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Gene Clue to Brain Asymmetry Revealed on Right Side
More Highly Expressed in Right Brain, Gene May Limit Local Capacity for Language
Two thirds of the way down the brain’s left hemisphere lies a furrow so famous it might well be the brain’s version of the Grand Canyon. Neurobiologists have been exploring the area in and around the left sylvian fissure for more than a century—ever since the 19th century French biologist Paul Broca proclaimed it to be the epicenter of language. And yet it remains a kind of terra incognita. One of the few things researchers have discovered is that the region, known as the perisylvian cortex, looks different on the left side of the brain from the right. But so far no one has pinpointed how—by the turning on and off of what genes—the two hemispheres have become asymmetric.
Photo by Steve Gilbert
Sun Tao (left), Christopher A. Walsh, and their colleagues have begun pinpointing the genes that underlie the human brain’s well-known asymmetry. They compared a language-producing region in the left hemisphere with its counterpart on the right, finding that one gene in particular was much more highly expressed on the right.
A team of HMS researchers has done just that, with surprising results. Many assumed that the asymmetry-producing genes, when found, would be more highly expressed on the left side of the brain than the right. Sun Tao, Christopher A. Walsh, and their colleagues compared the expression of genes in the left and right perisylvian cortices at critical moments of human embryonic development. Of the 27 genes they found, many were more highly expressed in the right hemisphere. A gene, LMO4, that showed the most consistent difference was much more highly expressed on the right. The findings appear in the May 12 online Science.
“We tend to assume teleologically, because of our focus on language being that most beautiful thing, that it must be endowed by some special mechanism in the left hemisphere,” said Walsh, a Howard Hughes investigator and the Bullard professor of neurology at HMS and Beth Israel Deaconess Medical Center. “In fact, it may just be normally repressed in the right hemisphere and allowed to take place in the left.”
Simple Twist of Fate
The researchers’ findings suggest that had events gone a little differently
in the human brain, language might have ended up on the right side. They found
that mouse brains also express the LMO4 gene in an asymmetrical way. But the
asymmetry was not predictable. Some mice expressed LMO4 at higher levels on
the right, others on the left.
“So there was potentially some random asymmetry in our evolutionary ancestors that became entrained in modern humans—imperfectly, though, because five to 10 percent of people actually have a reversed asymmetry,” said Walsh.
It was this minority of people with language on the right side of the brain that got the researchers thinking. Impressed as well by the observation that children with small strokes in the left hemisphere develop language on the opposite side, Sun, an HMS research fellow in neurology at BID, and Walsh developed a hypothesis. “We started thinking that you could probably accomplish the goal of making one hemisphere dominant in language by relatively subtle differences between the two hemispheres,” said Sun.
| “So there was potentially some random asymmetry in our evolutionary ancestors that became entrained in modern humans.” |
Making the Grade
To find these subtle gradient differences, Sun collected samples of the right
and left perisylvian cortices of human brains between 12 and 19 weeks of
embryonic development from a National Institutes of Health–funded
brain bank. Using a technique known as serial analysis of gene expression
(SAGE), he then compared
their gene expression patterns. Initially, he identified 79 differences—genes
that were expressed more or less on the right or left. Upon closer examination,
only 27 exhibited a consistent left–right variation.
One of these, LMO4, exhibited consistent differences in expression at two important stages, 12 and 14 weeks. To get a better picture, Sun tried mapping LMO4 expression in areas outside the perisylvian cortex, using in situ hybridization. Sure enough, the gene was expressed at equal levels on both the right and left sides of the brain. It was only when the researchers approached the perisylvian cortex that the right–left difference started appearing.
Obviously mice do not have language, but they do express LMO4, and they do so at higher levels in the motor and visual cortices. Sun and his colleagues found that about half of the mice expressed LMO4 at higher levels in the right hemisphere, half on the left. “You can think of it in two ways—as a stochastic asymmetry in mice, or you can think of it as nature never getting the two halves of the brain exactly right because nothing is ever perfect,” said Walsh.
It is still not clear what LMO4 is doing in the brain and why differences in its expression should matter. The researchers know that it is a transcription factor and believe it may be involved in selecting one type of connection as opposed to another. If so, it could be receiving instructions from earlier, possibly more critical, genes. “We want to look at these earlier stages to find out what the genes are that guide the patterning,” said Sun.
They are not expecting to find language genes. “It is safe to assume that the asymmetry that ended up leading to language is unlikely to have appeared because of language,” said Walsh. “It is likely to have appeared for some other reason and basically got coopted by language.”