HAR1 makes us human?

Here's a cool paper pre-published in Nature on-line. Pollard, Haussler et al have analysed the human, chimpanzee, mouse and rat genomes in search of sequences that show evidence of rapid evolution in humans. They found one sequence in a region they have called HAR1 (Human Accelerated Region) which is highly conserved in other animals. For example, between chicken and chimpanzee there are only two substitutions in the 118 base pair region. Between chimpanzee and human there are 18 differences, all of which have occurred in the human lineage. The rate of evolution in HAR1 is about 70 times what would be expected from observing this region in other species. HAR1 is clearly under strong positive selection.

HAR1 is not a protein coding gene - it codes instead for RNA. But the most interesting thing about HAR1 is that it is expressed in the developing brain, specifically in the developing cortex of the embryo between nine and 17 weeks of gestation. It seems to act in conjunction with the protein reelin that is known to be implicated in the multi-layer patterning of the human cortex. No-one knows yet what the function of the HAR1 RNA is, but our understanding of the functions of non-protein-coding regions of the genome is in its infancy. However, we can reasonably infer that HAR1 influences the patterning of the mammalian and bird cortexes and that the big differences between the human sequence and that of other animals is one of the things that makes us uniquely human.

Everything about molecular biology is turning out to be more complex than anyone imagined 20 years ago. Most of the other sequences of highly accelerated evolution in the human genome seem to be in non-protein coding regions. In the last few years we have discovered that more than 60% of the conserved (and therefore probably functional) part of the mammalian genome is in non-protein coding regions. What does it all do? We don't know as yet - in fact, we've only just scratched the surface.

It was a rather humbling experience for us all when it was seen that humans and mice had about the same number of genes. Many scientists had predicted that humans, as befitted our status as the most complex beings on earth, would have many more genes than other animals. It turned out they were wrong. What's more, the human and mouse protein coding differed in regions that didn't seem to have much to do with special humanity - most of the difference was in the nose and the balls. But now, it's becoming clear that there is much more to a genome than making proteins and that makes everything much, much more complicated.

As for complications, well, in the same issue of Nature, Segal et al present data about the importance of the physical arrangement of DNA in the cell. Until recently, scientists have concentrated on the logical coding, ie the protein coding sequences - now it is turning out that the physical arrangement of DNA in the cell is important too. That also makes things much more complicated. More about this next time.