Annual report : 2000 / Burroughs Wellcome Fund.

  • Burroughs Wellcome Fund
Date:
2000
Catalogue details

Licence: Attribution 4.0 International (CC BY 4.0)

Credit: Annual report : 2000 / Burroughs Wellcome Fund. Source: Wellcome Collection.

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    Functional Genomics: Answering the Big Questions Sudhir Kumar, Ph.D., is not content with answering the easy questions. He goes right to the heart of biology. How did life begin? How and when did mammals evolve? How do changes in genes cause disease? With so much gene sequence data now available, Dr. Kumar, an assistant professor of biology at Arizona State University, believes that it is actually possible to ask such questions and even to expect to find some answers. He combines his knowledge of computer science, mathematics, and evolutionary biology to locate patterns in DNA sequences. These “functional footprints,” as he calls them, provide insight into why related genes sometimes have different functions. By locating these footprints, Dr. Kumar hopes to provide a database of information available for bench scientists to ask new questions about what genes do. He also hopes to learn how ancestral genes evolve to provide new functions. Dr. Kumar believes that along the way, identification of the gene footprints will bring biomedical research closer to understanding the genetic basis of disease. A pioneer in the post-sequencing era, Dr. Kumar is a recipient of one of 11 Burroughs Wellcome Fund Innovation Awards in Functional Genomics, made to celebrate the dedication of BWF’s new headquarters building. “In choosing awardees, we were looking for scientists who are combining computational methods with labora- tory experimentation to move the entire field of functional genomics forward,” says Nancy Sung, Ph.D., BWF program officer. “Dr. Kumar has demonstrated that he understands a combined approach can be more powerful than doing either computation or experimentation alone.” As the number of gene sequences has grown, the sheer volume of data requires that computer-based approaches become an integral tool for the molecular biologist. Dr. Kumar's strategy already turned heads, when he used computational methods to estimate that the ancestors of modern groups of mammals diverged 30 million to 40 million years earlier than had been previously predicted. Now he is using the methods he developed to tackle the massive computational challenges of functional genomics. Dr. Kumar and his colleagues look for functional footprints by searching for key mutations, random mis- takes in the “spelling” of a gene that cells make when they copy DNA during cell division. Most such changes are of no consequence, but over millions of years of evolution, certain mutations led to changes in the role a particular gene or protein plays in the cell. These changes are the footprints that Dr. Kumar hopes to locate among the mil- lions of gene sequences that have been spelled out in large-scale gene sequencing projects. Traditionally, scientists studying the effects of gene mutations would take a best guess at how a mutation might change a gene function, and then conduct time- consuming experiments for every prediction to determine if they were correct. Dr. Kumar is using the power of com- putation to reduce guesswork and help researchers narrow the possible locations in genes that are crucial to their function. For example, he studies a gene family called PAX, whose nine members play important regulatory roles, including development of the eye. In humans, mutations in a gene called PAX6 can lead to a malformed iris. In mice, mutations of the same gene cause the animals to be born with small eyes. Using statistical techniques, Dr. Kumar and his colleagues identified a set of functional footprints and predicted that they would be important for PAX6 action. Meanwhile, another group of researchers found that one of these footprints changes PAX6’s ability to do its job, resulting in the malformed eye. “My goal is to predict gene function and to identify mutations at the primary sequence level that may be responsible for differences in gene function,” Dr. Kumar says. “We use computation to correlate mutations with the known function of a gene.” When he finds a footprint in a gene whose function is unknown, he can use that sequence information to predict what the gene may do. “Then using our data,” he says, “scientists can make more informed decisions about which sequences to look at in detail using laboratory experiments.” Dr. Kumar and his colleagues also are using their knowledge of the rate of mutations to estimate how long ago major groups of mammals, such as primates and rodents, and groups of eukaryotes, such as plants, animals, and fungi, became distinct species. As a member of the National Aeronautics and Space Administration’s astro- biology team, Dr. Kumar is even involved in helping to understand how and when life first originated on earth. But Dr. Kumar is really only at the starting point in his efforts. The vast majority of gene sequence is uncharted territory, and that is where he says his BWF award will really make a difference. “This Burroughs Wellcome Fund grant allows me to hire additional scientists who will be creating the database of functional footprints,” he says. “We will also create a Web site where scientists can search our results looking for information about their gene of interest. Then, we will really see the science of functional genomics accelerate.”
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