Geschwind has been captivated by this asymmetry, and by its relationship to handedness. Roughly 90 percent of us are right-handed, and nearly all righties depend on that left “perisylvian” region for speech and language. (About 40 percent of lefties instead rely on the right perisylvian region or use both hemispheres.) “There’s some kind of benefit to the kind of processing that’s going on in language–which is extremely rapid processing–to keep everything in one circuit in one hemisphere,” he concludes.
The process that creates asymmetry often goes amiss in people with dyslexia, schizophrenia, or autism–all disorders with links to language problems. So Geschwind and others have set about hunting for genetic aberrations implicated in language disorders and for genes linked to differences in brain asymmetry, such as those related to handedness.
While the discovery of the mutation in FOXP2 required great effort (and a dollop of luck), all told it involved analyzing the DNA of no more than 50 people. In contrast, no simple mutation of a single gene is likely to disrupt brain asymmetry or cause dyslexia, schizophrenia, or autism. Rather, these problems are caused by subtle aberrations in genes and networks of genes working in concert. That subtlety forces researchers to collect and sort through DNA from hundreds if not thousands of people. For example, the Autism Genome Project, a large international collaboration in which Geschwind participates, performed an analysis of more than 1,400 families that have at least two members affected by autism-spectrum disorders. This massive study didn’t isolate a single mutant gene, but it did find intriguing links between the disorders and missing or extra copies of a region of chromosome 11. Such variations can increase or decrease the amount of protein produced by genes, with unpredictable effects.
Geschwind also contributed to a study, led by Oxford’s Clyde Francks, that revealed some of the intricate connections among language-related disorders, brain asymmetry, and handedness. The study began as a hunt for a gene that controls handedness in dyslexics. Previous reports had suggested that dyslexics are more likely to be left-handed and that left-handed people are more likely to have reduced asymmetry. Francks and his colleagues could not corroborate that suggestion, but they did find a region of chromosome 2 that seemed linked to left-handedness. They then examined the DNA of pairs of healthy left-handed brothers: the same linkage to chromosome 2 surfaced, evidence that a gene or genes in that region might influence handedness. Adding still more bizarre connections, the team performed a study of siblings with schizophrenia, which implicated the same region.
To find the gene or genes at the heart of this knot of links, the researchers compared the same region of chromosome 2 in healthy right-handed people, healthy left-handed people, and people with schizophrenia. They found four DNA differences that distinguished the schizophrenics from the mentally healthy lefties; the location of these variations led them to a gene called LRRTM1. Geschwind collaborated in the work that helped identify where in the human brain LRRTM1 was turned on, or expressed: it probably helps shape forebrain structures and influences how neurons connect. He suspects that in early gestation, it also contributes to brain asymmetry.
Francks and his colleagues think that certain variants of LRRTM1 somehow decrease production of the LRRTM1 protein during fetal brain development. Presumably, reduced levels of LRRTM1 could have contributed to reduced brain asymmetry, tilting the developmental scales toward left-handedness and schizophrenia–and potentially toward a variety of speech and language problems.
All this adds up to little more than a list of genes that may or may not be involved in creating speech and language: FOXP2; genes that FOXP2 interacts with; genes with copy number anomalies implicated in autism; and an aberrant gene connected to schizophrenia and left-handedness. Moving from correlations between genes and disorders to knowledge of the neural circuitry that allows a human but not a chimp to ask, “To be, or not to be?” requires researchers to find connections between seemingly disparate findings. To that end, Geschwind and others are turning to evolutionary studies that analyze these genes in other species and compare them with the human versions. Such studies may also provide clues to how humans evolved the capacity for language.