This is the central question that we seek to answer. We apply both computational and experimental approaches in our study.

To design powerful tools for genetic research

• Can you predict genetic interactions?

  Genetic interactions specify how genes function together to carry out a biological process. Genes are more likely to interact with each other if they have related phenotypes, similar expression profiles, or interacting orthologs. We have designed a bioinformatic system, GeneOrienteer, to integrate these data with proper statistical models to predict genetic interactions.

   
• Can you build a robot biologist?

  The bottleneck of genetic research is measuring defects caused by gene inactivation. We have developed an automatic imaging system, QuantWorm, to quantitatively measure multiple C. elegans phenotypes such as locomotion, chemotaxis, sex ratio, body length, lifespan, and reproduction. In collaboration with Dr. Marcia O'Malley's group, we have developed a robotic sample handling system.

   

To identify gene networks underlying development and behavior

• What genes are involved in movement disorders?

  We screened over 200 mutants of neuronal signaling genes for movement disorders. For each mutant, we measured 76 parameters of locomotive behaviors. We discovered 87 genes whose inactivation causes movement defects, including 50 genes that had never been associated with locomotive defects. Computational analysis predicted a functional network of these genes. Our data can be accessed at WormLoco.

   
• Do worms fear death?

  We found that C. elegans can detect and avoid a chemical cue released from injured nematodes. Genetic analysis mapped the genetic and cellular circuitry modulating this alarm response. We are studying the chemical identity of this alarm cue.

   
• How do genes regulate sex ratio?

  There are over 100 genes whose mutation can cause an increased percentage of males in C. elegans, including brd-1 and brc-1, which are homologs of human breast cancer genes BARD1 and BRCA1. We applied quantitative epistasis analysis to map the interaction network of these genes. We also found that the majority of genes interacting with brd-1 and brc-1 are also required for DNA damage response as knockdown of these genes increased the rate of apoptosis and embryonic lethality after UV exposure.

   
• How do genes regulate body size?

  There are over 100 genes whose mutation can cause body size defects C. elegans, including many human disease related genes. We are using quantitative epistasis analysis to map the interaction network of body size genes.

   

To elucidate environmental contexts of genome function

• Are these chemicals toxic or therapeutical?

  In collaboration with Drs. Qilin Li (Environmental Engineering) and Vicki Colvin (Chemistry), we are using C. elegans to examine possible toxicity effects of engineered nanoparticles and to identify the molecular pathways affected by the nanoparticle exposure. In this screen, animals were exposed to various chemicals and we analyze the effects of the chemicals on worm lifespan, behavior, and development. Any chemical with either toxic or therapeutical effects will be further analyzed using various mutants to identify its molecular targets

• How does a virus interact with host genes?

  The RNA virus Orsay infects C. elegans only. Its genome encodes only three proteins: Capsid, RNA polymerase, and Delta. In collaboration with Dr. Jane Tao (Biochemistry and Cell Biology), we are studying the structure and function of these proteins to understand how they interact with C. elegans host cells.

Hypothesis-driven research is a process of two steps: hypothesis generation and experimental verification. We develop and apply high-throughput tools for both steps in our exploration. We use bioinformatics to predict genetic interactions and automation to expedite experimental testing. With this systems biology approach, we expect to bring new insights to genome function.