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Sequencing with a Shotgun: An Interview with Stephen Goff

Stephen Goff



Lisa Mattle
The Scientific American 50¿s Research Leader of the Year award went to a trio of biologists: Stephen Goff of Syngenta¿s Torrey Mesa Research Institute, Yang Huanming of the Beijing Genomics Institute and Jun Yu of the University of Washington Genome Center. These researchers provided gene sequences¿lists of genetic building blocks, called nucleotide bases, that make up an organism¿s chromosomes¿for two types of rice, a crop that feeds more than half of the world¿s population. One study, led by Huanming, unveiled a draft sequence for Oriza sativa indica, a subspecies that is common in most of Asia. Another team, directed by Stephen Goff and Jun Yu, published a similar study on O. s. japonica, usually grown in Japan. Both studies appeared in the April 5, 2002, issue of Science. This work should trigger better versions of many cereals in the future. We asked Goff to tell us about this work. --Mike May

SA: How did you get started looking at genomes and what attracted you to rice?

SG: The choices were: looking at expressed genes or entire genomes. Rice is evolutionarily related to corn, wheat, barley and the other major cereals. Its is also the smallest genome¿430 million bases¿of all the cereals. If you just look at crop production worldwide, about 60 to¿I¿ve read as high as¿72 percent is three species: corn, wheat and rice. So, if you¿re going to focus on something, then the focus would be on the cereals, because the cereals are the major production, and they are evolutionarily related. We knew from previous work that there was some colinearity of the genomes. In other words, the positions of the genes along the chromosomes of rice were similar to the positions in corn and in wheat and in barely and in other cereals. The sequencing technology was advancing to the point where it made sense to not just look at expressed genes, but actually look at the genome. It was kind of the right time at the right place.

SA: When you were working on the sequence for rice, did you already know what a big splash it would create if you succeeded?

SG: We knew that rice was politically sensitive, because it¿s the major crop in Asia. But, we actually didn¿t know whether or not we would even publish it. There¿s a lot of additional work that goes into a publication that¿s not really necessarily the goal of a company. At the same time, it¿s something that you want to complete and get out there because it¿s important for developing countries and for sustained or subsistence farming. There's a lot of uses that go well beyond what a company can use it for. We are getting our use out of it, but it seemed appropriate to try to make it useful for other groups of people.

SA: One of the keys to this work was using shotgun sequencing. If you wanted to give someone an intuitive feel for this approach, what would you tell him or her?

SG: You just chop up the whole genome and computationally reassemble it after you¿ve sequenced small pieces of it. It¿s a computational challenge. There are positive and negative parts about shotgun sequencing. You don¿t get complete coverage, but it¿s a lot cheaper than other sequencing techniques. The computational challenge is big enough that people were really concerned about it. Now, I think it¿s agreed that is can be done on large genomes. When we started this project, the largest genome that had been sequenced by this method was really pretty small, a bacterial genome.

SA: What is the next research hurdle for knowledge related to the rice genome?

SG: Now it¿s a question of what do all the cereal genes do. Sequencing just gives you the raw information that allows you to predict the genes, and the gene predictions give you some hints from previous studies of what the proteins encoded by those genes may be doing. Then you need to prove it, and there¿s a lot of unknowns.

When Arabidopsis was sequenced, for example, only eight percent of the genes had been studied in a lab. There¿s a lot missing there. And it¿s probably a much smaller number for rice or any of the cereals. Even when you take in all the wheat information, all the maize information, compile it all with rice and say what the function of all those genes are, there¿s a very high percent that we still don¿t have any idea what they do. We might have some hints from pieces of the proteins that are encoded by those genes, but an actual piece of information on what they do is still not in anybody¿s notebooks or published any where. There¿s a lot more to learn. So, what¿s ahead? It¿s the functional genomics hurdle.


Mike May is based in Madison, Ind.
"The Scientific American 50," by staff (Scientific American, December 2002), is available for purchase at the Scientific American archive.
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