Different Genetic Functions Across Species Can Cause Problems for Autism Models | Spectrum

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Network news: Mapping of genes expressed together in the brain can shed light on their function.

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Some autism-related genes, such as SHANK3 and SCN2A, may have different functions in mice and humans, according to a new study. Research identifies evolutionary changes in which genes are expressed together in the brain and raises new concerns about the limits of model organisms to study neuropsychiatric disorders.

Mapping gene expression networks offers insight into gene functions, previous work has shown. Different types of cells, for example, can be identified by the gene patterns they tend to express – just as a person’s social network can suggest their role in society, says lead researcher Daniel Geschwind, distinguished professor. of Neurology, Psychiatry and Human Genetics at the University. of California, Los Angeles.

In the new study, Geschwind and his colleagues examined how these networks vary between humans, non-human primates, mice, and human cells in culture.

The study shows that expression patterns linked to neurons tend to be conserved between mice and humans. But the expression patterns linked to glia – the supporting cells of the nervous system that include astrocytes, microglia, and oligodendrocytes – are not. Instead, expression of the glial gene in humans appears to match that of cultured cells, monkeys, or chimpanzees better.

In addition, 70 genes associated with autism, as well as genes linked to other neuropsychiatric conditions, have divergent expression patterns between humans and mice, the mapping revealed.

Researchers shouldn’t give up on studying these genes in mice, says Geschwind. “But draw conclusions about neuropsychiatric disorders based on a mouse model in which the gene is not well conserved [between the two species] could be problematic.

Model citizens:

Geschwind and his colleagues analyzed data from 7,287 postmortem adult brain tissue samples collected by the Genotype-Tissue Expression Project and 6,667 mouse brain tissue samples collected in 30 previous studies. They generated gene expression networks in 12 regions of the human brain and 7 regions of the mouse brain and compared them.

Many gene networks are conserved, the team found. But the expression of 5,473 genes differs between the two species. Regions of the cerebral cortex, the outer layer of the brain, showed the most significant differences, while expression patterns in the cerebellum, which coordinates movement and synchronization, were more similar between species.

The genes associated with glia have shown more distinct patterns between humans and mice, suggesting that evolution has resulted in more changes among these cells, Geschwind explains. Genes linked to neurons, on the other hand, were more closely aligned. The results were published in January in Genome biology.

The researchers also generated gene expression networks for 2,933 tissue samples from six brain regions of macaque monkeys, baboons and chimpanzees. As with mice, networks of non-human primate genes associated with neurons were similar to those seen in the human brain. Expression patterns related to other cell types resembled those seen in humans more than those seen in mice, but these results are not statistically significant.

Different parallels have emerged for organoids in the human brain, clusters of neuronal tissue grown from stem cells. The team found that gene expression patterns from eight previous organoid studies matched human gene expression for astrocytes and neurons, but not for microglia or oligodendrocytes.

Know the limits:

The organoid findings make sense, says Alysson Muotri, professor of cellular and molecular medicine at the University of California, San Diego, who was not involved in the work. For example, most models of brain organoids do not naturally contain microglia, because these cells emerge from a different cellular source than neurons, he says. The new work suggests that adding microglia to organoids could make them a better model for autism, Muotri says.

That’s the kind of guidance researchers should get from the work, Geschwind says. Rather than being the “best” model organism overall, the results “highlight the pros and cons” of each for a given gene, he says.

As a researcher bracing for new work on a mouse model of autism, the results actually inspire confidence in what the model can and cannot do well, says Santhosh Girirajan, associate professor of genomics at Pennsylvania State University at University Park, who was not involved in the study.

“If you don’t respect the limits [of a model system] in your mind, your interpretation of what you find may not be correct, ”he says.

One limitation to the usefulness of the new findings, especially for autism research, is that the study only used adult brain tissue, which may not accurately represent gene expression during development. . Geschwind and his colleagues plan to expand their work to include the antenatal and postnatal networks when data for these periods becomes available.

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