A major interest of our lab is mutation in the human germline. We are using single molecule PCR analysis to study the patterns of mutational change that occur at human disease loci. Our studies on human mutation focus on loci that exhibit the paternal age effect. An example is the locus that codes for the FGFR3 protein. Mutations in this protein cause achondroplasia, the most common form of dwarfism. We are also studying Apert syndrome due to mutations in the FGFR2 gene. It has been known for a long time that older men are more likely to have children with these mutations. The basic premise of the paternal age effect is that as men age, they produce more sperm carrying a de novo mutation. Attempts to use sperm DNA to test this assumption were made for the first time only within the last few years. We are interested in two major features of the paternal age effect; 1) the reason for the fact that mutations that exhibit the paternal age effect occur only in males and 2) why the mutation frequency is 100-1000 times greater for these mutations than the average nucleotide site. We are focusing on the role that germline selection may play in increasing the frequency of these genetic conditions beyond the level of mutation events that give rise to a nucleotide substitution.

Aging and Development Biology, Biochemistry, Molecular Biology