What is Collaborative Cross Recombinant Inbred (CC-RI) mice?

I was nicely surprised to see that on October 30, 2014, journal Science published an online article, in advance of print, that described experimental results with Ebola virus using Collaborative Cross recombinant inbred (CC-RI) mice.

Just day before, on October 29, 2014, I suggested that the common laboratory mice strains, like B6 or Balb/c, may not represent an adequate experimental models to study viral-host interactions relevant for human health.

To overcome some of the limitations of common laboratory mice, the authors in this paper have used so-called Collaborative Cross recombinant inbred (CC-RI) mice.

Honestly, I have not heard about these mice until I read this paper. So I read a little bit about CC-RI mice to understand the advantage of using them in this study. It appears that these CC-R inbred mice are derived from eight founders (C57BL/6J, A/J, 129S1/SvImJ, NOD/ShiLtJ, NZO/H1LtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ) that capture around 90% of gene diversity in all mouse.

I would like to explain how CC-RI mice are useful. For example, take as an example Ebola virus and host susceptibility or resistance to it as in this paper.

How to study which genes confers resistance or susceptibility to Ebola? What will be your control? Any given laboratory mouse strain will have an unique response to Ebola virus. Trying to compare two laboratory mouse strains may provide information that one strain is more or less susceptible or resistance compared to other mouse strain [to Ebola virus], but it will not tell you what makes this difference. Why is that? Because gene difference between mouse strains is too huge and there is no way to pinpoint to any gene of gene loci.

Here is where having CC-RI mice are helpful. Starting from eight founder strains, CC-RI mice are derived by multiple, marker-assisted inter-crossing between founder strains and their F1 off-springs. In the end, one can get CC-RI mice that differs from other CC-RI mice with just small known loci in entire genome. This locus or loci may contain either just one gene or few genes. Of course, number of CC-RI mice strains will be in hundreds.

See Genetics. Feb 2012; 190(2): 389–401.

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Now, one can conduct experiment on these different CC-RI mice and determine what gene or gene loci are responsible for observed phenotype.

In this new science paper the authors have used 47 CC-RI mice strains, 4-5 mice per group or per time point. The authors found that endothelial tyrosine kinases Tek (Tie2), determines susceptibility to Ebola virus in CC-RI mice. TEK signaling promote activation of coagulation factors, such as thrombin, so it make sense if considering that Ebola virus affects blood coagulation timing.

This type of experiments require enormous resources (imagine conducting experiments on hundreds of different CC-RI mice strain with 5-8 mice in each strain).

I hope someone will come up with new idea how to do this type of screening easier way.

posted by David Usharauli

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