Could an ancient virus be a genetic driver of autism?

Summary: Genome and transcriptome analysis revealed that autistic BTBR mouse models had increased levels of endogenous retrovirus genes. BTBR/R models of ASD showed differences in the expression of a variety of genes that indicate endogenous retrovirus activation. BTBR/R mice exhibit autistic-like behaviors without reduced learning abilities.

Source: Kobe University

Autism (autism spectrum disorder) is a neurodevelopmental disorder that remains largely unexplored despite the rapid increase in the number of patients.

Reasons for this continued increase in the number of people diagnosed with autism include changes to diagnostic criteria and the spread of older fathers.

Autism is strongly linked to genetic factors and can be caused by abnormalities in DNA structure, such as copy number variations.

Animal models, particularly mice, are often used in research to shed light on the pathology of autism. Among these models, BTBR/J is a commonly used mouse model of the natural onset of autism.

Studies have reported various abnormalities in BTBR/J mice, including impaired corpus callosum (which connects the left and right hemispheres of the brain) and excessive signaling from the immune system.

However, it is not fully understood why this particular line displays autism-like behavioral abnormalities.

The aim of the present study was to shed light on the mechanism of occurrence of these autism-like behavioral abnormalities by performing a comparative analysis on BTBR/J and its subspecies BTBR/R.

search results

First, the researchers performed MRI scans on BTBR/J and BTBR/R mice to study structural differences in each brain region.

The results revealed that there were differences between BTBR/J and BTBR/R mice in 33 regions, including the amygdala. A particularly important difference discovered was that although the corpus callosum of BTBR/J is altered, that of BTBR/R is normal.

Next, the research group used the array CGH method to compare the copy number variations of BTBR/R with those of a normal mouse model (B6). They revealed that BTBR/R mice had significantly higher levels of endogenous retroviruses (ERVs) compared to B6 mice.

Moreover, qRT-PCR tests revealed that these retroviruses were activated in BTBR/R mice. In contrast, in B6 mice, there was no change in the expression of LINE ERV (which is classified in the same repetitive sequence), indicating that this retroviral activation is specific for BTBR.

Subsequently, the researchers performed single-cell RNA analysis on the tissue of embryonic BTBR mice (on the AGM and the yolk sac). The results provide evidence for ERV activation in BTBR mice, as expression changes were observed in a cluster of genes downstream of ERV.

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They also found that BTBR/R exhibits autistic-like behaviors without reduced learning ability, making it a more accurate model of autism than the widely used BTBR/J model. Credit: Neuroscience News via DALL-E2

Finally, the researchers studied in depth the differences between BTBR/J and BTBR/R at the behavioral level. BTBR/R mice were less anxious than BTBR/J mice and showed qualitative changes in ultrasonic vocalizations, which are measured as a way to assess communication ability in mice.

BTBR/R mice also showed more self-grooming behaviors and buried more marbles in the marble burying test.

Both of these tests were designed to detect repetitive behavioral abnormalities in people with autism. From the results, it was clear that BTBR/R exhibits more repetitive behaviors (ie, it is more symptomatic) than BTBR/J.

The 3-chamber social interaction test, which measures how far a mouse will approach another mouse, also revealed more pronounced social deficits in BTBR/R mice than in BTBR/J mice.

Additionally, a Barnes maze was used to perform a spatial learning test, in which BTBR/J mice showed reduced learning ability compared to B6 (normal mice). BTBR/R mice, on the other hand, showed similar ability to B6.

Overall, the study found that activation of the retrovirus leads to an increase in copy number variants in BTBR mice, resulting in the differences in behavior and brain structure seen in BTBR/J and BTBR mice. /R.

Further developments

BTBR/J mice are widely used by researchers as a mouse model of autism. However, the results of this study highlight the utility of the other line of BTBR/R mice as they exhibit autism-like behavior without compromising spatial learning ability. The findings also suggest that it may be possible to develop new treatments for autism that suppress VRE activation.

Additionally, there is a need to classify autism subtypes based on their mechanism of onset, which is an essential first step towards opening up new avenues of autism treatment.


The study was supported by funding from organizations including the following:

See also

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  • Scientific Research Assistance Grants (A) from the Japan Society for the Promotion of Science.
  • Strategic Research Program for Brain Science (SRPBS) of Japan Agency for Medical Research and Development (Psychiatric and Neurological Disorders)
  • Takeda Science Foundation

About this genetics and autism research news

Author: Townsend Truth
Source: Kobe University
Contact: Verity Townsend – Kobe University
Picture: Image is credited to Neuroscience News. Created with DALL-E 2 technology

Original research: Free access.
“An old model with new insights: Endogenous retroviruses drive evolution toward ASD susceptibility and hijack transcription machinery during development” by Toru Takumi et al. Molecular psychiatry


An old model with new insights: endogenous retroviruses drive evolution toward ASD susceptibility and hijack transcription machinery during development

The BTBR J+Itpr3tfThe /J strain (BTBR/J) is one of the most valid models of idiopathic autism, serving as a powerful advanced genetic tool to dissect the complexity of autism.

We found that a sister strain with an intact corpus callosum, BTBR TF/ArtRbrc (BTBR/R), had greater baseline autism symptoms, but moderate ultrasound communication/normal hippocampus-dependent memory. , which can mimic autism in the high functioning spectrum.

Curiously, the disrupted epigenetic silencing mechanism leads to a hyperactive endogenous retrovirus (ERV), a mobile genetic element of an ancient retroviral infection, which increases de novo copy number variation (CNV) formation in both BTBR strains.

This characteristic makes the BTBR strain a multi-locus model constantly evolving towards greater susceptibility to ASDs.

Moreover, active VRE, analogous to viral infection, evades the integrated stress response (ISR) of the host defense and hijacks the transcriptional machinery during embryonic development in BTBR strains.

These results suggest a dual role of VRE in the pathogenesis of ASD, driving long-term host genome evolution and mediating cellular pathways in response to viral infection, which has immediate effects on the Embryonic development.

The expression of wild-type Draxin in BTBR/R also makes this substrain a more accurate model for studying the central etiology of autism without the interference of altered forebrain tracts as in BTBR/J.

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