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Mammalian ALR proteins bind nucleic acids and initiate production of type I interferons or inflammasome assembly, thereby contributing to host innate immunity.ALRs are encoded at a single genetic locus. In mice, theAlrlocus is highly polymorphic at the sequence and copy number level. We suggest that one rapidly evolving member of theAlrfamily,Ifi207, was introduced to theMusgenome by a recent recombination event.Ifi207has a large, distinctive repeat region that differs in sequence and length in differentMusstrains. We show that IFI207 plays a key role in the STING-mediated response to cGAMP, DNA, and MLV, and that IFI207 controls MLV infection in vivo. Uniquely, IFI207 acts by stabilizing STING protein via its repeat region. Our studies suggest that under the pressure of host-pathogen coevolution, in a dynamic locus such as theAlr, recombination between gene family members creates new genes with novel and essential functions that play diverse roles in biological processes.

Hematopoietic stem cells (HSCs) reside in the bone marrow (BM), can self-renew, and generate all cells of the hematopoietic system. 1 Most hematopoietic lineages arise through successive, increasingly lineage-committed progenitors. In contrast, megakaryocytes (MKs), hyperploid cells that generate platelets essential to hemostasis, can derive rapidly and directly from HSCs. 2 The underlying mechanism is unknown however. Here we show that DNA damage and subsequent arrest in the G2 phase of the cell cycle rapidly induce MK commitment specifically in HSCs, but not in progenitors, through an initially predominantly post-transcriptional mechanism. Cycling HSCs show extensive replication-induced DNA damage associated with uracil misincorporation in vivo and in vitro . Consistent with this notion, thymidine attenuated DNA damage, rescued HSC maintenance and reduced the generation of CD41 + MK-committed HSCs in vitro . Similarly, overexpression of the dUTP-scavenging enzyme, dUTPase, enhanced in vitro maintenance of HSCs. We conclude that a DNA damage response drives direct megakaryopoiesis and that replication stress-induced direct megakaryopoiesis, at least in part caused by uracil misincorporation, is a barrier to HSC maintenance in vitro . DNA damage-induced direct megakaryopoiesis may allow rapid generation of a lineage essential to immediate organismal survival, while simultaneously removing damaged HSCs and potentially avoiding malignant transformation of self-renewing stem cells.

Mammalian ALR proteins bind nucleic acids and initiate production of type I interferons or inflammasome assembly, thereby contributing to host innate immunity. ALR s are encoded at a single genetic locus. In mice, the Alr locus is highly polymorphic at the sequence and copy number level. We suggest that one rapidly evolving member of the Alr family, Ifi207 , was introduced to the Mus genome by a recent recombination event. Ifi207 has a large, distinctive repeat region that differs in sequence and length in different Mus strains. We show that IFI207 plays a key role in the STING-mediated response to cGAMP, DNA, and MLV, and that IFI207 controls MLV infection in vivo. Uniquely, IFI207 acts by stabilizing STING protein via its repeat region. Our studies suggest that under the pressure of host-pathogen coevolution, in a dynamic locus such as the Alr , recombination between gene family members creates new genes with novel and essential functions that play diverse roles in biological processes.