The Neanderthal Genome Project
The Neanderthal Genome Project
A study with a lot of balls
From The Economist print edition
A brave attempt to sequence the Neanderthal genome
THE Human Genome Project is sooo yesterday. So what is a firm with a clever, new gene-sequencing technology to do in order to make a splash? Look yesterday squarely in the face, of course. And that is exactly what Jonathan Rothberg and Michael Egholm, of 454 Life Sciences, plan to do.
The particular yesterday they have in mind was about 40,000 years ago. It was the day when a man died in a cave in the Neander valley in what is now Germany. His skeleton is the type specimen of Homo neanderthalensis—Neanderthal man—and Dr Rothberg and Dr Egholm obtained permission to remove a few grams of the skeleton's right arm in order to extract the DNA therein. From it, they hope to work out a complete sequence of the chemical base pairs that constitute its genetic letters; in other words a Neanderthal genome.
Neanderthal man is a controversial creature. He inhabited Europe from 300,000 to 35,000 years ago, his disappearance coinciding with the arrival of Homo sapiens. Once, it was thought the one might be ancestral to the other. That is no longer believed. But the question of whether Neanderthals were deliberately exterminated by their more modern rivals, or merely outcompeted, is unresolved, as is that of whether the two species ever interbred. The Neanderthal Genome Project that Dr Rothberg and Dr Egholm have embarked on in collaboration with Svante Paabo, of the Max Planck Institute in Leipzig, may answer the second of those questions. It may also, by providing a genome that can be compared with both modern humans and chimpanzees, shed light on what it means, genetically, to be human.
The gene-sequencing technology used by 454 relies on specially designed chips with 1m or more tiny wells in them. The DNA to be analysed is broken up into fragments about 100 base pairs long (one of the advantages, from 454's point of view, is that time has already performed the task of breaking the DNA up into fragments of the right length). It is then shaken up in a mixture of water, a special silicone-based oil, a large quantity of tiny plastic balls, and the reagents of the polymerase chain reaction (a way of duplicating DNA to make small samples bigger).
The aim is to get the smallest sample possible—a single type of DNA molecule—into each well on the chip. That is done by shaking the mixture to create an emulsion of tiny, watery droplets in the oil. Get the conditions right, and many of the droplets will have a single DNA molecule in them, while most of the rest have none. The droplets will also contain the PCR reagents, which are soluble in water but not oil, and the plastic balls.
The next stage is to let the polymerase chain reaction do its work of multiplying the DNA strands in the droplets. The nature of the plastic means that the strands tend to stick to it, and the upshot is hundreds of thousands of balls each covered with a single sort of DNA. These can, with a little persuasion, be encouraged to drop into the wells on the chip. The DNA molecules on the balls can then be analysed by a technique that uses fluorescence to read the sequences of the bases of which they are composed.
Once the sequences of the DNA fragments have been obtained, the overlaps between them can be used to stitch them together into a complete message, as has been done for many other species. Those species, though, have still been alive. This will be the first time the genome of an extinct animal has been read.
Most of the Neanderthal genome is expected to resemble that of modern humans and (slightly less closely) modern chimpanzees, which are Neanderthals' two closest living relatives. The places of particular interest are those that the genome shares with neither species. Not only will these define what is uniquely Neanderthal, but they will also help to define what is unique to Homo sapiens, by showing which of its differences from chimpanzees are the result of common hominid heritage, and which the result of species-specific evolution.
Drs Rothberg, Egholm and Paabo hope to have their answer within two years. For Dr Paabo, the genome itself is the thing. It will be the culmination of a decade and a half of studying ancient DNA (and, along the way, providing the inspiration for “Jurassic Park”). Dr Rothberg and Dr Egholm, meanwhile, hope that this demonstration of their technology's power will lead to medical applications.
They aim to be able to sequence a human genome from scratch for $500,000. That is a lot of money, but peanuts compared with the billions spent on the Human Genome Project itself. And it is a small enough sum for it to be worthwhile looking at the entire genomes of people with diseases that have complex genetic causes, in order to see how they differ from healthy individuals.
Of course, technology gets cheaper all the time. One day, the firm hopes, its chip-and-ball technology will be cheap enough for clinical use. But if its collaboration with Dr Paabo bears fruit, it will surely be the cave-man connection that keeps it in the public eye.