Characterization of a strain-specific CD-1 reference genome reveals potential inter- and intra-strain functional variability

Abstract

Background: CD-1 is an outbred mouse stock that is frequently used in toxicology, pharmacology, and fundamental biomedical research. Although inbred strains are typically better suited for such studies due to minimal genetic variability, outbred stocks confer practical advantages over inbred strains, such as improved breeding performance and low cost. Knowledge of the full genetic variability of CD-1 would make it more useful in toxicology, pharmacology, and fundamental biomedical research. Results: We performed deep genomic DNA sequencing of CD-1 mice and used the data to identify genome-wide SNPs, indels, and germline transposable elements relative to the mm10 reference genome. We used multiple genome-wide sequencing data types and previously published CD-1 SNPs to validate our called variants. We used the called variants to construct a strain-specific CD-1 reference genome, which we show can improve mappability and reduce experimental biases from genome-wide sequencing data derived from CD-1 mice. Based on previously published ChIP-seq and ATAC-seq data, we find evidence that genetic variation between CD-1 individuals can lead to alterations in transcription factor binding. We also identified a number of variants in the coding region of genes which could have effects on splicing and translation of genes. Conclusions: We have identified millions of previously unidentified CD-1 variants with the potential to confound studies involving CD-1. We used the identified variants to construct a CD-1-specific reference genome, which can improve accuracy and reduce bias when aligning genomics data derived from CD-1 individuals.

Transposable elements acquire time- and sex-specific transcriptional and epigenetic signatures along mouse fetal gonad development

“…As such, they potentially contribute to the specie-specific characteristics of TESCO activity. In the same line, several studies have shown that TEs are highly heterogeneous between mouse strains (Nellaker et al, 2012;Jung et al, 2023) that can modify gene expression (Zhou et al, 2021) and chromatin dynamics (Ferraj et al, 2023). Therefore, we can speculate that strain-specific TEs could be involved in the sensitivity of a C57BL/6J background to sex reversal (Eicher et al, 1982;Eicher et al, 1996;Munger et al, 2009).…”

“…Concerning strain specificity, the motif composition might vary depending of the mouse strain and influence subsequent recognition by DNA-binding proteins as it has been shown for CTCF in the mouse CD-1 strain (Jung, et al, 2023).…”

Stem cell transcriptional profiles from mouse subspecies revealcis-regulatory evolution at translation genes

“…For analysis of transcriptomes of homozygous CAST/EiJ and C57BL/6J stem cells cultured in-house (see below), we downloaded raw reads and mapped them to the corresponding reference genome for the respective strain (CAST/EiJ or GRCm38). For validation of the role of candidate transcription factors in translation regulation in stem cells, we mapped RNA-seq from Ehmt2 knockout embryos (NCBI accession GSE71500; Auclair et al ., 2016) and their corresponding wild-type to the GRCm38 reference, and we mapped RNA-seq from Eed knockout stem cells and their corresponding wild-type to the CD-1 reference genome (NCBI accession GSE209815; Jung et al ., 2023).…”