Genetic tweaks built humans’ bigger brains

Experiments in mice show how to grow a wrinkled cortex

Big Brain

FOLD IT  A gene that only humans have can make the normally smooth outer layer of mouse brains develop folds similar to those in human brains (upper right center). The gene may have been important for the evolution of big human brains.

M. Florio and W. Huttner/Max Planck Institute of Molecular Cell Biology and Genetics

Human brains ballooned to about triple the size of their ancestors’ thanks to just a few genetic tweaks, new research suggests.

When scientists inject a gene found only in humans into the brains of mouse embryos, the normally smooth mouse brain develops the crinkles and folds reminiscent of wrinkly human brains, scientists report online February 26 in Science. The wrinkles are a sign that the brain’s outer layer, or cortex, is growing. 

That discovery closely follows a report from Duke University researchers who have found a genetic switch that boosts brain size. The human version of that switch produces a 12 percent larger cortex than a chimpanzee version does, the Duke team reports February 19 in Current Biology.

Together, the two studies present some of the first genetic clues about how human brains tripled in size starting about 2 million years ago. Some scientists thought it could take many genetic changes for evolution to plump up the human brain, says Mary Ann Raghanti, a biological anthropologist at Kent State University in Ohio who was not involved in either study. These new findings suggest that relatively few changes were necessary to inflate brain size, she says.

The Duke team’s findings provide evidence that pieces of DNA that regulate gene activity are important for shaping brain evolution. Called enhancers, these DNA bits help determine when during development, and in which tissues, a gene will turn on.

Duke developmental neurobiologist Debra Silver and evolutionary geneticist Gregory Wray and their colleagues examined enhancers that are evolving faster in humans than in other primates. The researchers zeroed in on one called HARE5, which turns on a gene called Frizzled 8 in the brain during development.

BIG BRAIN A piece of DNA called HARE5 that regulates a gene important in brain development may be partially responsible for why humans have such big brains. Here, HARE5 turns on a gene (blue) in the brain of a mouse embryo at day 14.5 of development. J. Boyd et al./Current Biology 2015

Human HARE5 has 16 differences from the chimpanzee version of the enhancer that alter brain development, the researchers found.

In mice engineered to possess a copy of the Frizzled 8 gene, adding the human version of HARE5 made nerve cells grow faster than in mice given the chimp version of HARE5. Mice with the human HARE5 developed a 12 percent bigger cortex than mice with the chimp enhancer — but that boost isn’t enough to explain the entire explosion of human brain size, Silver says.

A gene called ARHGAP11B can also build bigger brains, say Wieland Huttner, a molecular and cellular biologist at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany and colleagues. That gene is an imperfect copy of another gene and doesn’t work like the original gene, the team reports in the Science paper. Duplicating DNA is one of evolution’s favorite ways of creating genes with new functions, says Raghanti.

The gene was duplicated about 5 million years ago — after the common ancestor of modern humans and their extinct cousins Neandertals and Denisovans split from chimpanzees. Neandertals also had big brains. No Denisovan skulls have been found.

ARHGAP11B causes one type of primordial brain cell to switch to another type, Huttner and colleagues discovered. One part of the brain that makes new nerve cells in adults grew 50 percent thicker in mice that got a dose of the gene than in mice that didn’t. Injecting the gene into mouse brains also caused the cortex folding.

The studies are exciting, says evolutionary geneticist Evan Eichler of the University of Washington in Seattle, but are probably not the whole story of how humans got bigger brains. He’s concerned about the timing: ARHGAP11B appeared about 5 million years ago, but brain size didn’t really start to change until about 2 million years ago. “What the heck was it doing for 3 million years?” Eichler asks. The discrepancy suggests that other factors must have evolved during that time to spark the big brain explosion.

Just having a big brain didn’t necessarily make humans smarter, adds Huttner. More nerve cells would boost the brain’s processing power, but additional steps also were probably needed to wire it properly, he says.

Editor’s note: This story was updated on March 3, 2015, to correct the publication date of the Current Biology study.

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