Project 6: Application of chemical tools to human genetic circadian variants

Dr. Louis Ptácek and Dr. Ying-Hui Fu, Project Leaders

In The News

Several years ago, an autosomal dominant circadian rhythm variant was described in humans. We called this familial advanced sleep phase syndrome (FASPS). Since characterization of the initial large family and cloning and characterization of the gene and genetic variant causing this phenotype in that family, we have built a large database of clinical FASPS families. In sequencing candidate genes in probands from each of these families, we have identified genetic variants in 4 additional genes that cause the FASPS behavior. These human genetic variants will be engineered into orthologous genes of the mouse. These mice representing human circadian variants can be tested with chemical tools that are predicted to have effects on circadian function on other bases, as well as for biochemical alterations in function. As new human genetic variants are identified, mouse models will be generated and tested for circadian and other phenotypes.

Interestingly, our studies on subjects in FASPS families indicate that other aspects of behavior may be linked to circadian function (learning and memory, behavioral activation, etc.), which can be examined in mice in a more straightforward way. Thus the new knowledge gained from experiments in mice and in human FASPS subjects will occur in parallel and be synergistic for framing and testing new hypotheses.

Finally, it is interesting that the majority of our FASPS families who meet the strict criteria for the FASPS phenotype do not have recognizable genetic variations in the known candidate genes. This suggests that other non-coding variants in these genes may contribute to the phenotype and that other genes not predicted by work in model organisms also contribute to human circadian function. Thus, screening of these research subject DNAs for genetic variations in novel genes predicted by screens for chemical tools affecting circadian function will be an exciting opportunity to validate these genes and proteins in an independent way as being critical for circadian function.