Neanderthal Genome II: Sequence Published in Science

Results reveal genetic differences between Neanderthals and modern humans, and suggest some interbreeding
Friday, 07 May 2010

An international research team has sequenced the Neanderthal genome, using pill-sized samples of bone powder from three Neanderthal bones found in a cave in Croatia. The results appear in the 7 May issue of the journal Science.

The researchers, led by Svante Pääbo of the Max-Planck Institute for Evolutionary Anthropology in Leipzig, Germany, compared the Neanderthal genome with the genomes of five present-day humans from different parts of the world. The results reveal a variety of genes that are unique to humans, including a handful that spread rapidly among our species after humans and Neanderthals split from a common ancestor. These findings thus offer a shortlist of genomic regions and genes that may be key to our human identity.

The scientists also found that modern humans and Neanderthals most likely interbred, to a small extent, probably as modern humans encountered Neanderthals in the Middle East, after leaving Africa.

"Having a first version of the Neanderthal genome fulfils a long-standing dream. For the first time we can now identify genetic features that sets us apart from all other organisms, including our closest evolutionary relatives," said Pääbo.

"We have so many questions about the Neanderthals, not the least of which is, how much were they like us? The Neanderthal genome promises to be a fruitful source of information about the evolutionary events that produced modern humans and Neanderthals," said Andrew Sugden, Deputy and International Managing Editor at Science.

Neanderthals are our closest evolutionary relatives. They first appeared around 400,000 years ago, ranged across Europe and western Asia, and became extinct approximately 30,000 years ago.

The draft Neanderthal genome sequence being reported in Science represents about 60 percent of the entire genome. The genetic material that was sequenced came from single bones from three individual Neanderthals.

The sequencing effort involved multiple steps to deal with the challenges of sequencing ancient DNA. The researchers removed as little material as possible from the bones, using a delicate dentist's drill so as not to damage the fossils, and they conducted their lab research using sterile "clean-room" conditions, to avoid contaminating the material with DNA from present-day humans and other organisms. They also weeded out the much more abundant microbial DNA that had colonized the bones since the individuals died.

Modern humans and Neanderthals are so closely related that a comparison of their genomes must take into account the fact that for any particular part of the genome, a single modern human and a single Neanderthal could be more similar to each other than two modern humans would be.

Most of what we know about genetic variation among humans today is based on European populations. Seeking a broader picture, Pääbo and his colleagues sequenced the genomes of five present-day humans from southern Africa, West Africa, Papua New Guinea, China and France, and compared the Neanderthal genome to the genomes of these individuals.

The Neanderthal genome sequence proved to be slightly more similar to those of the non-African individuals.

More specifically, at any randomly chosen point in the genome where the sequence of two of the modern-day humans differed, there was a slightly higher chance that the Neanderthal genome matched that of the non-African individual than the African one. (In a supporting line of evidence, the authors report that Craig Venter's recently published genome sequenced contains segments that are closer to those of the Neanderthal genome than to those of the human "reference" genome, which includes a mixture of DNA of African and European ancestry.)

Though other explanations are possible, one of the simplest scenarios is that early modern humans interbred with Neanderthals in the Middle East, after leaving Africa and before spreading into Eurasia.

Approximately 1 to 4 percent of the modern human genome seems to be from Neanderthals, the authors estimate. Population models have suggested that when a colonizing population comes across a resident population, even a small amount of interbreeding can be widely reflected in the colonizing populations' genome, if that population then expands significantly. Thus, the relatively low percentage of Neanderthal DNA in the modern human genome may suggest that interbreeding was actually fairly limited.

The comparisons between the Neanderthal and modern humans also produced many other results that may ultimately be more important than the admixture discovery when it comes to giving us a better understanding of ourselves.

"It's cool to think that some of us have a little Neanderthal DNA in us, but, for me, the opportunity to search for evidence of positive selection that happened shortly after the two species separated is probably the most fascinating aspect of this project," Pääbo said.

His team devised a method to look for regions of the modern-human genome where new genes have spread through the population since the two species diverged. These genes are likely to have somehow improved early humans' odds for survival or reproduction.

The researchers screened the genomes of five modern-day humans from around the world to look for genomic regions with sequence variations that occur frequently in humans but not in Neanderthals, suggesting human-specific selection. Any variation shared with Neanderthals would presumably have been lost from these regions as the new genes swept through the early modern human population. The team found 212 regions with such variation. Among the 20 regions with the strongest evidence for positive selection were three genes that, when mutated, affect mental and cognitive development. These genes have been implicated in Down syndrome, schizophrenia and autism.

Other regions in this list of 20 included a gene involved in energy metabolism, and another that affects the development of the cranial skeleton, the clavicle and the rib cage.

"In all these cases it requires much, much more work. This is really just hints at what genes one should now study, and I'm sure we and many other groups will be doing that," Pääbo said.

The researchers also used the Neanderthal genome to produce the first version of a catalogue of genetic features that exist in all humans today but are not found in Neanderthals or apes. This catalogue will be valuable for scientists who study what sets humans apart from other organisms.

In a companion paper appearing in the same issue of the journal, another research team with many of the same authors and also led by Pääbo present a new technique to sequence select regions of the Neanderthal genome from especially degraded Neanderthal remains. Using a "target sequence capture" approach, the authors sharpened their focus on the protein-coding regions within several pieces of the genome of another Neanderthal individual from Spain. They identified 88 amino acid substitutions that have become fixed in humans since our divergence from the Neanderthals. More research will be necessary to determine how these changes may have affected human biology.

References:
The Neanderthal Genome Project

A Draft Sequence of the Neanderthal Genome
Richard E. Green, Johannes Krause, Adrian W. Briggs, Tomislav Maricic, Udo Stenzel, Martin Kircher, Nick Patterson, Heng Li, Weiwei Zhai, Markus Hsi-Yang Fritz, Nancy F. Hansen, Eric Y. Durand, Anna-Sapfo Malaspinas, Jeffrey D. Jensen, Tomas Marques-Bonet, Can Alkan, Kay Prüfer, Matthias Meyer, Hernán A. Burbano, Jeffrey M. Good, Rigo Schultz, Ayinuer Aximu-Petri, Anne Butthof, Barbara Höber, Barbara Höffner, Madlen Siegemund, Antje Weihmann, Chad Nusbaum, Eric S. Lander, Carsten Russ, Nathaniel Novod, Jason Affourtit, Michael Egholm, Christine Verna, Pavao Rudan, Dejana Brajkovic, Zeljko Kucan, Ivan Gusic, Vladimir B. Doronichev, Liubov V. Golovanova, Carles Lalueza-Fox, Marco de la Rasilla, Javier Fortea, Antonio Rosas, Ralf W. Schmitz, Philip L. F. Johnson, Evan E. Eichler, Daniel Falush, Ewan Birney, James C. Mullikin, Montgomery Slatkin, Rasmus Nielsen, Janet Kelso, Michael Lachmann, David Reich, and Svante Pääbo
Science 7 May 2010, Vol. 328. no. 5979, pp. 710 – 722, DOI: 10.1126/science.1188021

Targeted Investigation of the Neanderthal Genome by Array-Based Sequence Capture
Hernán A. Burbano, Emily Hodges, Richard E. Green, Adrian W. Briggs, Johannes Krause, Matthias Meyer, Jeffrey M. Good, Tomislav Maricic, Philip L. F. Johnson, Zhenyu Xuan, Michelle Rooks, Arindam Bhattacharjee, Leonardo Brizuela, Frank W. Albert, Marco de la Rasilla, Javier Fortea, Antonio Rosas, Michael Lachmann, Gregory J. Hannon, and Svante Pääbo
Science 7 May 2010, Vol. 328. no. 5979, pp. 723 – 725, DOI: 10.1126/science.1188046
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