Using the Neandertal genome to uncover human evolutionary history

Before the Neandertal genome release last week, I was reading (thanks to a correspondent) an essay that James Noonan wrote for the current Genome Research. The piece, titled, “Neanderthal genomics and the evolution of modern humans” is well worth reading. It’s a snapshot of what we might reasonably have anticipated would come out of the efforts to sequence Neandertal genomes, without the punchline – no recognition that we would ultimately turn out to have Neandertal genes.

It will take a while for paleoanthropologists to come to any kind of informed opinion about the importance of the current genome results. The quotes I’ve gathered from various newspaper sources include a pretty wide range of silly ideas. Maybe some of mine fall in that category. But generally I try to be informed by both archaeology and genetics, and I find that tends to avoid some of the silliest statements.

Note however, there is really no excuse at all for archaeologists saying silly things about the archaeological record.

Noonan’s point of view is that of a mainstream geneticists, and is clearly stated. It represents a widespread school of thought about Neandertal genetics, but (understandably) is mostly uninformed by the archaeological record. For example,

The primary motivation behind generating a Neanderthal reference genome is to determine how distinct modern humans really are from all earlier versions of humanity. We are the only remaining human species, and thus we do not know if Neanderthals or our other extinct relatives shared our capacity for invention, abstract reasoning, or language. We have had to speculate on these matters based on the bones, the settlements, and the artifacts Neanderthals left behind. The question of modern human and Neanderthal biological similarity is particularly compelling given the recent common ancestry of both species: Based on both genomic and mitochondrial sequence comparisons, the lineages leading to modern humans and Neanderthals likely diverged in Africa ?300,000700,000 yr ago (Krings et al. 1997; Serre et al. 2004; Green et al. 2006, 2008; Noonan et al. 2006). This genetic evidence has become folded into a narrative of modern human and Neanderthal evolutionary history that continues to frame comparative studies of both species. In its simplest form, the modern human and Neanderthal lineages continued on parallel evolutionary tracks subsequent to their divergence, with the descendants of one branch migrating to Europe and giving rise to Neanderthals, and the other branch remaining in Africa and eventually producing us (White et al. 2003; Mellars 2004; Hublin 2009; Tattersall 2009). The modern human colonization of Europe ?40,000 yr ago potentially brought both lineages back into widespread contact (Mellars 2004). Given their very recent common ancestry, how much did the species have in common at this point? Were modern humans and Neanderthals capable of interbreeding, and, if so, did it happen to any appreciable extent? Or were the species so different that no meaningful exchange of information could occur?

Well, you know my answer to those questions.

I quoted this part because I think the earlier part of the passage deserves comment. Will the genetics tell us more about the cognitive relations of Neandertals and their contemporaries? Maybe eventually, but for the time being there is a tremendous void in our understanding of functional genetics. We really know nothing about the relationship of genetic variants to the “capacity for invention, abstract reasoning or language.”

Compare the situation to “personalized genomics.” If we sequence somebody’s genome and find new variants, for the most part we have no way of predicting what they do. And even the genes have functionally apparent properties – for example, a stop codon – there still may be no practical way to test the hypothesis that it influences a given phenotype.

The archaeological record is actually pertinent to cognition in a way that the genetic evidence isn’t yet. That doesn’t mean we have many answers – we’re still groping the dark. But if I want to know about the evolution of human cognition, the archaeology is a much better place to start.

What we know about the archaeology seems very clear: Most of the things that later MSA Africans did, Neandertals also did. There were differences, which may have been important – but those differences don’t exceed the variation of material culture in later human populations.

That doesn’t rule out that Neandertals may have been cognitively different from us in some important ways. But when we look at the complexity of the material record within Africa, I think it is fair to say that Neandertal behavior fits comforably within the continuum represented by MSA people. “Behavioral modernity” is broadly shared, and doesn’t clearly track lines of biological differences. Rachel Caspari and Sang-Hee Lee’s work on mortality differences are another concrete illustration of the ways that material culture and behavior do not track with anatomy in these populations.

In the short term, the most important influence of understanding the Neandertal genome will be what it tells us about phylogenetics and demographic history. That is what got all the attention last week, and will continue to occupy many of us in the next few months.

Even though the news of interbreeding is fascinating, working out the phylogenetic relationships of Pleistocene humans is only a first step towards understanding their evolutionary history. Noonan focuses on strategies for uncovering which genetic changes were important to recent human and Neandertal phenotypic evolution. In this respect, the essay could serve as an introduction to the two papers released in Science last week. It explains a bit about why the Neandertal genome is useful for uncovering functional changes in the human genome, and what may prove useful to drive this inquiry further. For example, from near the end of the essay:

These studies illustrate a general strategy toward an understanding of biological differences between modern humans and Neanderthals, in which the first step is the reverse genetic analysis of genes and gene regulatory elements showing human-specific or Neanderthal-specific sequence changes. In this approach, changes in basic molecular functions, such as enhancer activity, protein-DNA interactions, or receptor-ligand binding affinity are identified in synthetic assays. The phenotypic consequences of these molecular changes can then be assessed in mouse models: A recent study describing the introduction of a "humanized" version of FOXP2 into the mouse genome by gene targeting is one early example (Enard et al. 2009). The data from such studies, combined with a growing body of information on human gene function, the effects of genetic variation on human phenotypes, and comprehensive efforts to functionally annotate the human genome, would provide the foundation for more sophisticated hypotheses concerning the biological similarity of modern humans and Neanderthals than can be generated from the paleoanthropological record alone.

Now, in light of last week’s data release, we know some things about these general topics. The evolution of human-specific changes in conserved regions, for example, apparently mostly preceded the human-Neandertal common ancestor. There are few amino acid changes in recent (post-Neandertal) evolution that have become fixed worldwide – the new studies counted only 88. There are only 212 estimated selective sweeps not present in the Neandertal genome.

Those are manageable numbers.

Of course, we shouldn’t underestimate how hard it will be to untangle the interactions among these human-specific changes. It may require testing not each change one by one, but many possible combinations of the changes, since we don’t necessarily know their order. And it is not only the fixed changes that are important to morphological and behavioral evolution, polymorphisms will also be important. Among those polymorphisms will be later, strongly selected changes that may substantially modify the “fixed” substitutions – in a few cases, may even reverse them.

But this isn’t a hopeless prospect anymore, it’s a practical research program. The genetic changes that are nearly fixed in living people but absent in Neandertals represent one of the earliest – possibly the first – instances of geographic isolation and selection in Homo sapiens. They are one aspect of a pattern that has become increasingly important in later human populations, as the pace of adaptation has accelerated beyond the ability of gene flow to disperse adaptive alleles. Reconstructing this history will tell us about the shared evolutionary dynamics of humans and Neandertals, and the ecological particularities that may have made both populations phenotypically different.

References:

Noonan JP. 2010. Neanderthal genomics and the evolution of modern humans. Genome Res 20:547-553. doi:10.1101/gr.076000.108