It’s sad, but true, that much of what is known about how the human mind works has been learned by studying broken brains. Injury caused by illness or accident thus shows the jobs of the part of the brain that has been damaged, from the list of disabled functions. Similarly, “injuries” to the genome, which result from deletions or duplications of stretches of DNA, sometimes have clear effects that can illuminate the functioning of healthy brains. At the AAAS meeting, the US National Institute of Mental Health and Carrie Bearden of the University of California, Los Angeles, told participants about the latest findings related to two of these genetic injuries.
Some segments of the genome are at particular risk of being lost or duplicated during the process of meiosis, when pairs of chromosomes exchange genetic material before the formation of the egg and sperm. This is because they are associated with stretches of DNA that contain matching sequences of genetic letters. These matching flanks can confuse the molecular machinery that makes the swap. Sometimes due to this confusion the relevant clause is omitted. Sometimes the section in question gets duplicated. Any individual inheriting a chromosome will thus either lack or have a surplus of genes that are part of the affected segment.
Dr Berman works on the part of chromosome 7 whose deletion causes Williams syndrome, identified in 1961 by a doctor of that name. Dr Bearden’s work on DiGeorge syndrome, also identified by the same name in 1968, and caused by deletion of part of chromosome 22. Both are equivalent, recently noted, resulting from an extra copy of the labile chromosomal section. As the two researchers explained, comparing the under- and over-representation of these classes deepens understanding of the neurological roles of genes in them.
People with Williams syndrome have a wide variety of symptoms. Some are structural, such as a specific face shape. Others are behavioral – a tendency to be talkative, sociable, good at recognizing faces (though poor at visual-spatial tasks) and having good empathy with others. In short, they are the opposite of autism. People who have the inversion of the syndrome, known as Dup7, have a different face shape. They also learn to talk later than usual, are poor at recognizing faces (though good at visual-spatial tasks), and are antisocial. These latter symptoms are associated with autism.
Dr Burman highlights the role of two genes, GTF2I and LIMK1, found in the affected area. GTF2I encodes a type of protein called a general transcription factor. Transcription factors initiate the production of RNA copies of genes which then serve as instructions for making proteins. As has been suggested, GTF2I is involved in several such subtypes, which may help to explain the disparate manifestations of Williams syndrome. LIMK1 encodes an enzyme known to be involved in brain development.
hard copies
Dr Berman and his group have demonstrated a correlation between the “dose” of these genes (whether there are one, two or three copies) and the size of the brain regions affected. Magnetic-resonance imaging (MRI) has shown that the total brain volume increases with the number of copies of the affected chromosomal region (therefore smaller than normal with the deletion, and larger than normal with Dup7). But all this development takes place in the largest part, the cerebrum. The second largest part, the cerebellum, is inverted.
He has toned things down now. Within the cerebrum, she has found, the amount of gray matter in a region called the intraparietal sulcus, which is known to be involved in visual attention (and thus visual-spatial awareness), is dose-dependent on LIMK1. In contrast, the volume of another region, the insula, which has been linked to emotions such as compassion, is dependent on the dose of GTF2I. Those findings match up well with genes in brain function.
Doctor. Bearden had a similar approach with DiGeorge syndrome and vice versa. As is the case with Williams and Dup7 syndromes, the deletion or addition of part of a chromosome has multiple effects. In this case, one of the most intriguing is that the deletion often results in symptoms of schizophrenia, whereas the addition protects against the condition.
Using MRI, Dr. Bearden was able to correlate all of this with systematic differences in the thickness and surface areas of certain parts of the cerebral cortex. Those with the deleted segment had thicker, but less folded cortices than those with intact chromosomes. Those with duplications had thinner, but more convoluted cortices.
How having an extra copy of this segment of DNA protects against schizophrenia is not yet clear, but the investigation is ongoing. If this can be determined, it could be an important step toward treating this troublesome condition.
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© 2023, The Economist Newspaper Limited. All rights reserved. From The Economist, published under license. Original content can be found at www.economist.com
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