The use of synthetic oligonucleotides as specific probes for genetic sequence variations was pioneered by R. Bruce Wallace, working at the City of Hope National Medical Center in Duarte, California. In 1979 Wallace and his coworkers reported the use of ASO probes to detect variations in a single-stranded bacterial virus, and later applied the technique to cloned human genes. In 1983 and 1985 Wallace's lab reported the detection of the mutation for sickle cell anemia in samples of whole genomic DNA, although this application was hampered by the small amount of label that could be carried by the ASO.
Fortunately PCR, a method to greatly amplify a specific segment of DNA, was also reported in 1985. In less than a year PCR had been paired with ASO analysis. This combination solved the problem of ASO labeling, since the amount of target DNA could be amplified over a million-fold. Also, the specificity of the PCR process itself could be added to that of the ASO probes, greatly reducing the problem of spurious binding of the ASO to non-target sequences. The combination was specific enough that it could be used in a simple Dot blot, avoiding the laborious and inefficient Southern blot method.