Citation | Distinguished for his pioneering work on fragile sites in human chromosomes and his discovery of trinocleotide repeat instability as a novel mechanism for human genetic disease. He was the first to show that fragile site expression in lymphocytes could be influenced by cell culture conditions, in particular withdrawal of folic acid, and used this discovery to develop reliable cytogenetic methods for detecting rare folate-sensitive fragile sites, including that for fragile X syndrome, the most common form of familial mental retardation. He was the first to clone the fragile X locus and to show that both the fragile site and mental retardation resulted from remarkable instability in a (CGG)n trinucleotide repeat array. He further showed that (CGG)n repeat instability was also responsible for an autosomal fragile site. His discovery of triplet repeat "dynamic mutation" has not only clarified the unusual genetics of fragile X mental retardation, but has opened up a much wider new field in human genetics and has provided the conceptual basis for identifying loci involved in other neurological diseases, including Huntington's chorea and myotonic dystrophy, which result from dynamic mutation. |