Evo-devo and HACNS1

Science has a very important paper in the current issue about the evolution of a gene enhancer in hominids, expressed in forelimb development and concentrated toward the first digit. The enhancer is a conserved sequence named HACNS1, it exhibits a stronger signature of recurrent selection on the human lineage than any other conserved enhancer sequence. In transgenic mice, the human version of this enhancer triggers gene expression in the forelimb, concentrated toward the thumb side, and some other parts of the body, notably the pharyngeal arches (which give rise to elements of mouth, throat and larynx), eye and ear. The research is by Shyam Prabhakar and others at Lawrence Berkeley National Lab, and involves Edward Rubin and James Noonan, otherwise prominent in the Neandertal genome sequencing.

I think this is an extraordinarily important result. You don’t see me write those words very often. This is a paper that every biological anthropologist should read. It gives an extremely good example of the importance of developmental regulation to human evolution. We will see many more papers like this one in the coming years. This is one of the genes that makes us human.

Ed Yong of Not Exactly Rocket Science has written a nice online review of the research, and Science has accompanied it with a perspective piece by Gregory Wray and Courtney Babbitt. Here’s a quote from that article:

To test the function of this region, they genetically engineered mouse embryos to express a construct composed of human HACNS1, the promoter element of a heat shock gene, and a reporter gene. Their results show that human HACNS1 drives expression in the mesenchyme of the early developing forelimb, and later developing hindlimb, in these mouse embryos. A comparison of expression patterns driven by macaque, chimpanzee, and human orthologs of HACNS1 revealed that consistently strong forelimb expression is a unique property of the human version. By testing various combinations of human and chimpanzee HACNS1 sequences, the authors narrowed down the relevant functional mutations to an 81-base pair region containing 13 substitutions that arose during human evolution. This concentration of substitutions is highly unusual relative to the genome as a whole, implying positive selection on this region during human origins.

The press are going with the story that the evolution of this gene may underlie the unique evolution of human manual dexterity. It’s a good hypothesis, but I think there is a more accurate way of putting the situation. We see that the enhancer has effects in different areas of the developing embryo. Its action is therefore pleiotropic: changing its function in one area might well screw up its action somewhere else. So at the very least, this is an enhancer that must satisfy multiple constraints. Strong evolutionary change in its sequence may reflect changes in one of those functions, or more than one. But at the very least, it implies that the hominid developmental program not only satisfies different fitness constraints than in the human-chimpanzee common ancestor, but that these changes required repeated changes.

We don’t know how long it would have taken all these nucleotide substitutions to happen. But we might find signs in the fossil record of such a sequence of events, if we had enough bones, and if we had more information about the effects of different forms of the gene on the adult phenotype. For example, the relatively long thumbs of the Hadar hominids (compared to chimpanzees and gorillas) suggest that the sequence of changes started early in hominid evolution. There’s a hypothesis.

But like I said, I wouldn’t rule out other possible functions of the enhancer as targets for selection. It is plausible (as a hypothesis) that the enhancer with the most selected substitutions on the human lineage might be more likely than others to have been selected for multiple functions. And we have plenty of reasons to suspect selection on its other targets, particularly the developing mouth, throat and ear.

It may even be that the evolution of human thumbs was a side effect of evolution in the throat, or vice versa. That’s the kind of weird world evo-devo makes for us!


Prabhakar S and 9 others. 2008. Human-specific gain of function in a developmental enhancer. Science 321:1346 - 1350. doi:10.1126/science.1159974

Wray GA, Babbitt CC. 2008. Enhancing gene regulation. Science 321:1300-1301. doi:10.1126/science.1163568