The 129 strain-derived passenger mutations in ACKR1-deficient mice alter the expression of PYHIN and Fc-gamma receptor genes.

Most genetically modified mice have been produced using 129 strain-derived embryonic stem cells. Despite ample backcrosses with other strains, these may retain characteristics for 129 passenger mutations, leading to confounding phenotypes unrelated to targeted genes. Here we show that widely used Ackr1-/-129ES mice have approximately 6 Mb of the 129-derived genome retained adjacently to the Ackr1 locus on chromosome 1, including several characteristic polymorphisms. These most notably affect the expression of PYHIN and Fc-gamma receptor genes in myeloid cells, resulting in the overproduction of IL-1β by activated macrophages and the loss of Fc-gamma receptors on myeloid progenitor cells. Therefore, caution is warranted when interpreting Ackr1-/-129ES mouse phenotypes as being solely due to the ACKR1 deficiency. Our findings call for a careful reevaluation of data from previous studies using Ackr1-/-129ES mice and underscore the limitations and pitfalls inherent to mouse models produced using traditional genetic engineering techniques involving 129 embryonic stem cells.