Blogging on Peer-Reviewed Research

You don't have to tell me, I know I'm late to the party: the news about the draft Neandertal genome sequence was announced last week, and here I am getting around to it just now. In my defense, I did hastily rewrite one of my presentation to include a long section on the new genome information, so at least I was talking about it to a few people. Besides, there is coverage from a genuine expert on Neandertals, John Hawks, and of course Carl Zimmer wrote an excellent summary. All I'm going to do now is fuss over a few things on the edge that interested me.

This was an impressive technical feat. The DNA was extracted from a few bone fragments, and it was grossly degraded: the average size of a piece of DNA was less than 200 base pairs, much of that was chemically degraded, and 95-99% of the DNA extracted was from bacteria, not Neandertal. An immense amount of work was required to filter noise from the signal, to reconstruct and reassemble, and to avoid contamination from modern human DNA. These poor Neandertals had died, had rotted thoroughly, and the bacteria had worked their way into almost every crevice of the bone to chew up the remains. All that was left were a few dead cells in isolated lacunae of the bone; their DNA had been chopped up by their own enzymes, and death and chemistry had come to slowly break them down further.

Don't hold your breath waiting for the draft genome of Homo erectus. Time is unkind.

We have to appreciate the age of these people, too. The oldest Neandertal fossils are approximately 400,000 years old, and the species went extinct about 30,000 years ago. That's a good run; as measured by species longevity, Homo sapiens neandertalensis is more successful than Homo sapiens sapiens. We're going to have to hang in there for another 200,000 years to top them.

The samples taken were from bones found in a cave in Vindija, Croatia. Full sequences were derived from these three individuals, and in addition, some partial sequences were taken from other specimens, including the original type specimen found in the Neander Valley in 1856.

Samples and sites from which DNA was retrieved. (A) The three bones from Vindija from which Neandertal DNA was sequenced. (B) Map showing the four archaeological sites from which bones were used and their approximate dates (years B.P.).

The three bones used for sequencing were directly dated to 38.1, 44.5, and 44.5 thousand years ago, which puts them on the near end of the Neandertal timeline, and after the likely time of contact between modern humans and Neandertals, which probably occurred about 80,000 years ago, in the Middle East.

Just for reference: these samples are 6-7 times older than the entire earth, as dated by young earth creationists. The span of time just between the youngest and oldest bones used is more than six thousand years old, again, about the same length of time as the YEC universe. Imagine that: we see these bone fragments now as part of a jumble of debris from one site, but they represent differences as great as those between a modern American and an ancient Sumerian. I repeat once again: the religious imagination is paltry and petty compared to the awesome reality.

A significant revelation from this work is the discovery of the signature of interbreeding between modern humans and Neandertals. When those humans first wandered out of the homeland of Africa into the Middle East, they encountered Neandertals already occupying the land…people they would eventually displace, but at least early on there was some sexual activity going on between the two groups, and a small number of human-Neandertal hybrids would have been incorporated into the expanding human population—at least, in that subset that was leaving Africa. Modern European, Asian, and South Pacific populations now contain 1-4% Neandertal DNA. This is really cool; I'm proud to think that I had as a many-times-great grandparent a muscular, beetle-browed big game hunter who trod Ice Age Europe, bringing down mighty mammoths with his spears.

However, it is a small contribution from the Neandertals to our lineage, and it's not likely that these particular Neandertal genes made a particularly dramatic effect on our ancestors. They didn't exactly sweep rapidly and decisively through the population; it's most likely that they are neutral hitch-hikers that surfed the wave of human expansion. Any early matings between an expanding human subpopulation and a receding Neandertal population would have left a few traces in our gene pool that would have been passively hauled up into higher numbers by time and the mere growth of human populations. In a complementary fashion, any human genes injected into the Neandertal pool would have been placed into the bleeding edge of a receding population, and would not have persevered. No uniquely human genes were found in the Neandertals examined, but we can't judge the preferred direction of the sexual exchanges in these encounters, though, because any hybrids in Neandertal tribes were facing early doom, while hybrids in human tribes were in for a long ride.

Here's the interesting part of these gene exchanges, though. We can now estimate the ancestral gene sequence, that is, the sequences of genes in the last common ancestor of humans and Neandertals, and we can ask if there are any 'primitive' genes that have been completely replaced in modern human populations by a different variant, but Neandertal still retained the ancestral pattern (see the red star in the diagram below). These genes could be a hint to what innovations made us uniquely human and different from Neandertals.

Selective sweep screen. Schematic illustration of the rationale for the selective sweep screen. For many regions of the genome, the variation within current humans 0 is old enough to include Neandertals (left). Thus, for SNPs in present-day humans, Neandertals often carry the derived -1 allele (blue). However, in genomic regions where an advantageous mutation arises (right, red star) and sweeps to high frequency or fixation in present-day humans, Neandertals will be devoid of derived alleles.

There's good news and bad news. The bad news is that there aren't very many of them: a grand total of 78 genes were identified that have a novel form and that have been fixed in the modern human population. That's not very many, so if you're an exceptionalist looking for justification of your superiority to our ancestors, you haven't got much to go on. The good news, though, is that there are only 78 genes! This is a manageable number, and represent some useful hints to genes that would be worth studying in more detail.

One other qualification, though: these are 78 genes that have changes in their coding sequence. There are also several hundred other non-coding, presumably regulatory, sequences that are unique to humans and are fixed throughout our population. To the evo-devo mind, these might actually be the more interesting changes, eventually…but right now, there are some tantalizing prospects in the coding genes to look at.

Some of the genes with novel sequences in humans are DYRK1A, a gene that is present in three copies in Down syndrome individuals and is suspected of playing a role in their mental deficits; NRG3, a gene associated with schizophrenia, and CADPS2 and AUTS2, two genes associated with autism. These are exciting prospects for further study because they have alleles unique and universal to humans and not Neandertals, and also affect the functioning of the brain. However, let's not get confused about what that means for Neandertals. These are genes that, when broken or modified in modern humans, have consequences on the brain. Neandertals had these same genes, but different forms or alleles of them, which are also different from the mutant forms that cause problems in modern humans. Neandertals did not necessarily have autism, schizophrenia, or the minds of people with Down syndrome! The diseases are just indications that these genes are involved in the nervous system, and the differences in the Neandertal forms almost certainly caused much more subtle effects.

Another gene that has some provocative potential is RUNX2. That's short for Runt-related transcription factor 2, which should make all the developmental biologists sit up and pay attention. It's a transcription factor, so it's a regulator of many other genes, and it's related to Runt, a well known gene in flies that is important in segmentation. In humans, RUNX2 is a regulator of bone growth, and is a master control switch for patterning bone. In modern humans, defects in this gene lead to a syndrome called cleidocranial dysplasia, in which bones of the skull fuse late, leading to anomalies in the shape of the head, and also causes characteristic defects in the shape of the collar bones and shoulder articulations. These, again, are places where Neandertal and modern humans differ significantly in morphology (and again, Neandertals did not have cleidocranial dysplasia — they had forms of the RUNX2 gene that would have contributed to the specific arrangements of their healthy, normal anatomy).

These are tantalizing hints to how human/Neandertal differences could have arisen—by small changes in a few genes that would have had a fairly extensive scope of effect. Don't view the many subtle differences between the two as each a consequence of a specific genetic change; a variation in a gene like RUNX2 can lead to coordinated, integrated changes to multiple aspects of the phenotype, in this case, affecting the shape of the skull, the chest, and the shoulders.

This is a marvelous insight into our history, and represents some powerful knowledge we can bring to bear on our understanding of human evolution. The only frustrating thing is that this amazing work has been done in a species on which we can't, for ethical reasons, do the obvious experiments of creating artificial revertants of sets of genes to the ancestral state — we don't get to resurrect a Neandertal. With the tools that Pääbo and colleagues have developed, though, perhaps we can start considering some paleogenomics projects to get not just the genomic sequences of modern forms, but of their ancestors as well. I'd like to see the genomic differences between elephants and mastodons, and tigers and sabre-toothed cats…and maybe someday we can think about rebuilding a few extinct species.

Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, Fritz MH, Hansen NF, Durand EY, Malaspinas AS, Jensen JD, Marques-Bonet T, Alkan C, Prüfer K, Meyer M, Burbano HA, Good JM, Schultz R, Aximu-Petri A, Butthof A, Höber B, Höffner B, Siegemund M, Weihmann A, Nusbaum C, Lander ES, Russ C, Novod N, Affourtit J, Egholm M, Verna C, Rudan P, Brajkovic D, Kucan Z, Gusic I, Doronichev VB, Golovanova LV, Lalueza-Fox C, de la Rasilla M, Fortea J, Rosas A, Schmitz RW, Johnson PL, Eichler EE, Falush D, Birney E, Mullikin JC, Slatkin M, Nielsen R, Kelso J, Lachmann M, Reich D, Pääbo S. (2010) A draft sequence of the Neandertal genome. Science 328(5979):710-22.