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John Fondon: Evolution and the Slippery Genome

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Title: Postdoctoral fellow, UT Southwestern Medical Center

Education: PhD, UT Southwestern, 2003

Recommended by: Skip Garner

It was at the urging of his PhD advisor that John “Trey” Fondon first came upon the question which he has pursued to this day. Fondon's advisor, Skip Garner, suggested that he run their newly developed repeat polymorphism prediction algorithm on coding sequences to find human coding polymorphisms. At first, Fondon says, he was rather skeptical. “But when I saw the results, I was amazed.”

“It wasn't just the large number of human proteins with slippage-prone repeats, but the identities of the proteins — Hox genes, BMPs, signal transducers — all genes whose names and roles were familiar to me from my background in developmental biology,” he says. The question that was staring him in the face: do these repeats facilitate evolution? “Potential solutions to longstanding problems in evolution, such as D'Arcy Thompson's transformations and the astounding speed of vertebrate evolution, suddenly seemed within my grasp,” he says.

Fondon has pursued this evolutionary question using dogs as a model system. “What we've learned is that dogs have this very interesting feature in their genome in that they mutate their microsatellites at a higher rate than humans or even cats do,” he says. He is currently using computer simulation to determine the conditions under which having such a slippery genome would be advantageous. The computer model takes into account factors like the size of a population and the cycle of climatic changes over the last few million years, and how those connect to changes in selection.

For Fondon, having a great core sequencing facility within arm's reach is a boon to his research. Most of his budget is basically split down the middle between sequencing and mouse work. Although he says it would be nice not to have to fork over so much money for in-house sequencing, he is quick to point out that it's the quality control and easy access that make the slightly higher cost worthwhile. “We really like to be able to walk over to the person actually doing the sequencing and talk to them about troubleshooting,” he says. Fondon and his team, who work with highly repetitive, GC-rich regions, are looking for microsatellites that are heterozygous. The problem is that these result in a very messy read, which most commercial sequencing outfits aren't used to handling. “Advances in DNA seq-uencing that make it less expensive would be great, and they're coming, and periodically we go and evaluate commercial sequencing companies,” he says. “But we don't have much confidence in the data.”

Looking ahead

Over the next 10 years, Fondon would like to identify the possible mutations that allow for variation in how mammals evolve, as well as in their morphological variation. Fondon says it would be “a dream come true” if he could pair high-throughput morph-ological phenotyping of mice, dogs, and humans with morphometric software capable of analyzing skeletal elements. He also notes that measuring the dimensions of bones and other subtle mutational effects definitely slows down the workflow in his lab.

Publications of note

Fondon and his UT Southwestern colleague Skip Garner published a study in PNAS entitled “Molecular origins of rapid and continuous morphological evolution” which proposed their hypothesis on tandem repeats and evolution. The study presents a comparison of repetitive elements in the developmental genes of 92 dog breeds. The paper suggests that tandem repeat slippage mutations speed up the evolution process. The researchers used data from his study of DNA repeats influencing morphological variations in domestic dog breeds.

The Nobel goes to…

“Discovering the means by which genomes guide the evolution of their host organisms,” he says.

 — MD

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