The genome is more than a parts list — it functions as an assembly manual that directs when and where genes are to be expressed in response to signals conveyed by proteins. Although new technologies have been perfected that provide a genome-wide view of the expression of mRNA, the blueprint for proteins, it has still not become clear how regulatory DNA codes for mRNA’s expression. Decoding the regulatory part of the genome is challenging, however, as more genomes are sequenced, it becomes possible to compare regions of regulatory DNA and infer functional units.

Dr. Siggia’s lab has developed an algorithm called Stubb to identify regulatory modules computationally. Using Stubb, his lab has scanned the genome of the fruit fly Drosophila melanogaster to calculate the number and location of clusters of binding sites. Fruitful tests include the segmentation gene hierarchy, which patterns the developing embryo through a genetic cascade. Dr. Siggia’s lab is using this signaling pathway as a prototype of combinatorial control to determine new blastoderm patterned genes as well as new regulatory modules. The Stubb algorithm also can examine related genomes and score regulatory regions by their degree of functional variation. By computationally screening the large set of blastoderm modules, Dr. Siggia has found modules that disappeared or moved to nonhomologous but adjacent regions of the genome.

The Siggia lab has also exploited an underappreciated resource to decipher the function of regulatory DNA: modeling the binding preferences of transcription factors by homology with the database of protein-DNA co-crystals. The lab has shown that even a modest bias toward the correct motif can substantially boost the performance of tools that rely only on sequence. Dr. Siggia and his colleagues have also modeled the sequence dependence of the binding between a nucleosome and DNA, thus looking simultaneously at nucleosomes and factors as they compete for binding to the DNA.

As the cost of resequencing entire genomes decreases, new kinds of bioinformatics experiments have become possible. In collaboration with the Tomasz lab, Dr. Siggia has examined the evolution of a Staphylococcus aureus infection in a single patient as it developed resistance to antibiotics over a three month period. The Siggia lab sequenced the first and last isolates and found only 34 point mutations, which appeared incrementally in the strains isolated at intermediate times from the patient. By analyzing the sequences, Dr. Siggia identified about a quarter that could plausibly impact resistance, and showed that a number of the same operons were also mutated in other resistant strains.

Another collaboration, with Rockefeller’s Frederick Cross, uses analysis of gene expression in yeast to design experiments that probe the “grammar” of regulatory elements. Though seldom stated, most of the sites of the best-characterized factors in yeast do not imply expression for their cognate genes, and chip analysis and comparative sequence data has not yet revealed what the inhibitory motifs might be. Selection experiments in yeast, using randomly ligated regulatory elements, has generated hundreds of functional and nonfunctional promoters, built from a very limited number of “words.”

Another area of interest for the Siggia lab is in modeling cell division. The cell cycle in budding yeast is a network for which most of the parts are known, yet predicting how they will work together remains a challenge. Together with the Cross lab, Dr. Siggia is making movies of growing yeast colonies over five or more divisions while following various markers. The analysis of these movies using custom software has led to several new insights into the transitions between phases of the cell cycle, the effects of various feedbacks, and the function of “well studied” genes. The natural fluctuations of the cell cycle provide an assay for size control, unbiased by gene deletion, which Dr. Siggia suggests will lead to a quantitative model of this illusive phenomenon. Using a new flow cell technology, he and his colleagues have recently worked to phase lock the cell cycle to an external clock in much the same way that circadian oscillators are locked in phase to light.

CAREER

Dr. Siggia received his A.B. in physics in 1971 and his Ph.D. in physics in 1972, both from Harvard University. He was a junior fellow at Harvard from 1972 to 1975, and then was assistant professor at the University of Pennsylvania for two years before moving to Cornell University where he became professor of physics in 1985. He has been a long-term visitor or consultant at the University of Paris in Orsay, École Normale Supérieure in Paris, the Santa Barbara Institute for Theoretical Physics, Bell labs and Los Alamos National Laboratory. Dr. Siggia came to Rockefeller University in 1997. Dr. Siggia received a John Simon Guggenheim Fellowship in 1988. He was an Alfred P. Sloan Research Fellow from 1980 to 1982.