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Peter K. Dearden.

One key question in biology is what makes us different as a species. Humans have a remarkable set of adaptations that distinguish us from even our closest living relatives. We walk upright, we have larger brains, we use language, and we are consummate tool-makers and users. From the point of view of an alien, perhaps, these differences may be subtle, but they are key to our spread around this planet, and the ability, for better or worse, to modify our environment. These differences must be encoded somewhere in our genes. Something about the way our DNA works, or is organised, must underpin these differences in our biology. Such differences are key targets for scientists seeking to understand the biology of our species.

Before we sequenced the human genome, we thought that we probably had hundreds of thousands of genes in our genome, as compared to the 13,000 odd in flies and worms. Sequencing our genome  indicated that actually we have around 20,000, and that that number is pretty much the same in all mammals. Sequencing the genomes of the Gorilla  and the Chimpanzee showed that our genomes are very similar to theirs. Comparing the DNA sequence of genes in our genome with those in other primates indicates that we do not have a huge pile of ‘extra’ genes that make us humans, or help us run our huge brains. Indeed it is very hard to identify any genes that are only in our genome, and not in any other species. We do have variants of genes, however, our version of a gene may differ slightly from the version in other primates. Of course this is true within our species, different people often have different versions of the same gene.

We are beginning to understand, however, that the differences between species may not be due to differences within genes, but in the way genes are turned on or off; the regulation of genes. While the best-known examples are in insects (for example see here ) changes in gene regulation, with no change in the genes themselves, may underlie much species difference.

Recently the knowledge about our closest relatives has been dramatically improved. Advances in DNA sequencing allowed us to sequence the genome of a Neanderthal despite them being extinct and only their bone fragments remaining. Even more excitingly, such sequencing has even identified new as previously unknown human species, including the mysterious Denisovans. Now a much more complete version of the Neanderthal genome has been produced, by a group in Germany. By sequencing the DNA from a toe bone, this group has show that the bone is from a Neanderthal, and increased the amount of sequence data from this species. The authors of this paper report all kinds of interesting things, but towards the end of the paper, they start to talk about the genetic differences between us and Neanderthals. It’s thrilling!

The authors determine that we have 96 differences, within only 87 protein-coding genes, from Neanderthals. Outside genes, they catalogue around 3000 differences that might change the regulation of genes. We can only hope that somewhere within this catalogue are the genetic determinants of human-ness.

But wait, how different are Neanderthals to us? They made tools, they may have had language, they walked upright, they buried their dead, and we had sex with them. Should we perhaps we be looking for changes that we share with Neanderthals that aren’t in more distant relatives?

More importantly, how can we ever know which of those changes in the genome make us us? We could never do an experiment that would put a human version of a gene or regulatory sequence in a Neanderthal, because they are extinct. Nor would we modify a human genome to put in a Neanderthal sequence, because of the obvious ethical issues. If we cannot test what these differences in our genome do, how can we ever know which bits of our genome encode our unique biology, and which encode the unique biology of our relatives?