论文标题：The evolution of a series of behavioral traits is associated with autism-risk genes in cavefish
Written by Masato Yoshizawa et al
Digital identification code: 10.1186/s12862-018-1199-9
Whether multiple changes in animal behavior have a common genetic basis across species is one of the most important questions in evolutionary biology. Blind cavefish, an interesting species that can be used to study this problem, exhibit symptoms similar to those of human autism spectrum disorder (ASD). In a paper published in BMC Evolutionary Biology, a team of researchers used the fish as an animal model to study the genetic mechanisms behind autism.
Mexican carp exists in two different forms: a surface fish in the river, and a relatively rare cave-dwelling fish that has no eyes and is found in isolated caves in North America.
Surface fish are typical of river fish, forming schools of fish, sleeping at night, paying a balanced attention to food, predators and mates, and swimming calmly in the water while resting. In contrast, cavemen swim non-stop, rarely interact with their partners or sleep, exhibit repetitive patterns of behavior, such as whirling between water jets, and have higher levels of cortisol, an anxiety hormone, in their blood.
Two different forms of Mexican carp: surface fish and burrowing fish.
These symptoms are similar to those of people with autism, characterized by difficulty interacting socially with others, hyperactivity, insomnia, attention deficits, and anxiety.
These shared behaviors between humans and fish have different levels of complexity, but they appear to be driven by evolutionarily conserved neural pathways. For example, emotion-based behavior, attention, social interaction, and sleep regulation all rely on conservative neural networks in the brain, such as the cortical region, thalamus, hypothalamus, and pineal glands.
Recent findings suggest that the behaviors observed in cavefish are evolutionarily conserved between fish and humans.
ASD-risk genes in cavefish Autism risk genes in cavefish
We conducted a comprehensive study of homologous genes of human autism risk genes in cavefish and found some striking similarities between cavemen and humans through these genes.
In cavemen and autism patients, most homologous genes of autism risk genes have the same gene expression trends (upregulation or downregulation). This similarity is very high compared to other rodent models of autism and neurons from induced pluripotent stem cells from autistic patients.
Experimental setup
Mexican Lisa: Surface fish
We also investigated the evolution of genes in the cavefish lineage and found that the gene at risk of autism evolved twice as fast as other genes in the cavefish genome. Interestingly, the autism risk gene is also actively selected in humans.
We are currently testing the effects of human autism treatment drugs on fish social behavior. We believe that the basic neural networks that produce autism-like behaviors during the evolution of fish and humans are the same.
We and other research teams believe that many of the behaviors of burrowing fish help find food in the dark. But how did the autism risk gene evolve in humans?
Human geneticist Polimanti et al. believe that autism is positively correlated with children's intelligence, college attendance, and years of schooling. Weiner et al. argue that many autism risk genes are thought to have a cumulative effect that causes autism. In other words, people with mutations in only certain autism risk genes may have better academic achievements; however, if many mutations are present in many autism risk genes, they are more likely to develop autism.
Autism in other species behaves like a similar behavior
Aside from burrowing fish, we don't yet know of any animal model that naturally shows a range of behaviors associated with autism. However, a recent study by Shpigler et al. suggests that the gene for autism risk is an evolutionary conservating gene and regulates sociality in bees and humans.
We still know little about the evolution of social and other behaviors during adaptation, as many of these behaviors are extremely complex and regulated by multiple genes. Through comparative studies of humans, burrowing fish, and bees, animals may adapt to new environments and change their behavior by altering autism risk genes.
It may be interesting to study whether autism risk genes have been altered in other rapidly evolving species, such as the cichlid fish in the East African lake region, the peacock fish in Trinidad, and the green chameleon.
In the case of similar behaviors in autism, deer rats will exhibit repetitive behaviors in new environments. In addition, there are some reared mutant mice, including BTBR mice and knockout mice, which have lost functional autism risk genes, many of which exhibit social disturbances, lack of interest in the population, altered vocal patterns, stereotyped repetitive behaviors, and more.
All of these are considered autism-like behaviors, which are expressed with the same molecular and neural mechanisms. However, these models did not show physical defects (such as immunodeficiency or digestive damage) that occur in autism. We found that cavemen show similar changes in both systems in addition to a series of similar behaviors for autism, so cavemen may be able to fill gaps in their understanding of the autism system and provide a basis for new autism treatments.
summary:
Background
An essential question in evolutionary biology is whether shifts in a set of polygenic behaviors share a genetic basis across species. Such a behavioral shift is seen in the cave-dwelling Mexican tetra, Astyanax mexicanus. Relative to surface-dwelling conspecifics, cavefish do not school (asocial), are hyperactive and sleepless, adhere to a particular vibration stimulus (imbalanced attention), behave repetitively, and show elevated stress hormone levels. Interestingly, these traits largely overlap with the core symptoms of human autism spectrum disorder (ASD), raising the possibility that these behavioral traits are underpinned by a similar set of genes (i.e. a repeatedly used suite of genes).
Result
Here, we explored whether modification of ASD-risk genes underlies cavefish evolution. Transcriptomic analyses revealed that > 58.5% of 3152 cavefish orthologs to ASD-risk genes are significantly up- or down-regulated in the same direction as genes in postmortem brains from ASD patients. Enrichment tests suggest that ASD-risk gene orthologs in A. mexicanus have experienced more positive selection than other genes across the genome. Notably, these positively selected cavefish ASD-risk genes are enriched for pathways involved in gut function, inflammatory diseases, and lipid/energy metabolism, similar to symptoms that frequently coexist in ASD patients. Lastly, ASD drugs mitigated cavefish’s ASD-like behaviors, implying shared aspects of neural processing.
Conclusion
Overall, our study indicates that ASD-risk genes and associated pathways (especially digestive, immune and metabolic pathways) may be repeatedly used for shifts in polygenic behaviors across evolutionary time.
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期刊介绍：BMC Evolutionary Biologyis an open access, peer-reviewed journal that considers articles on all aspects of molecular and non-molecular evolution of all organisms, as well as phylogenetics and palaeontology.
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