In a study analyzing the exomes of over 28000 individuals, researchers have discovered that so-called “jumping genes” appear to be behind rare developmental disorders in some children. The findings were published in Nature Communications.
DNA doesn’t always stay in the same place; some pieces have an adventurous streak and make a habit of moving around the genome. Such mobile fragments are known as transposons or “jumping genes” and are present in tens of thousands of copies in our genome. There are two classes of these genetic elements; only one, the retrotransposons, is active in humans.1
Depending on their destination, transposons can have a significant impact. The insertion of a transposon can potentially lead to gene inactivation, changes in gene expression levels, or even chromosome duplication.2 As a result, transposons have been implicated in multiple diseases, including hemophilia and cancer.1
Consequently, first author Eugene Gardner, Ph.D., and colleagues set out to investigate if transposons also had a role to play in developmental disorders.
The Deciphering Developmental Disorders project
The Deciphering Developmental Disorders (DDD) project was launched in 2010, with the aim of providing genetic diagnoses for children with severe previously undiagnosed developmental disorders, by collecting DNA and clinical information and performing analysis using the latest microarray and sequencing methods. It was within the scope of this project that the study into the role of transposons was carried out.
Gardner and colleagues analyzed the exome, or coding, sequences of children with an undiagnosed developmental disorder, as well as those of their parents.3 They were looking for variation in the exome that was derived from the insertion of transposons – and they found it.
“In our study, we have worked to identify copies that have jumped into genes that have been identified as likely causes of developmental disorders. So, just as a single change in the bases of your DNA code can cause rare developmental disorders, so too can transposons,” says Gardner.
From identifying the traces of transposon insertion, the authors were able to provide genetic diagnoses for three children. Although this was always a possibility, it nonetheless took them by surprise.
Of this, Gardner explains: “New transposon insertions are so rare that, when we started this study, we set up a rough expectation of between 0–10 diagnoses in our 10,000 recruited patients. While we ultimately got the range correct, if the mutation rate proved to be a little lower, we might have not been able to make any diagnoses.”
“While that would have been fine from a basic science question, ultimately our goal is to help our patients and it feels great to even make a small contribution.”
These findings are amongst several already made by the DDD project. “To me I think the single largest breakthrough is the sheer scale of the project — DDD has helped thousands of families around the UK and Ireland to understand the underlying causes of their or their child's disorder,” says Gardner. “This is made possible by a strong partnership between clinicians and researchers which enable both parties to better understand the underlying genetic causes of developmental disorders.”
Of the transposon study, Gardner is hopeful that the findings will have a positive impact: “For the present — this result will provide some sense of closure regarding the cause of their child’s developmental disorder and allow parents/caregivers to seek out other families that may have a related disorder based on the gene that we have reported back. Additionally, our results paired with genetic counseling can help parents with future reproductive decisions.”
“For the future — my hope is this will convince clinicians that, at least in undiagnosed cases, it is worthwhile to look at less common types of genetic variation such as transposons to try and get a diagnosis for every child where possible.”
Eugene Gardner, Ph.D. was speaking to Holly Large, Editorial Assistant for Technology Networks.
- Hancks and Kazazian Jr. (2016) Roles for retrotransposon insertions in human disease. Mobile DNA. DOI: https://doi.org/10.1186/s13100-016-0065-9
- Muñoz-López and García-Pérez (2010) DNA Transposons: Nature and Applications in Genomics. Current Genomics. DOI: https://doi.org/10.2174/138920210790886871
- Gardner et al. (2019) Contribution of retrotransposition to developmental disorders. Nature Communications. DOI: https://doi.org/10.1038/s41467-019-12520-y