology (2023).
2. Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses. Scientific Reports (2024).
3. Chemically induced mutations in a MutaMouse reporter gene inform mechanisms underlying human cancer mutational signatures. Communications Biology (2020).
4. Duplex sequencing identifies genomic features that determine susceptibility to benzo(a)pyrene-induced in vivo mutations. BMC Genomics (2022).
5. Estimation of the frequency of inherited germline mutations by whole exome sequencing in ethyl nitrosourea-treated and untreated gpt delta mice. Genes and Environment (2016).