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The Sequence Gazer

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Marcella McClure is a hippie, a rabble-rouser, and the most knowledgeable person in the world when it comes to retroid agents

by Adrienne Burke

 

What Marcie McClure knows about the genome doesn’t show up on the maps delivered to you in Science and Nature in February.

McClure, who teaches molecular evolution and genomic analysis at Montana State University, has drawn on molecular biology, virology, and bioinformatics — not to mention a manic energy level, a lifetime of yoga study, and an extraordinary talent for inferring biologically meaningful patterns in sequence alignments — to discover and publish more about predicted functions of retroid agents than any other scientist.

Among numerous in silico projects she is pursuing at the moment is construction of a complete map of retroid agents — retroviruses, retransposons, retroposons, and other elements that encode for the enzyme with the ability to transcribe RNA into DNA — hidden in the bowels of the human genome. According to McClure, and as David Baltimore noted in Nature’s recent genome edition, a significant chunk of so-called junk DNA is comprised of reverse transcriptase agents, some of which are integral to human life, others which control cellular gene regulation to cause diseases such as AIDS and hepatitis.

Retrovirus researcher John Coffin, a Tufts professor of molecular biology and microbiology who has known McClure for 10 years, says her work ekes out “important clues to how we evolved and how infectious agents evolved — the major ways our genome has been rearranged and filled out over the eons.” Her map, he says, “will provide us with an important catalogue and description of what has or could have happened.”

McClure envisions her work enabling creation of robust hidden Markov models representing the sequences of pathogenic genomes leading to better-designed antivirals.

“If we can get a handle on how these things are changing by looking at a large enough sampling, then maybe we can say, ‘Oh, the most probable changes that this virus is going to undergo are X, Y, and Z. Let’s make a drug that covers all of those,’” she says.

Rosy Prober

During a poster session at the Pacific Symposium for Biocomputing in Hawaii this year, McClure ¯ a petite woman in rose-lensed glasses, auburn-tinted hair, and a matching sundress ¯ drew attention to her own poster by pronouncing, “I am the world’s leading expert on retroid agents.”

Her lab, which is funded by a five-year, $1 million grant from the Institute of Allergies and Infectious Diseases, has used a reverse transcriptase query sequence in a BLAST search to retrieve about 15 percent of the data from the finished version of NCBI’s Human Genome Database. (The finished version, which comprised only 24 percent of the whole genome at the time of her study, is free of redundancy — an important factor when you’re studying repetitive sequences, McClure notes.)

The probe is a set of 20 consensus sequences. “We took each one of these reverse transcriptase sequences representing a whole diversity of this family of genes and we probed each chromosome individually,” McClure explains. “We found that some chromosomes (X and Y) have a lot of these agents, some only have a few. Although estimates must be refined, it appears that as much as 30 percent of the human genome is comprised of retroid agents.”

Intent on finding out how many retroids she could identify in Celera’s database, McClure sent her query sequence to a technician in Rockville. “They’ve had our probe for months. When we asked them for the results they told us that they didn’t know what to do with all these data,” she says. “They couldn’t understand how I could give them a single probe that would pull back so much data.”

The problem is classic McClure. Since 1984, when advisors couldn’t make sense of her molecular biology PhD thesis that relied on computational biology methods, people have often been unsure how to handle Marcie McClure.

Barefoot Bioinformatician

At 17, McClure was already on a science path when she dropped out of Catholic high school and the Washington Junior Academy of Sciences to have a baby. Later she found herself in San Diego, a 21-year old divorced mother of two, considering medical school. A self-professed free spirit, she recalls, “I thought I’d become a barefoot doctor.”

But while earning a BA in biology at UC San Diego (where Craig Venter was her labmate), McClure fell in love with a virology graduate student who influenced her decision to pursue a PhD in molecular biology at Washington University School of Medicine.

After a three-year postdoc in Russ Doolittle’s lab at UCSD and a year of unemployment — “Who was going to hire me? There were no jobs in computational genomics! There was no human genome project!” — McClure landed in Michael Waterman’s math department working on multiple sequence alignments.

After her first grant proposal for a computational approach to determining retroid agent function was shuffled around from NIH’s biostatisticians to the virologists, McClure submitted a list of 30 people she considered qualified to review her work. Since then, she says, NIH categorizes her proposals under “ad hoc grants.”

But even with her first $1 million award in hand in 1988, McClure couldn’t get an academic appointment. At his invitation, she spent four years sharing Walter Fitch’s lab at UC Irvine, all the while “applying madly for jobs.” She eventually took a virology position in the biology department of University of Nevada, Las Vegas. But after two more $1 million grants, McClure defected to the Department of Microbiology at Montana State in Bozeman, where she also started the bioinformatics wing of the Center for Computational Biology.

McClure is an admitted rabble-rouser. She became infamous, she says, for publicly “tearing apart” the work of a speaker during an Intelligent Systems in Molecular Biology Meeting. At PSB this year she avoided one speaker in the halls. If he asked her what she thought of his work she would have to tell him, and it wouldn’t be pretty.

Queen’s University computer scientist Janice Glasgow, McClure’s shopping-excursion partner at academic meetings, says, “She’s outspoken and it puts the hackles up in some people.” But, Glasgow adds, “She certainly has the respect of the community.”

Stanford bioinformatics expert Russ Altman tells why: “Marcie was the first bioinformatics professional I know who fully appreciated the extent to which retroid elements would be found in the human genome.” McClure’s work, he says, “may lead to a classification of repetitive and duplicated DNA as something more than ‘junk’ and might actually help us get down to a real understanding of how the human genome has existed in its ecosystem and acquired its contents through non-traditional evolutionary means — such as lateral transfer from viruses.”

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