Human-like APOBEC3 gene expression and anti-viral responses following replacement of mouse Apobec3 with the 7-gene human APOBEC3 locus

Abstract

The seven human APOBEC3 (hA3) genes encode polynucleotide cytidine deaminases that play vital roles in restricting replication of viruses and retrotransposons. However, off-target A3 deamination of the cellular genome is a major source of somatic mutations in human cancer. The ability to study A3 biology in vivo is hindered by the fact that the solitary murine Apobec3 gene (mA3) encodes a cytoplasmic enzyme, with no apparent mutagenic activity. Transgenic expression of individual hA3 genes in mice has helped to confirm their oncogenic potential but important questions including which hA3 genes are active in different tissue contexts and how they function in concert when under control of their cognate promoters cannot be addressed using these models. Here we describe humanization of the mouse mA3 locus by integration of a modified BAC clone encompassing the entire 7-gene hA3 locus from human chromosome 22 replacing mA3 on mouse chromosome 15. APOBEC3 mice are viable and fertile and hA3 gene expression in cells and tissues correlates strongly with expression in corresponding human cells and tissues, indicating human-like regulation of hA3 gene expression in the mice. Splenocytes from this line display a functional human A3 response to Friend Murine Leukaemia Virus (F-MLV) infection. We propose that the Hs-APOBEC3 mouse will uniquely model the function of the complete hA3 locus in a living organism and that it will serve as a useful background upon which to model human cancer, as well as assisting drug discovery efforts.