So similar yet so different
Whenever I go to the zoo, I could easily spend my entire visit hanging out with our not-so-distant relatives, the chimpanzees. To say we humans are similar to them is quite an understatement. Sharing 96% of our DNA, chimps are more closely related to us than they are to gorillas. And when you just compare our genes – that is, the segments of DNA that contain instructions for making proteins – we’re even more indistinguishable.

Chimps and Humans: So similar yet so different

And yet you wouldn’t mistake a human for a chimp. I mean, I do have hairy arms, but they’re not that hairy. So what accounts for our very different appearance if our genes are so similar?

To seek out answers, a CIRM-funded team at Stanford University used both human and chimp induced pluripotent stem cells (iPSCs) to derive cranial neural crest cells (CNCCs). This cell type plays a key role in shaping the overall structure of the face during the early stages of embryo development. In a report published late last week in Cell, the team found differences, not in the genes themselves, but in gene activity between the human and chimp CNCCs.

Enhancers: Volume controls for your genes
Pinpointing the differences in gene activity relied on a comparative analysis of so-called enhancer regions of human and chimp DNA. Unlike genes, the enhancer regions of DNA do not provide instructions for making proteins. Instead they dictate how much protein to make by acting like volume control knobs for specific genes. A particular volume level, or gene activity, is determined by specific combinations of chemical tags and DNA-binding proteins on an enhancer region of DNA.

Enhancers: DNA segments that act like a volume control knobs for gene activity (Image source: FANTOM Project, University of Copenhagen)

The researchers used several sophisticated lab techniques to capture a snapshot of this enhancer tagging and binding in the CNCCSs. They mostly saw similarities between human and chimp enhancers but, as senior author Joanna Wysocka explains in a Stanford University press release, they did uncover some differences:

Joanna Wysocka

“In particular, we found about 1,000 enhancer regions that are what we termed species-biased, meaning they are more active in one species or the other. Interestingly, many of the genes with species-biased enhancers and expression have been previously shown to be important in craniofacial development.”

PAX Humana: A genetic basis for our smaller jawline and snout?
For example, their analysis revealed that the genes PAX3 and PAX7 are associated with chimp-biased enhancer regions, and they had higher levels of activity in chimp CNCCs. These results get really intriguing once you learn a bit more about the PAX genes: other studies in mice have shown that mutations interfering with PAX function lead to mice with smaller, lower jawbones and snouts. So the lower level of PAX3/PAX7 gene activity in humans would appear to correlate with our smaller jaws and snout (mouth and nose) compared to chimps. Did that just blow your mind? How about this:

The researchers also found a variation in the enhancer region for the gene BMP4. But in this case, BMP4 was highly related to human-biased enhancer regions and had higher activity in humans compared to chimps. Previous mouse studies have shown that forcing higher levels of BMP4 specifically in CNCCs leads to shorter lower and upper jawbones, rounder skulls, and eyes positioned more to the front of the face. These changes caused by BMP4 sound an awful lot like the differences in human and chimp facial structures. It appears the Stanford group has established a terrific strategy for tracing the genetic basis for differences in humans and chimps.

So what’s next? According to Wysocka, the team is digging deeper into their data:

“We are now following up on some of these more interesting species-biased enhancers to better understand how they impact morphological differences. It’s becoming clear that these cellular pathways can be used in many ways to affect facial shape.”

And in the bigger picture, the researchers also suggest that this “cellular anthropology” approach could also be applied to a human to human search for DNA enhancer regions that play a role in the variation between healthy and disease states.