Differing gene functions and mouse modeling

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Joined: 25 Aug 2013
Age: 63
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Location: Long Island, New York

23 Feb 2021, 5:29 am

Differing gene functions across species may pose problems for autism models

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

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

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

What’s more, 70 autism-associated genes, as well as genes linked to other neuropsychiatric conditions, have divergent patterns of expression between humans and mice, the mapping revealed.

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

Many gene networks are conserved, the team found. But the expression of 5,473 genes differs between the two species.

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

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

One limit on the utility of the new results, particularly for autism research, is that the study uses only adult brain tissue, which may not accurately represent gene expression during development.

Professionally Identified and joined WP August 26, 2013
DSM 5: Autism Spectrum Disorder, DSM IV: Aspergers Moderate Severity.

It is Autism Acceptance Month.