Allan C. Spradling, Ph.D., principal investigator and director, department of embryology, Carnegie Institution for Science; investigator, Howard Hughes Medical Institute
The biggest current obstacle to further advances in metazoan biology and medicine is limited understanding of chromosome replication. How epigenetic information is faithfully transmitted during this process remains a puzzle equivalent in magnitude to the problem of genetic inheritance in the mid-20th century. Dr. Spradling and his colleagues have developed a procedure using GFP variegation that allows epigenetic inheritance to be followed at the single cell level during the progenitor phase of Drosophila follicle cell development. By identifying enhancers and suppressors of variegation, they have found that the histone demethylase Lsd1 plays a critical role in a complex with CoREST in maintaining the progenitor state and controlling the onset of cell differentiation via a cell autonomous process of chromatin and cell cycle changes. Follicle cells switch to the endocycle as they start to differentiate, like virtually all larval and many adult cell types. Using NextGen sequencing of DNA from giant polytene cells of the larval salivary gland, the lab has shown that sporadic incomplete replication during the endocycle S phase alters the germline genome at thousands of sites that differ in every cell. These highly non-random but individually rare alterations encompass at least 20 percent of the euchromatic genome and change the structure and dosage of genes and regulatory regions in ways predicted to enhance the diversity of gene expression. Large genes encoding IgG superfamily proteins, cell surface and adhesion proteins and key transcription factors are preferentially affected, suggesting that incomplete replication is functionally important in at least some cell types, such as the developing nervous system. Incomplete replication may be a widespread mechanism even in diploid cells that in certain circumstances leads to targeted somatic DNA alterations of potential significance.
Dr. Spradling earned his PhD. in cell biology in 1975 at the Massachusetts Institute of Technology, where he used Drosophila polytene chromosomes as genome arrays to study transcription, and found that heat shock causes a universal genetic response. Following work as a research assistant at MIT, he was a postdoctoral fellow from 1976 to 1979 at Indiana University, and in 1980 he joined the Carnegie Institution of Washington. Dr. Spradling has been an adjunct professor at Johns Hopkins University since 1983 and has been a Howard Hughes Medical Institute investigator since 1988. He was was appointed director of the Carnegie Institution in 1994. A member of the National Academy of Sciences (NAS) since 1989, Dr. Spradling has been awarded many prizes for his work, including the NAS Molecular Biology Award and the Newcomb Cleveland Prize (both jointly with Gerry Rubin), the E.J. Conklin Award of the Society for Developmental Biology, the G.W. Beadle Award of the Genetics Society of America, the M.C. Chang Award and the 2008 Gruber Prize in Genetics.