Comparative　genome　sequencing　analysis　of　a　lincomycin-resistant　strain　of　Streptomyces　coelicolor　A3(2)　and　the　wild-type　strain　identified　a　novel　mutation　conferring　a　high　level　of　lincomycin　resistance.　Surprisingly,　the　new　mutation　was　an　in-frame　DNA　deletion　in　the　genes　SCO4597　and　SCO4598,　resulting　in　formation　of　the　hybrid　gene　linR.　SCO4597　and　SCO4598　encode　two　histidine　kinases,　which　together　with　SCO4596,　encoding　a　response　regulator,　constitute　a　unique　two-component　system.　Sequence　analysis　indicated　that　these　three　genes　and　their　arrangement　patterns　are　ubiquitous　among　all　Streptomyces　genomes　sequenced　to　date,　suggesting　these　genes　play　important　regulatory　roles.　Gene　replacement　showed　that　this　mutation　was　responsible　for　the　high　level　of　lincomycin　resistance,　the　overproduction　of　the　antibiotic　actinorhodin,　and　the　enhanced　morphological　differentiation　of　this　strain.　Moreover,　heterologous　expression　of　the　hybrid　gene　linR　in　Escherichia　coli　conferred　resistance　to　lincomycin　in　this　organism.　Introduction　of　the　hybrid　gene　linR　in　various　Streptomyces　strains　by　gene　engineering　technology　may　widely　activate　and/or　enhance　antibiotic　production.