Wheat streak mosaic virus (WSMV) causes streak mosaic disease in wheat (Triticum aestivum L.) and has been an important constraint limiting wheat production in many regions around the world. Wsm2 is the only resistance gene discovered in wheat genome and has been located in a short genomic region of its chromosome 3B. However, the sequence nature and the biological function of Wsm2 remain unknown due to the difficulty of genetic manipulation in wheat. In this study, we tested WSMV infectivity among wheat and its two closely related grass species, rice (Oryza sativa) and Brachypodium distachyon. Based on the phenotypic result and previous genomic studies, we developed a novel bioinformatics pipeline for interpreting a potential biological function of Wsm2 and its ancestor locus in wheat. In the WSMV resistance tests, we found that rice has a WMSV resistance gene while Brachypodium does not, which allowed us to hypothesize the presence of a Wsm2 ortholog in rice. Our OrthoMCL analysis of protein coding genes on wheat chromosome 3B and its syntenic chromosomes in rice and Brachypodium discovered 4,035 OrthoMCL groups as preliminary candidates of Wsm2 orthologs. Given that Wsm2 is likely duplicated through an intrachromosomal illegitimate recombination and that Wsm2 is dominant, we inferred that this new WSMV-resistance gene acquired an activation domain, lost an inhibition domain, or gained high expression compared to its ancestor locus. Through comparison, we identified that 67, 16, and 10 out of 4,035 OrthoMCL orthologous groups contain a rice member with 25% shorter or longer in length, or 10 fold more expression, respectively, than those from wheat and Brachypodium. Taken together, we predicted a total of 93 good candidates for a Wsm2 ancestor locus. All of these 93 candidates are not tightly linked with Wsm2, indicative of the role of illegitimate recombination in the birth of Wsm2. Further sequence analysis suggests that the protein products of Wsm2 may combat WSMV disease through a molecular mechanism involving protein degradation and/or membrane trafficking. The 93 putative Wsm2 ancestor loci discovered in this study could serve as good candidates for future genetic isolation of the true Wsm2 locus.