Stuart K. Kim, Ph.D.

Associate Professor of Developmental Biology and Genetics

The genomes for three animals have now been sequenced, providing biologists with a wonderful and powerful tool to explore the genetic basis of metazoan life. Nearly all of the genes have been identified in worms, flies and humans, and the next step is to uncover their function. We have produced DNA microarrays containing essentially every gene in C. elegans, and are using them as powerful functional genomics tools to examine expression changes on a global scale and thus speed up the process of genetic analysis. The use of DNA microarrays has allowed us to enter a new age in molecular genetics in which we can dissect cell, developmental and disease pathways more completely and more sensitively than ever before.

We are using global approaches to study development, behavior and aging in C. elegans. We have developed a method to isolate RNA from specific tissues, and used it to determine gene expression profiles for the germ line, muscles and neuronal tissues. We have scanned the entire genome for genes regulated by Ras signaling, Hox transcriptional control, and sex regulation. We are conducting a large study of gene expression changes during aging, in both normal worms and in long-lived mutants. Not only have these projects identified hundreds of new tissue-specific genes, but they have yielded several surprising results that only became apparent using a whole-genome approach. We have found that the entire X chromosome is inactivate in the germ line, and that expressed genes appear in bunches along the chromosome possibly due to chromatin domains. We have found a significant overlap between Ras targets in worms and cancer targets in humans, showing that the downstream response to Ras may be conserved during evolution and identifying key downstream targets of Ras signaling. Finally, we have discovered a significant overlap between aging-regulated genes and dauer genes (dauer is an alternative form that lives more than ten times longer than normal worms), possibly identifying genes that play an important role in the aging program.

We have performed more than 1200 C. elegans DNA microarray experiments, and have assembled them into a large gene expression database. One can now profile gene expression changes and find co-regulated genes not only from one experiment but from a wide variety of developmental and growth conditions. We visualized co-expressed genes using a three-dimensional gene expression topomap, in which co-regulated genes appear close together on one of 44 gene expression mountains. The expression toppomap can be used to ascribe functions to the large fraction of genes in the genome whose functions were previously unknown.