Maynard Olson

Olson proposes new approaches to understanding genome

Dr. Maynard Olson instructs students to make a list of the different genetic traits they would be able to identify by observing people on a crowded street. “How many mutations underlying these differences have researchers identified?” Olson asks. “The answer is very close to zero, no matter how long the list.”

An internationally recognized geneticist, Olson said the development of new technology for identifying genes has led to an imbalance between the amount of data we have gathered and the amount of knowledge we have acquired. Researchers can relatively easily identify and sequence genes, but identifying the function of genetic mutations that give rise to all the variations within the human phenotype is monumentally difficult.

Olson, director of the UW Genome Center and professor of genetics and medicine (medical genetics) and adjunct professor of computer science, suggests it is time for researchers to embrace new ideas to further our understanding of this “wild-type” human.

He proposed one such idea in the January issue of the American Journal of Human Genetics and will discuss it in detail in a Science in Medicine lecture, titled “What Is a’Wild-Type’ Human?” on March 5, from noon to 1 p.m. in room T-625, Health Sciences Center.

To understand the biology of natural populations, Olson suggests taking a “less-is-more” approach. He said that loss of gene function in fact may be an evolutionary response to environmental shifts. “Geneticists don’t usually like to think of genetic loss as a selective evolutionary factor,” he said.

Most of our current knowledge of the human genome is based on mutations that have been identified based on genetic diseases. We know, for instance, that breast cancer in women can be caused by mutations of the BRCA1 and BRCA2 genes and that cystic fibrosis is caused by a mutation in the CFTR gene in both parents of affected individuals.

Olson argues that gene therapy efforts to cure diseases by “fixing” mutations so far have not succeeded. Even small advances in gene therapy, which was hyped 10 years ago as the answer to curing every human genetic disease, happen very slowly. “When you move away from what we’ve learned on the basis of genetic diseases, our knowledge evaporates,” Olson said.

Moreover, he continues, there is evidence that loss of gene function may be “adaptive.”

In the last few years, genetic research has suggested that mutations of certain chemokine receptors may give a person “relative resistance” to the AIDS virus. CCR5 is the name of one receptor that HIV-1 targets as an entry-point for its invasion of the cell. People with genetic mutations of these receptors are either resistant to infection or progress to AIDS more slowly.

“I’m making a plausibility argument that this type of genetic loss occurs in many species, from bacteria to mice to humans,” Olson said. “What if even healthy phenotypes are caused by genetic loss, or ‘broken’ genes? What if the problem isn’t as complicated as it looks?”

Olson concedes that studying genetic loss is an optimistic approach. Modern techniques allow researchers to identify “broken” genes quite easily, whereas looking for subtle changes between genes is very difficult. Excellent tools are available to look for the broken genes, Olson said. “What I’m proposing is that we get on with it,” he added.

He has been one of the architects of the U.S. Human Genome Project. He returned to the UW in 1992 from Washington University in St. Louis as a founding faculty member in the Department of Molecular Biotechnology led by Dr. Leroy Hood.

A pioneer in yeast genetics, Olson is widely known for developing systematic approaches to the analysis of complex genomes. His research includes the determination of the first complete electrophoretic karyotype of a eukaryotic organism and the development of computer-based methods for the construction of whole-genome physical maps based on clone fingerprints.

In 1994, he was inducted into the National Academy of Sciences. ¶

Will Morton