Wednesday, September 27, 2006

How Neandertal DNA Will Shed Light on Human Genes

Michael Egholm of 454 Life Sciences talks about his company's ambitious project to sequence the Neandertal genome.

By Emily Singer

Neandertals, our most closely related cousins, vanished approximately 30,000 years ago, leaving only traces of their existence. Now scientists in Germany and Connecticut plan to resurrect their DNA, potentially shedding light on our own unique evolutionary path.

Collecting and analyzing DNA from fossilized bones has been notoriously difficult--ancient genetic material is often degraded and contaminated with other types of DNA. But new sequencing technologies promise to extract volumes of genetic information from this molecular stew. A unique sequencing method developed by Connecticut-based 454 Life Sciences can analyze the sequence of thousands of DNA fragments in parallel, allowing the high volume of sequencing needed for the ambitious project to sequence the Neandertal genome.

Michael Egholm, vice president of 454 Life Sciences, and a speaker at Technology Review's Emerging Technology Conference this week, promises that the results will be exciting. Egholm and collaborators will compare the Neandertal sequence to that of humans and chimpanzees to identify uniquely human genes. The project could shed light on the evolution of human traits, such as language and complex thought. Here, Egholm tells us how researchers plan to complete the project and what they hope to find.

Technology Review: Will this be the first attempt to sequence Neandertal DNA?

Michael Egholm: Svante Pääbo of the Max Planck Institute, our collaborator on the current project, has analyzed mitochondrial DNA from Neandertal samples. He was able to infer that Neandertals and homo sapiens came from a common ancestor and split approximately half a million years ago.

For the last several years, Pääbo, who more or less invented analysis of ancient DNA, had been trying to find a way to sequence the rest of the genome. He was on the verge of abandoning the research when he got a call from 454's founder, Jonathan Rothberg, who had always been interested in ancient DNA and was looking for the best people in the field to do an ancient DNA project.

TR: What are the biggest challenges in sequencing Neandertal DNA?

ME: There is almost none of it around--so Neandertal DNA is incredibly precious. The biggest challenge in actually sequencing the DNA is the fact that 95 percent of the genetic material in a Neandertal bone is microbial--from ancient bacteria. So when we sequence, we use brute force [running thousands of sequencing experiments in parallel to generate enough DNA sequences to separate the bacterial from the Neandertal DNA --TR]. In order to generate three billion bases of Neandertal DNA [about the length of the genome] we'll need to generate 20 times more bases of sequence, for a total of 60 billion bases for this project.

Another big challenge is that ancient DNA is so degraded--the DNA we use comes from a 38,000-year-old bone found in a cave in Croatia. The pieces are mostly 80 to 100 bases long, which is just enough for us to make sense of it. In order to piece together the genome, we take the DNA sequence we generate and map it against the human sequence.

We also worry about contamination from human DNA. Because we're working with a sample that is genetically so similar to us, it could be easily mixed up. We've spent a lot of time devising analysis to make sure we have ancient DNA. In that sense, DNA degradation is actually our friend: it gives a signature of old DNA.