If reproductive isolation was to be caused by a single mutation, then the first individual to carry this mutation would likely have a very low fitness. At the extreme, in a purely sexually reproducing species without hermaprohiditism, this individual carrying the first mutation causing reproductive isolation would have no-one to reproduce with and would have a fitness of zero.
Hence, reproductive isolation is unlikely to arise from a single mutation as these mutations are unlikely to raise into appreciable frequency. Hence, Dobzhansky and Muller (and Bateson) created this minimalist model involving only two loci with negative epistatic interactions.