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Making Sense of the Neandertal Genome

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Ed Green
Title: Postdoctoral Fellow, Max Planck Institute for Evolutionary Anthropology
Education: University of California, Berkeley, PhD, 2005
Recommended by: Steven Brenner

Ed Green fell into studying the Neandertal genome. He'd arrived at the Max Planck Institute in Leipzig ready to dive into a study of alternative splicing in primates. Instead, he took on sequencing the Neandertal. "[I] just happened to be at the right place at the right time with the right skill set to look at the Neandertals as this high-throughput sequencing technology was coming online," he says. And, of course, he says it's a really interesting project.

So far, the Neandertal Genome Project has reached a little more than one-fold coverage of the genome. The challenge now, Green says, is making sense of all that next-gen sequence data. "The sequence comes from these 40,000-year-old DNA fragments that are short and full of chemical damage," he says. "One of the most difficult things is putting them together into a genome assembly and then interpreting what it means in terms of recent human evolution."

And because this ancient DNA has such "weird features," as Green says, many of the tools normally used in genome projects need to be revamped. "Conceptually, it's something like a resequencing project [but] because of the peculiarities of ancient DNA, pretty much everything has to be reinvented, from the mapping software to the analysis software. All components of this have to be custom-designed," he says.

However, there is only so far back in time you can go. "There is this rather hard limit of about 100,000 years beyond which DNA is very rarely, if ever, recoverable," Green says. It would be great, he adds, if there could be some way to eke DNA out of Australopithecine or Homo erectus to get a look at the evolutionary forces at play when people diverged from chimpanzees or became bipedal or discovered fire. "There's no comparison genome that is recoverable from fossils that would tell us what was going on 2 million years ago, for example, or 4 million years ago," he says.

Green will soon be setting up his own lab at the University of California, Santa Cruz. There, he will be returning to some of his other research interests while continuing to work on the Neandertal genome. He's interested in studying gene regulation and the evolution of gene expression using next-generation sequencing, particularly in non-model organisms. "There's a lot of really cool biology that happens outside out of model organisms and now the tools are in place to go after this interesting biology," he says.

Looking ahead

Coming up, Green says that fast and easy sequencing will allow researchers to move beyond model organisms and even take advantage of natural experiments. "It will be easy to query these natural experiments that are happening all the time and the variation that exists in natural populations now," he says. "Instead of making a particular mutant of a certain gene that you are interested in, it will be possible to just go out and sequence from a large population and find the mutant you are interested in."

Publications of note

In 2008, Green was part of the paper called "A complete Neandertal mitochondrial genome sequence determined by high-throughput sequencing" in Cell. "I think we did not only a really good analysis of what the evolutionary story was there, but learned a lot about what ancient DNA looks like by having such high coverage of this mitochondrial genome," he says. "We could assemble finished-quality sequence and learn how to do that from ancient DNA. I think it set the standard for the field with that assembly and that analysis."

And the Nobel goes to...

As for winning the Nobel Prize, Green says he'd be perfectly happy to win for studying the Neandertal genome and for its insight into human evolution. However, he'd rather receive it for something he hasn't yet done.

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