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Transposon-Based Screen for Key Genes in Brain Development

Our team has developed a new genetic selection procedure that uses a transposon-based system to target genes involved in brain development. This method has helped to discover successfully more than 30 genes that may be associated with brain development disorders. This breakthrough result was published in prestigious journal Nature Communications in 2018.

Many neonatal brain developmental diseases, such as microcephaly, lissencephaly, and mental retardation, have been identified as having a genetic component. The genetic mutations that can cause abnormal brain development are still a question that scientists are looking to answer. However, due to the large size of the human genome and the high level of genetic variation found in humans, identifying naturally occurring mutations that cause abnormal brain development in humans is difficult. Furthermore, analyzing each individual gene and its correlation to a disease is very often an almost impossible task.

We utilized transposons to induce gene mutations and this led to the discovery of more than 30 key genes that appear to be involved in brain developmental disorders.

In order to search for such genetic mutations, our team approached the problem from a different angle. We came up with a novel idea of inducing genetic mutations in neural progenitors and observing the relationship between each mutation and possible effects on their development in the brain. His team injected a gene with the ability to transpose in mammals into mouse brain neural stem cells with the aim of inducing mutations. This method allowed usto identify the specific genetic mutations that affected the growth, differentiation, transfer, and connectivity of neural cells during the developmental phase of the mouse brain. Applying this new selection process, our team was able to identify 33 genes that seem to have a role in brain development.

Due to the fact that majority of genes that are present in humans are also present in the mouse, the brain maturation processes of these two species are also very similar. Thus we began working closely with Dr. Shang-Yeong Kwan of Taipei Veterans General Hospital, Department of Neurology's Neurological Institute and Professor Chi-Hung Lin and his team from the VYM Genome Research Center with the aim of comparing the identified genes in mice and those present in infant epilepsy patents. Together we discovered that many of the newly identified mutations showed a close correlation between mice and humans. This means that this novel transposons selection process in mouse is able to rapidly pinpoint the genetic cause of abnormal brain maturation in humans. Simultaneously, this method has also resulted in the discovery of a number of new genes that have yet to be fully investigated. This research will help future scientists to explore the relationship between genetics and abnormal brain maturation.

We stated that the idea of utilizing transposons to induce mutation emerged because natural genetic mutations occur rarely in nature and therefore finding such a mutated gene in humans is very time consuming. Nevertheless, many species, such as maize and insects, and even human beings, have transposons in their genomes, which inspired us to use these as a tool to facilitate mutation in a mouse system. Moreover, many animals share a large number of common genes with human beings, and therefore applying an animal model not only overcomes difficulties associated with using humans being as an experimental system, but also allows the use of the mouse model to discover how these genes affect brain development and the cellularmechanisms involved.

Our team have come up with this new method that breaks some of the barriers associated with a traditional genetics study that targets either mice or humans. We were able to pinpoint genes related to brain development without individually examining the more than 20,000 genes needed in a human study. This is a huge contribution to basic biological science and has vast further applications in the medical field. Identifying genes related to brain development will also enable the development of early screening methods, which in turn should lead new treatment methods for humans.

This research originated totally in Taiwan, starting from the initial brainstorming, which led to obtaining the necessary funding and then the execution of the research. It also involved interdisciplinary cooperation between National Yang Ming University and Taipei General Veterans Hospital. The research received funding from the Ministry of Science Technology ¡§Excellent Young Investigator Grant,¡¨ from the National Health Research Institutes ¡§Career Development Grant¡¨ program and the Ministry of Education's ¡§The Aim for the Top University Project¡¨ fund. Finally, the important fruitful results were published in Nature Communications, one of the world's-leading journals and were also reported by GeneOnline.

 



Last updated 6/13/2013. Copyright© 2013 Jin-Wu Tsai. All rights reserved.