AbstractThe great gerbil (Rhombomys opimus) is a social rodent living in permanent, complex burrow systems distributed throughout Central Asia, where it serves as the main host of several important vector-borne infectious diseases and is defined as a key reservoir species for plague (Yersinia pestis). Studies from the wild have shown that the great gerbil is largely resistant to plague but the genetic basis for resistance is yet to be determined. Here, we present a highly contiguous annotated genome assembly of great gerbil, covering over 96 % of the estimated 2.47 Gb genome. Comparative genomic analyses focusing on the immune gene repertoire, reveal shared gene losses withinTLRgene families (i.e.TLR8, TLR10and all members ofTLR11-subfamily) for the Gerbillinae lineage, accompanied with signs of diversifying selection ofTLR7andTLR9. Most notably, we find a great gerbil-specific duplication of theMHCII DRBlocus.In silicoanalyses suggest that the duplicated gene provides high peptide binding affinity forYersiniaeepitopes. The great gerbil genome provides new insights into the genomic landscape that confers immunological resistance towards plague. The high affinity forYersiniaepitopes could be key in our understanding of the high resistance in great gerbils, putatively conferring a faster initiation of the adaptive immune response leading to survival of the infection. Our study demonstrates the power of studying zoonosis in natural hosts through the generation of a genome resource for further comparative and experimental work on plague survival and evolution of host-pathogen interactions.