|Source: Greg Wray|
The story about how humans evolved bigger brains begins some seven million years ago in central Africa. There, in a dense rainforest, there lived the last ancestor that we share with our closest living relatives. Our evolutionary paths diverged when the global climate changed and a new habitat took shape. While ancestors of chimpanzees retreated deeper into the rainforest to subsist on a diet mainly of fruits, our ancestors found themselves in on strange, new, dry grassland.
The savanna would mean a new way of life for our ancestors. They’d learn to use tools, communicate with each other using language, and work together to hunt animals for food. Based on fossil evidence and stable isotope data, our hominin ancestors shifted to a diet where meat was a principal energy source about two million years ago. It would be a major shift in diet that coincided with an increase in cranial capacity.
Now, scientists like Greg Wray, a professor of biology at Duke University, are beginning to better understand the genetic basis for the adaptation to eating meat and how it guided the development of our larger brains. During his plenary talk at the Council for the Advancement of Science Writing’s (CASW) “New Horizons in Science 2012” annual conference in Durham, North Carolina, Wray said that the Encyclopedia of DNA Elements (ENCODE) project gave scientists like himself a “detailed street map” for seeking out the genetic changes that took place since the divergence of humans and chimpanzees over evolutionary time.
Wray said that the major diet shift to meat eating is written right into the “software” that runs our genes: the regulome. Previous to ENCODE, these non-coding regulatory regions were thought of only as “junk” DNA. In this new post-ENCODE, however, scientists are finding that these regions have central regulatory roles in the genome and may play a central role in adaptation and divergence of species.
In the regulome, Wray said, his lab found that evidence of genetic changes resulting from our ancestors’ change in diet that would mean stark differences in how we metabolize fats and sugars in comparison to chimpanzees. The genetic changes could also explain how we’re able to feed our energy-hungry brains and why we are more susceptible to specific diseases such as diabetes.
Mini-ENCODE for humans and chimps
The lab focused their research on five tissue samples because of their importance in understanding dietary adaptations—cerebral cortex, cerebellum, liver, adipose tissue, and skeletal muscle. The research would be like a “mini-ENCODE” comparing evolutionary changes between humans and chimpanzees since their divergence from a last common ancestor.
According to Wray, his lab found a “huge signal” of changes in cell signaling genes that meant a lot of coordination going on between metabolism, development, and neural functions. For example, of the 61 genes that are known participants in insulin signaling, 31, almost half, were different. The differences in insulin signaling genes may explain why humans are so much more susceptible to diet-related diseases such as type 1 and 2 diabetes than are chimpanzees. “That’s what’s changed between humans and chimps,” he said.
What’s not changed are more general functions involved in DNA transcription, replication, and repair; RNA processing and translation; and protein translation and localization.
Looking at general patterns, Wray also found a lot of signals for metabolism and neural function changes. When humans are compared to rhesus macaques, the changes are still clear along the longer evolutionary span. However, comparing chimps to rhesus macaques finds that the neural signaling is gone while the metabolism signal is still there.
“If you do this kind of analysis for these functional categories, you can start to parse out what’s different about human evolution versus other aspects of primate evolution,” Wray said.
Fat cells behave differently in humans versus chimps
In humans versus chimps, Wray said, there are also stark differences in how we store fat, produce fat, (de novo synthesis of fatty acids) and how we burn fat for energy (beta-oxidation) because of differently regulated genes. “Pretty much every aspect of fat cell function has been altered between humans and chimps,” Wray said.
Investigating further, Wray’s lab used adipose tissue stem cells from humans and from chimps and performed a series of petri dish experiments. The cells were grown “under different diets”—that is to say that they grew in the presence of either more carbohydrate, oleic acid (which is the dominant fatty acid found in meat), or linoleic acid (the dominant fatty acid found in grains).
A clear signal was returned: each of the enzymes for fatty acid synthesis was higher among the human adipose tissue cells. In a habitat where the principal energy source would switch from simple sugars from fruit to fatty acids from meat, it’d make sense to have these enzymes upregulated. The findings could explain how humans were able to grow brains thrice the size.
“If you’re going to make a bigger brain, a brain that’s about three times larger than the chimp-human ancestor, you need to make a whole lot more building material,” he said. “You don’t need to just make these membrane materials you need to constantly turn them over. So the flux through this pathway is probably pretty important to building a bigger brain.”
Although with the reward of a bigger brain through an adaptation to push more fatty acids through pathways came an unintended side effect, Wray said. Another major shift in diet at the agricultural revolution would introduce a large amount of omega-6 fatty acids. A high influx of omega-6 fatty acids would produce higher levels of arachidonic acid, involved in production of pro-inflammatory eicosanoids implicated in insulin resistance and atherosclerosis.
Expensive-tissue hypothesis at the metabolic level
Making larger brains came with other costs, as well, and it had to do with a tradeoff of energy allocation. The brain is an exceptionally energy-hungry tissue consuming almost 10-fold higher than the rest of the body even while asleep. “What that means is that if you triple the size of the brain, you’re not making one organ a little bigger, you’re essentially raising the energy budget of the body by a lot,” Wray said.
As anthropologists and physiologists have long argued, a larger brain meant taking energy away from somewhere else, preferably another energy-hungry tissue. “Expensive-tissue hypothesis” may be partly explained by the fact that our human guts are a little shorter and our muscles are smaller than that of chimpanzees. But it’s “not enough,” Wray said. His lab suggests that the regulome could explain the tradeoff from a metabolic and molecular level, not at the level of gross organ size.
Sugar transporters show signals of positive selection in the regulatory region, Wray said. A couple of genes called SLC2a1 and SLC2a4 (SLC – transport protein; 2 – sugar transport; a1 and a4 and so forth are different members of those families) are uniquely positioned to mediate the tradeoff. SLC2a1 is expressed predominantly in the brain and SLC2a4 is expressed predominantly in the skeletal muscle.
“We hypothesized that if you increase the expression of the brain transporter and decrease the expression of the muscle transporter, the common point of energy metabolism (glucose)—is going to be allocated differently, just by mass action” Wray said.
What Wray’s lab found was that when they compared brain specific expression of the sugar transporter, it was much higher in humans than it was in chimps and rhesus macaques. In muscle, conversely, it’s higher in chimpanzees than it is in humans. Double the glucose transporters in the brain and half in the muscle would mean a four-fold difference in glucose getting across the membrane into the brain. As a way of maximizing energy supply to the brain “that’s pretty large change,” Wray said.
Comparatively, it is well known in the medical field that children with deficiencies in glucose transporters (Glut1 deficiency syndrome) have cognitive deficits. “The brain literally starves,” Wray said. “We had to have that increase [in glucose transporters] in the metabolic scope of the brain to allow it to get bigger.”
Of mice and bigger brains
During the last few minutes of his talk, Wray shared with his audience one other project his lab was working on, shared as a teaser: It was to clone out pieces of the regulome thought to be responsible for changes in human and chimp brains and testing them in mice embryos.
Wray’s lab found that mice embryos with either the “chimp enhancers” or the “human enhancers” had strong signals of neural stem cells production and greater neuron production. In particular, the embryos with the human enhancers came on stronger and lasted longer.
“What we haven’t done yet is see what happens if these mice grow up and see if they have cognitive changes, behavioral changes, or detail changes in the structure of their brains,” Wray said. Those big-brained mice are going to grow up?
Questions and FADS
After Wray’s talk, there were plenty of questions asked by his audience, who were mainly science writers attending Science Writers 2012 (see Keith Eric Grant’s #sciwri12 Storify story). These included ones about his own diet — less starch, some animal products, mostly fruits and vegetables, a higher omega-3 to omega-6 ratio — and how Richard Wrangham hypothesis that cooking could explain energy tradeoff might’ve figured into the equation — yes, Wray agreed, cooked food is easier to digest and absorb.
There was also a question about whether or not Wray’s lab would be looking at comparing the human regulomes with that of other hominin species such as Denisovan and Neandertal. It was something, Wray said, that he was definitely looking into doing in the future.
One of the questions I asked Wray was about genetic variation between different human populations, specifically with regards to the FADS region of the genome. The region has been subject of special interest and speculation among researchers because variations of rate-limiting enzymes encoded by FADS1 and FADS2 for biosynthesizing long-chaing fatty acids may also help explain larger brains.
“I think it’s a layered processing,” he said. “Originally, there was probably upregulation of the FADS genes simply because we had so much more fatty acids in our diet. That probably coincided with the shift to a more animal-rich diet.”
Wray added that because both the omega-6s and omega-3s flow through enzymes encoded by the FADS region, it also may explain why a post-agricultural revolution diet higher in grains puts us at higher risk of chronic disease. The high omega-6 to omega-3 ratio of our modern diets puts us “way out of balance,” he said, with more omega-6s moving through pathways to produce pro-inflammatory compounds.