PALEOGENOMICS · Team reconstructs ancestral sequence in silico
BY KEVIN DAVIES
January 15, 2005 | Bioinformatics researchers have re-created part of the genome sequence of an ancestral mammal that lived 70 million to 80 million years ago. If it all sounds a little like the plot of Michael Crichton's bestseller Jurassic Park, that's not surprising. However, lead investigator David Haussler (University of California at Santa Cruz) stresses that his motives are rooted in evolution rather than economics.
Researchers in comparative genomics align stretches of DNA sequence from different species to monitor rates of mutation during evolution. For example, Eric Green (National Human Genome Research Institute), who collaborated with Haussler's team, has sequenced 1.1 million bases of chromosomal DNA flanking the cystic fibrosis gene from 19 mammals.
Using that data set, Haussler and former postdoc Mathieu Blanchette, now at McGill University, decided to re-create this stretch of the genome from the common ancestor of all placental mammals — a shrew-like animal found in Asia. They succeeded, claiming 98-percent accuracy in the paper published in December's Genome Research.
REALLY OLD GENES: David Haussler led the effort to sequence a mammal that lived about 70 million years ago.
"What we come up with is not going to take us anywhere near Jurassic Park," Blanchette insists. "There are many reasons why the ancestral genome could not be put in a living organism — technical reasons, it is difficult to synthesize long DNA sequences. But the main thing is we show we can reconstruct the ancestor with 98-percent accuracy, and that's nice, but it's not enough to make that organism livable. There will be a few [DNA] errors in crucial places."
Blanchette's approach of "computerized paleogenomics" re-created in silico the DNA sequence of the "boreoeutherian" mammalian common ancestor. He wrote a computer program that aligned the 19 mammalian genome sequences, including human, chimpanzee, gorilla, mouse, dog, and cat, charting positions where DNA bases had been substituted, inserted, or deleted. "Then we try to figure out the evolutionary events that could produce the events that led to the alignment," Blanchette says.
Simulation studies show that the reconstructed ancestral sequence could account for the evolution of present-day mammalian species with an estimated 95-percent accuracy. By including additional mammalian sequences, Blanchette says that accuracy would reach 98 percent.
The authors write that "in coming years, such reconstructions may help in identifying and understanding the genetic features common to eutherian mammals and may shed light on evolution of human or primate-specific traits." Blanchette says he is now preparing to extrapolate this approach to the entire genome. "There's no big technical issue in scaling up to the whole genome," he says.
PHOTO BY TIM ARCHIBALD