Our Latest Study: The Link between Mobile Element Content and Autism-risk Genes
“An extremely large number of genes have been associated with autism. The functions of these genes span numerous domains and prove challenging in the search for commonalities underlying the conditions. In this study, we instead looked at characteristics of genes themselves, specifically in the nature of their transposable element content. Utilizing available sequence databases, we compared occurrence of transposons in autism-risk genes to randomized controls and found that transposable content was significantly greater in our autism group. These results suggest a relationship between transposable element content and autism-risk genes and have implications for the stability of those genomic regions” (Williams et al., 2013).
This month our publication, “Tranposable Elements Occur More Frequently in Autism-risk Genes: Implications for the Role of Genomic Stability in Autism,” was released in Translational Neuroscience. It’s the first in what we hope will be a line of investigations focusing on characterizing aspects of high-risk autism gene stability. To summarize, while most current research is focused on determining what these genes do in a variety of contexts and how they may ultimately lead to an autism phenotype, we instead are more interested in figuring out how and why these genes mutate in the first place.
Because our article may be a tad, shall we say, unapproachable for readers with little knowledge in this area of study, this blog post is primarily to serve as a “translation”. I hope this post can make things a little clearer and explain what this may all mean. But before I do any of that, I should first explain what a transposable element is for those who are unfamiliar.
Transposable elements (TE) are small sequences of the genome that are capable of some form of mobility. They are also often referred to as “mobile elements” because of their capacity to move around the genome. TEs are comprised of two larger categories, the transposons and retrotransposons. Transposons are segments of DNA which can excise themselves from a local sequence, move elsewhere, and splice themselves back in. Retrotransposons, on the other hand, don’t really move around but instead make RNA copies of themselves (usually when a nearby gene is also being transcribed); these RNA copies are then reverse transcribed into free-floating DNA which then, like the DNA transposon, splices itself back in (or piggybacks the splicing machinery of another retrotransposable element) [for review, see 1].
The human genome contains approximately 50% mobile element content. However, the vast majority of that content is extinct, meaning that is is no longer able to move around the genome. This happens due to the accumulation of mutations in the TE sequence which ultimately prevents it either from excising/copying itself or reinserting. In addition, the majority of TEs reside in intronic (i.e., non-coding) regions of DNA.
In our study, we used a bioinformatics approach to investigate TE content in high-risk autism-related genes. A gene list was derived from the database, AutismKB, and then compared to a listing of randomized control genes (for full content, see the end of our publication). What we found was that not only were autism-related genes more likely to house TE content, but they tended to house large numbers of TEs (100+).
Just to be clear, the majority of these TEs which were the subject of our study are extinct, meaning they’re not technically “mobile” anymore. So when discussing the relevance of this study to autism, we’re not talking about the majority of related mutations occurring because segments of genome are jumping around and promoting gene instability during insertion. What we are talking about though is how the extinct TE content, the characteristics of the sequences themselves, may be affecting rates of mutation in these genes.
In order to understand this, one really has to picture a gene as a 3D object whose tendency towards stability is defined by its shape. It’s shape is in turn determined by its DNA sequence (of which these TEs are an important part) and its interaction with molecular partners that regulate it, like proteins, RNA, and even metal ions like zinc. Since rates of mutation are driven by all these factors combined, you can imagine that the presence or absence of TE sequences in a given gene would definitely alter its overall shape and thereby affect the rates of mutation for that gene as well as the partners that are able to bind to it.
The funny thing about transposable elements is that they themselves tend to form unstable configurations. And when inserted into a genome, if the local DNA comes under any torsional strain such as occurs during transcription (gene expression), then these little TE sequences are known for jutting out of the double helix and forming outcroppings, like hairpin structures, triple helices, cruciforms, and other random coils. Look at the image below used as an analogy. In the lower portion of the image, the rubberband is placed under greater strain compared to the rubberband above it.
In the case of TE sequences in DNA, they have more of a tendency to break with the double helix under strain and form single strand (and some double-stranded) configurations which jut out of the traditional conformation, e.g., this next image.
Four problems can occur when this happens:
When the DNA is being replicated either into DNA or RNA, you don’t necessarily get a reliable copy of the original because the replication machinery can actually skip structures like hairpins as if they weren’t even there, like in the image above.
Alternatively, if the hairpin forms in just the wrong place, the replication machinery can actually stall and gene expression fails.
When structures like hairpins or random coils form in the DNA during replication, this can also potentially lead to inappropriate expansion of certain segments, especially repetitive sequences (think of the CGG repeat expansions associated with Fragile X Syndrome).
When alternative structures like hairpins form, there is some evidence to suggest that they may get “stuck” and need to be cut out of the DNA and repaired, potentially leading to inaccurate repair of the original sequence [2, 3].
The interesting thing about segments of DNA which house numerous TEs is that they seem to have attracted even more TEs over evolutionary time. If you look at any given gene with intronic TE content, usually you will find all types of mobile elements contained therein, which is surprising considering the different sequences these elements individually target for insertion. Not only does it suggest that coding regions may have a hard time accommodating TE insertion ultimately selecting against it, but it also suggests that introns attract TE insertion. And the more TEs, the more TEs they attract over the epochs. And the greater the TE content, the more unstable that region is overall. Just look at some of the largest genes in the human genome known for high rates of mutation, several of them also high-risk autism genes like CNTNAP2 and DMD, which house thousands of intronic mobile elements.
Scientists have traditionally been most interested in the coding regions of DNA, waving away intronic happenstances with the assumption that introns just don’t matter that much. But our study suggests differently. It suggests that the entire gene is important when it comes to stability and that introns can be an indicator of that gene’s history as well as its modern-day tendency to mutate.
So ultimately, I guess the question becomes: How does this knowledge help us in understanding autism? This kind of knowledge can aid us not only in dividing autisms into their many complex causations, genetic, epigenetic, and ecological alike, but also perhaps in seeing commonalities amongst them. And so while it’s currently difficult to predict what kinds of interventions may eventually be made available through such knowledge, it’s certain that the more we do know the greater means we’ll have to offer for improving the lives of autistic people.
And, yes, that’s a really fancy shmancy way of me saying “I don’t really know”. But we need to figure out as much as we can so that we can have as many options at our disposal as possible. You never quite know where science is going to take you until you go there.
NOTE: For anyone who would like to read the original publication and can’t get access, please email me and I’d be happy to send you a copy.
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