X chromosome exerts additional influence on brain development | Spectrum

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X-tra effects: Areas of the brain showing an inordinate influence of the X chromosome (yellow) support functions such as attention, decision-making, and sensory and motor skills.

The X chromosome exerts a stronger than expected genetic influence on the structure of several regions of the brain, according to a new study. The X-linked genes that may underlie this oversized influence have links to autism and intellectual disability.

“There were already hints that the X chromosome was likely to be visible, with its involvement in the brain,” says lead researcher Armin Raznahan, head of the section on developmental neurogenomics at the US National Institute of Mental Health. Many genes on the X chromosome, including those that cause several autism-related conditions, such as fragile X syndrome and Rett syndrome, are expressed in the brain, for example.

But the new findings suggest that the X chromosome, although it contains only 5 percent of the human genome, has a privileged role in brain formation – a role that may be particularly relevant for developmental conditions. What’s more, this influence may be stronger in men than in women, according to the study.

“What they show is that X is fundamentally different,” said David Glahn, a professor of psychology at Harvard University, who was not involved in the new study. “It’s off the scale.”

Research over the past decade has linked genetic variation to changes in characteristics of the brain, such as overall size or patterns of connectivity between regions, Glahn says. But “the X chromosome and the Y chromosome are fundamentally under-studied” because including them requires additional analytical work, he says.

This oversight may soon disappear, thanks to powerful datasets that compile gene sequencing and brain imaging data from tens of thousands of people. The new work is the latest in a series of studies that harness the UK Biobank, which houses the genetic and imaging data of nearly 40,000 people.

“The ability to examine [the] The X chromosome and the influence on the structure of the brain was really not possible until these huge datasets were recently available, ”says Neda Jahanshad, associate professor of neurology at the University of Southern California in Los Angeles, which did not participate in the study. “This is a really important initial investigation into this. “

X files:

Raznahan and his colleagues analyzed genetic data and magnetic resonance imaging scans of 32,256 adults, about half of whom are women, from the general population.

From brain scans, the researchers determined the thickness, volume, and area of ​​358 regions of each participant’s cortex. They looked for links between these structural features and changes in the participants’ genetic code, then calculated the proportion of variation in cortical features related to that of the X chromosome. Raznahan and his team reported their findings in July in Neuroscience of nature.

The X chromosome exerts a greater influence on the structure of several regions of the brain, including the prefrontal cortex, the sensorimotor cortex and the temporo-parietal junction, than its genomic size would suggest, the researchers found. And this pattern was more apparent for the surface than for the thickness or volume of a region of the brain. In fact, genetic variation on the X chromosome accounts for more than 20 percent of the variation in the surfaces of multiple regions, according to the study.

The influence of the chromosome on the temporo-parietal junction is particularly intriguing when it comes to autism, Glahn says. The activity and withdrawal of the region is related to theory of mind, or the ability to intuition the feelings and thoughts of others. Some people with autism find this skill difficult.

Networks involving attention, decision-making, and sensory and motor functions significantly overlap with the areas of the brain most influenced by X chromosome variation, the researchers also found, suggesting that the X chromosome supports the adaptive behavior, explains Raznahan.

“The structural organization certainly gives a first glimpse,” Jahanshad says. But a key next step is to correlate genetic variation on the X chromosome with functional imaging data patterns and actual behavioral traits. (Raznahan says he plans to do just that in follow-up studies.)

Sexual effects:

A separate analysis yielded 20 X-linked genes which are associated with the surface regions of the brain that show strong influences from the X chromosome as a whole. Several of these genes are involved in intellectual disability, hydrocephalus and autism.

The work complements another UK Biobank study, published in April in the same journal, in which a separate team focused on specific genes on the X chromosome linked to brain characteristics, such as the integrity of nerve bundles in the brain. .

The influence of the X chromosome on brain anatomy was more than twice as strong in men as in women, Raznahan’s team also showed. The degree of this difference in heritability between males and females correlated with the degree of gender differences in the cortical surface, which tends to be greater in males.

While the X chromosome plays a more important role in determining certain aspects of brain structure in men than in women, as the results suggest, it may be a compensation for men with only one X. , while women have two.

The findings add yet another round of evidence for the often contested idea that there are sex differences in the brain. But it’s unclear how the X chromosome might affect these differences or how they relate to actual behavior, Glahn says. “What’s really interesting about it is just asking these questions about the difference between the sexes.”

Overall, the new work serves as a call to action for researchers to include the X chromosome as they probe the genetic makeup of the brain, Raznahan says. “We would be delighted if this work would in any way help encourage people to further study the X chromosome.”

Quote this article: https://doi.org/10.53053/QCAF1417

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