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Using Genetics to Understand Autism

By: Sai Srihaas Potu

The last few decades have witnessed a dramatic increase in the recorded prevalence of autism. Recent figures estimate that approximately 1% of the population in the entire world has some sort of autism spectrum condition. The rise in the measured prevalence of autism has been accompanied by much new research. During this process, biologists have taken a new approach to decipher the roles of genes associated with autism.

Fish cannot display symptoms of autism, schizophrenia, or other human brain disorders. However, a team of MIT biologists has shown that zebrafish can be a useful tool for studying the genes that contribute to such disorders.

Led by developmental biologist Hazel Sive, the researchers set out to explore a group of about two dozen genes known to be either missing or duplicated in autistic patients. Most of the genes’ functions were unknown, but the MIT study revealed that nearly all of them produced brain abnormalities when deleted in zebrafish embryos.

The findings should help researchers pinpoint genes for further study in mammals. Autism is thought to arise from a variety of genetic defects; this research is part of a broad effort to identify culprit genes and develop treatments that target them.

Sive recalls that some of her colleagues chuckled when she first proposed studying human brain disorders in fish, but she believes that it is a logical starting point. Brain disorders are difficult to study because most of the symptoms are behavioral, and the biological mechanisms behind those behaviors are not well understood. Those genes tend to be the same across species, conserved throughout evolution, from fish to mice to humans, though they may control somewhat different outcomes in each species.

In the study, Sive and her colleagues focused on a genetic region known as 16p11.2, first identified by Mark Daly, a former Whitehead researcher who identified a type of genetic defect known as a copy number variant. A typical genome includes two copies of every gene, one from each parent; copy number variants occur when one of those copies is deleted or duplicated and can be associated with pathology.

The core 16p11.2 region includes 25 genes. Both deletions and duplications in this region have been associated with autism, but it was unclear which of the genes might produce symptoms of the disease.

Sive and her postdocs began by identifying zebrafish genes analogous to the human genes found in this region. In zebrafish, these genes are not clustered in a single genetic chunk but are scattered across many chromosomes. The researchers studied one gene at a time, silencing each with short strands of nucleic acids that target a particular gene and prevent its protein from being produced.

For 21 of the genes, silencing led to abnormal development. Most produced brain deficits, including improper development of the brain or eyes, thinning of the brain, or inflation of the brain ventricles, cavities that contain cerebrospinal fluid. The researchers also found abnormalities in the wiring of axons, the long neural projections that carry messages to other neurons, and in simple behaviors of the fish. The results show that the 16p11.2 genes are very important during brain development, helping to explain the connection between this region and brain disorders.

Furthermore, the researchers were able to restore normal development by treating the fish with the human equivalents of the genes that had been repressed. That allows you to deduce that what you’re learning in fish corresponds to what that gene is doing in humans. The human gene and the fish gene are very similar.

To figure out which of these genes might have a strong effect on autism or other disorders, the researchers set out to identify genes that produce abnormal development when their activity is reduced by 50 percent, which would happen in someone who is missing one copy of the gene. This correlation is not seen for most genes, because some many other checks and balances regulate how much of a particular protein is made.

The researchers identified two such genes in the 16p11.2 region. The first one is called kif22 and it codes for a protein involved in the separation of chromosomes during cell division; another, aldolase a, is involved in glycolysis, the process of breaking down sugar to generate energy for the cell.

In a new study, Sive’s lab is working with Stanford University researchers to explore the effects of the silencing of these genes on mice. They are also doing molecular studies in zebrafish in order to get a better idea of how defects in certain pathways might bring about neurological disorders.

Autism or ASD is a complex neurodevelopmental condition that causes difficulties with social interaction and favors a strict adherence to routines and predictable patterns. There are different types and severities of ASD. Some autistic people can live independently, while others require more sustained care and support. The causes are currently unknown, but researchers have identified several genes that may have links to the development of ASD.

Research is ongoing, and treatments that might improve the quality of life for autistic people are underway. Current therapies include occupational therapy, speech therapy, and various forms of communication support. With the help of technology, researchers hope to truly understand the biological, physiological, and genetic mechanisms that control autism in order to develop advanced treatment options in the near future.


1. Alicia Blaker-Lee, Sunny Gupta, Jasmine M. McCammon, Gianluca De Rienzo, Hazel Sive. Zebrafish homologs of 16p11.2, a genomic region associated with brain disorders, are active during brain development, and include two deletion dosage sensor genes. Disease Models and Mechanisms. 2012.

2. Elsabbagh M, Divan G, Koh Y. Global prevalence of autism and other pervasive developmental disorders. Autism Research. 2012.

3. Ingersoll B, Hopwood CJ, Wainer A, Donnellan MB. A comparison of three self-report measures of the broader autism phenotype in a non-clinical sample. Journal of Autism and Developmental Disorders. 2011.


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