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Protein coding variation in the J:ARC and J:DO outbred laboratory mouse stocks provides a molecular basis for distinct research applications. | LitMetric

AI Article Synopsis

  • Outbred laboratory mice (Mus musculus) are popular in biomedical research due to their high reproduction rates and availability, and high throughput genome sequencing (HTS) helps ensure the genetic quality and reproducibility of studies using these mice.
  • A study on a newly established Swiss-derived outbred population (J:ARC) utilized exome sequencing to explore their genetic architecture and found characteristics typical of well-maintained outbred stocks, comparing it to the Diversity Outbred (J:DO) stock.
  • The J:DO stock showed greater genetic variation and interindividual variability but had a higher frequency of potentially damaging genetic variants, indicating that diverse genetic backgrounds can help buffer against harmful mutations under varying selective pressures.

Article Abstract

Outbred laboratory mice (Mus musculus) are readily available and have high fecundity, making them a popular choice in biomedical research, especially toxicological and pharmacological applications. Direct high throughput genome sequencing (HTS) of these widely used research animals is an important genetic quality control measure that enhances research reproducibility. HTS data have been used to confirm the common origin of outbred stocks and to molecularly define distinct outbred populations. But these data have also revealed unexpected population structure and homozygosity in some populations; genetic features that emerge when outbred stocks are not properly maintained. We used exome sequencing to discover and interrogate protein-coding variation in a newly established population of Swiss-derived outbred stock (J:ARC) that is closely related to other, commonly used CD-1 outbred populations. We used these data to describe the genetic architecture of the J:ARC population including heterozygosity, minor allele frequency, LD decay, and we defined novel, protein-coding sequence variation. These data reveal the expected genetic architecture for a properly maintained outbred stock and provide a basis for the on-going genetic quality control. We also compared these data to protein-coding variation found in a multiparent outbred stock, the Diversity Outbred (J:DO). We found that the more recently derived, multiparent outbred stock has significantly higher interindividual variability, greater overall genetic variation, higher heterozygosity, and fewer novel variants than the Swiss-derived J:ARC stock. However, among the novel variants found in the J:DO stock, significantly more are predicted to be protein-damaging. The fact that individuals from this population can tolerate a higher load of potentially damaging variants highlights the buffering effects of allelic diversity and the differing selective pressures in these stocks. While both outbred stocks offer significant individual heterozygosity, our data provide a molecular basis for their intended applications, where the J:DO are best suited for studies requiring maximum, population-level genetic diversity and power for mapping, while the J:ARC are best suited as a general-purpose outbred stock with robust fecundity, relatively low allelic diversity, and less potential for extreme phenotypic variability.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10085793PMC
http://dx.doi.org/10.1093/g3journal/jkad015DOI Listing

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