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TR: How will 454’s sequencing technology make this ambitious project possible?

ME: It’s simply a numbers game. Because you have to throw out 19 out of 20 of your reads [due to the presence of so much bacterial DNA], you need to be able to do a lot of sequencing. We generate a quarter of a million reads per run, while standard capillary sequencing only generates 96 reads at a time. [A “read” refers to the number of DNA fragments that can be sequenced, or read, in a single sequencing reaction.]

We have already generated a few test-runs of a million bases of Neandertal DNA. Before then, only a few hundred bases of sequence were known, so we’ve increased the knowledge of Neandertal DNA dramatically. We hope to have a paper on this published soon.

TR: What do you expect to learn from the Neandertal genome?

ME: We know something dramatic happened in modern man within the last 200,000 years, which is a long time after we split from the Neandertal genome. So we’re trying to find the so-called “human genes,” possibly the genes involved in the evolution of language, abstract thinking, and planning.

The chimp genome was recently sequenced, so scientists have been able to compare chimp and human DNA to try to figure out what makes us different–there are about 35 million base pairs that are different. Chimps and humans diverged about five million years ago, while Neandertals split only half a million years ago. So you could say they are 10 times closer to us than chimps and therefore make a better comparison.

We believe we can use the Neandertal genome as a signpost for our own genome. Our approach is to look at the 35 million base pair differences between chimp and man. Then we ask a simple question: Is Neandertal like chimp or human on those sites?

TR: How far along are you? Any early results?

ME: We’ve sequenced about seven million bases so far. Based on analysis from the first million bases, Neandertals were like humans about 96 percent of the time [meaning: at the sites of the genome where modern humans and chimps differ, the Neandertal sequence was much more likely to resemble modern humans, while it was the same as the chimp only four percent of the time.]

The parts we’re really interested in are the four percent where Neandertals are like chimps rather than humans. We hope those genes will be those that confer higher executive function. Genes for talking, cognition, or brain development would be most exciting. We imagine that as people find new genes they suspect are unique to humans and are involved in higher-order cognition, we’ll be able to compare to them the Neandertal genome and see if they are different.

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Tagged: Biomedicine

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