Searching for Genetic Fossils

brains_largeThe hunt for human origins typically takes the form of fieldwork, with teams of paleontologists scouring the earth for the fossil that will add to the story of how our strange species came to be. That search has taken scientists from Africa to Siberia, adding a pelvic bone fragment here and a skull pan here to build a mosaic depiction of human divergence from other primates. But even as the fossil data accumulates – occasionally bringing more controversy than clarity – scientists are uncovering missing chapters of human origin in less glamorous, albeit cleaner, setting of the laboratory.

Call it genetic anthropology, if you will – the search for DNA changes that set humans and chimpanzees onto different paths with the very different outcomes of zookeeper and zoo resident. A fine example of this practice was on display Tuesday at the weekly Institute for Genomics and Systems Biology lecture, given by Duke University’s Gregory Wray at the invitation of University of Chicago students.

Wray’s specialty lies in computational analysis of genes and gene regulation, with studies that produce graphically appealing representations of the genetic differences between humans and other primates. Taking inspiration from geneticist Mary Claire King, who has long argued that humans are the product of relatively subtle changes in gene regulation, Wray applied his complex calculations to look for small genetic differences that could account for actual physical and behavioral traits.

One difference between chimps and humans that you don’t need a Ph.D. to observe is head size – the human skull, and the brain inside of it, is 2-3 times the size of the chimpanzee skull. All of those fossil findings can be loosely organized into a 2 million-year progression toward larger head size, with the occasional detour – neanderthals, for instance, have a larger head-to-body ratio than modern humans. Evolving a bigger head and brain is no small feat either; though the brain is only about 2 percent of total body mass, it eats up about 20 percent of an organism’s calories, which means growing a bigger brain requires diverting energy away from other parts of the body. Those facts were the basis of an anthropological theory called the Expensive Tissue Hypothesis, which gave Wray a clue for where he might find molecular cues important in both brain evolution and human origins.

“If you’re going to study trait evolution, if you’re going to go fishing, you might as well go for the big kahuna,” Wray said. “What’s more interesting as a trait than the evolution of the human brain?”

So Wray’s lab looked at proteins critical for distributing energy – glucose transporters, which allow sugar to pass from blood into cells. There’s a whole family of glucose transporters that, conveniently for Wray’s purposes, localize to different tissues of the body. Importantly, GLUT1 is responsible for transporting sugar into the neurons of the brain, while GLUT4 is responsible for sugar transport in muscle. Wray’s lab determined that both of these genes had undergone “positive selection” in humans – a sign that natural selection had favored one version of the gene over another.

That natural selection has produced some pretty remarkable differences between humans and chimps, they found. For the brain-specific transporter (GLUT1), humans express 2-1/2 times more of the protein than chimps do. For the muscle-specific transporter (GLUT4), it’s reversed – chimps express nearly two times more protein than humans. The result is a significantly different distribution of energy between the two species, paralleling the greater role and bigger size of the brain in us humans.

Excitingly, the critical role of this gene has already been reverse-proven through genetic diseases, Wray said. Humans with one normal GLUT1 gene and one defective gene show a variety of neural issues, including cognitive development and learning disabilities. If the second GLUT1 gene is so disrupted that it’s essentially absent, the mutation is fatal pre-birth via a very telling defect: microcephaly, or “small head.”

“[The brain] basically starves, it becomes necrotic,” Wray said. “Our bigger brains need this extra level of expression.”

Of course, the GLUT4 gene is not a magic bullet, and could not by itself explain the vast difference between humans and our primate cousins. Other genes have been spotlighted by researchers due to promising data about their role in human origins, from the “speech gene” FOXP2 to genes that control anatomy and development. The brain alone likely required a whole slew of genes to move from the smaller organ possessed by the common ancestor of humans and chimpanzees to its current form.

“What we think of in terms of the evolution of brain size is that both developmental and physiological genes are probably going to be critical in this process…and probably multiple mutations in multiple genes contributed to this,” Wray said.

Fossil hunters are increasingly aware of the power of genetics to back up their work – the recent finding by Svente Paabo and colleagues of a potential new human ancestor was based almost entirely on genetic data from a fingerbone fossil. But, as Wray’s lecture showed, even with no fossil at all, geneticists may be able to add to the story of human origins from the comfort of their own laboratory. No chisel required.

About Rob Mitchum (526 Articles)

Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.

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