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Brain size/intelligence controlled by a single gene

A gene called Angiopoietin-1 (Ang-1) drives brain size and intelligence in fish according to a new study out of UCL, Stockholm University and University of Helsinki.

Fish with larger brains and higher intelligence had higher expression of Ang-1 gene, and when expression levels of Ang-1 were experimentally reduced, brains shrunk. These trends were seen in two unrelated species of — guppies (Poecilia reticulata) and zebra fish (Danio rerio). This indicates expression of Ang-1 is important for brain growth and development in fish generally.

The study, published in Proceedings of the Royal Society B, identified in fish the underlying genetics of natural variation in brain size and cognitive abilities. Which means Ang-1 could play an important role in the brain development of other vertebrates, including humans. But future research is required to establish this, according to the scientists.

Populations of guppies were selected for having either a large or a small brain, with presumed differences in intelligence. The next step was a complete genome analysis of differently expressed genes. With a 10% difference in brain size between the large and small-brain guppies and following genetic analysis, Ang-1 was identified as the only gene expressed at different levels in each population. Further experiments in zebra fish by collaborator Professor Pertti Panula at Helsinki University, confirmed that Ang-1 is a driver for brain size.

Professor Judith Mank, University College London (UCL) Biosciences, said: "We were surprised to see that only a single gene was up-regulated in the large-brained guppies. Given the complexity of the brain, we expected that the genetics would be very intricate, but this suggests that changes in brain size are underpinned by relatively simple genetic mechanisms."

The protein encoded by Ang-1 is known to play an important role in growing new blood vessels and forming new brain cells in mice, which may indicate an important role for Ang-1 in brain growth of other animals, even in humans, say the scientists behind the study.

"Other genes may be involved in brain growth in young, developing fish but no other genes were found to vary in their expression in adult fish other than Ang-1. Future studies will aim to investigate the role of Ang-1 and possibly other genes in the formation of differently sized brains in developing embryos.

"We don't yet know if Ang-1 is important in human brain development. It isn't on the list of genes typically studied in relation to human brain size. But, as it plays a role in forming new blood vessels in humans, there may be a connection as large brains need a bigger blood supply — particularly during growth. This presents us with an exciting opportunity to investigate the role of Ang-1 across different vertebrates."

Dr Niclas Kolm, Stockholm University

Based on new artificial selection experiments in the guppy, the team now plans to study age-specific gene architecture involved in both brain structure and brain function.

Abstract
Brain size varies substantially across the animal kingdom and is often associated with cognitive ability; however, the genetic architecture underpinning natural variation in these key traits is virtually unknown. In order to identify the genetic architecture and loci underlying variation in brain size, we analysed both coding sequence and expression for all the loci expressed in the telencephalon in replicate populations of guppies (Poecilia reticulata) artificially selected for large and small relative brain size. A single gene, Angiopoietin-1 (Ang-1), a regulator of angiogenesis and suspected driver of neural development, was differentially expressed between large- and small-brain populations. Zebra fish (Danio rerio) morphants showed that mild knock down of Ang-1 produces a small-brained phenotype that could be rescued with Ang-1 mRNA. Translation inhibition of Ang-1 resulted in smaller brains in larvae and increased expression of Notch-1, which regulates differentiation of neural stem cells. In situ analysis of newborn large- and small-brained guppies revealed matching expression patterns of Ang-1 and Notch-1 to those observed in zebrafish larvae. Taken together, our results suggest that the genetic architecture affecting brain size in our population may be surprisingly simple, and Ang-1 may be a potentially important locus in the evolution of vertebrate brain size and cognitive ability.

The work was kindly funded by the European Research Council, the Swedish Research Council, the Austrian Science Fund, Academy of Finland and the Sigrid Juselius Foundation.

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