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Emily Casanova
Research assistant, University of South Carolina
The genes of autism are old. Not only old – really old. They are older than fish, older than insects and even older than sea sponges. In fact, many autism genes are older than multicellular life itself.
In addition to being extremely old, as my colleagues and I reported in our last April article, these old genes are particularly sensitive to mutations.1. And when mutations occur, the resulting effects can be profound. The more a gene is conserved – the more its sequence has remained constant among the species – the more likely it is that mutations on that gene will have significant effects.
People with these mutations often have physical deformities, which occur at a higher than expected rate2. This suggests that autism genes are involved in orchestrating the development of many parts of the body, not just the brain. Many also act as regulators of gene expression, helping to control the timing of development.3.4. These old biological processes are part of the toolkit of life. The genes of autism are fundamental, developmental and evolutionary.
Curiously, the ancient genes of autism also tend to have a characteristic structure: they are long and many produce large proteins.5.
However, the long genes of autism do not take more real estate DNA just for large proteins. Most of the length of these genes consists of introns, the non-coding segments of DNA located between the protein coding regions. The introns contain a high density of highly conserved sequences, which help regulate the expression of this gene.
Research suggests that large genes in autism are subject to complex forms of regulation. In fact, autism genes tend to produce a wide variety of RNA transcripts, protein production patterns, and these distinct versions of a protein are custom designed for various functions.
Overall, these data tell us that autism genes play nuanced, complex and fundamental roles throughout the body.
The presence of regulatory sequences in autism genes also provides geneticists with sequences to target for clinical studies. Significant research efforts to identify autism-related mutations have relied primarily on gene sequencing, leaving introns and other non-coding DNA relatively unexplored.
Our research, along with that of other groups working in the field of autism genetics, provides the impetus to look for mutations in these noncoding regions.
Gene Network:
Old genes are often the foundation of younger gene networks. Scientists have discovered that the older a gene is, the more important the network it interacts with6. The genes of old autism are no exception1.
Why is it important? To understand, imagine a large web of knots spider. Some nodes, called "hubs", are connected to many other smaller nodes, while smaller nodes have fewer connections. If you pull on a node of this Web site, you move closely connected neighboring nodes. Since hubs have more connections, there is a good chance that you will change hubs no matter where you go.
Likewise, every time you mutate a gene, it affects its immediate neighbors. And every time you change a gene at random in this large network, you are likely to affect an autism gene. With this model, it is easy to see how many different mutations could engage in a larger network of autism, leading to a similar phenotype despite a wide variety of mutations in the human population.
It is true that the study of the structure and evolution of a gene may seem somewhat academic. But in doing so, we provide a context and a predictive power through which we can consider the larger field of autism genetics. This understanding can ultimately lead to faster progress in diagnosis and treatment. We are also beginning to see a story emerge about the evolution of the genome and its role in the emergence of a disease such as autism.
Emily Casanova is assistant professor of research at bmedical sciencies at the University of South Carolina Medicine School Greenville.
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