Transposons play hopscotch across the genome Hopscotch

Statistically speaking, your genome is mostly junk.

Less than two per cent of it is made up of actual genes – stretches of DNA carrying instructions that tell cells to make protein molecules. A larger (and hotly debated) proportion is given over to regulatory ‘control switches’, responsible for turning genes on and off at the right time and in the right place. There are also lots of sequences that are used to produce what’s known as ‘non-coding RNA’. And then there’s a whole lot that is just boring and repetitive.

As an example, the human genome is peppered with more than half a million copies of a repeated virus-like sequence called Line-1 (also known as L1).

Usually these L1 repeats just sit there, passively padding out our DNA. But a new study from our researchers in Cambridge suggests that they can start jumping around within the genome, potentially contributing to the genetic chaos underpinning oesophageal cancer.

Let’s take a closer look at these so-called ‘jumping genes’, and how they might be implicated in cancer.

Genes on the hop

The secret of L1’s success is that it’s a transposon – the more formal name for a jumping gene. These wandering elements were first discovered in plants by the remarkable Nobel prize-winning scientist Barbara McClintock, back in 1950.

They’re only a few thousands DNA ‘letters’ long, and many of them are damaged. But intact L1 transposons contain all the instructions they need to hijack the cell’s molecular machinery and start moving.

Firstly, their genetic code is ‘read’ (through a process called transcription) to produce a molecule of RNA, containing instructions for both a set of molecular ‘scissors’ that can cut DNA, together with an unusual enzyme called reverse transcriptase, which can turn RNA back into DNA.

Together these molecules act as genetic vandals. The scissors pick a random place in the genome and start cutting, while the L1 RNA settles itself into the resulting gap. Then the reverse transcriptase gets to work, converting the RNA into DNA and weaving the invader permanently into the fabric of the genome.

This cutting and pasting is a risky business. Although many transposons will land safely in a stretch of unimportant genomic junk without causing any problems, there’s a chance that one may hopscotch its way into an important gene or control region, affecting its function.

So given that cancers are driven by faulty genes, could hopping L1 elements be responsible for some of this genetic chaos?

In fact, this idea isn’t new.

More than two decades ago, scientists in Japan and the US published a paper looking at DNA from 150 bowel tumour samples. In one of them they discovered that an L1 transposon had jumped into a gene called APC, which normally acts as a ‘brake’ on tumour growth. This presumably caused so much damage that APC could no longer work properly, leading to cancer.

Because every L1 ‘hop’ is a unique event, it’s very difficult to detect them in normal cells in the body. But tumours grow from individual cells or small groups of cells, known as clones. So if a transposon jump happens early on during cancer development, it will probably be detectable in the DNA of most – if not all – of the cells in a tumour.

Thanks to advances in DNA sequencing technology, it’s now possible to detect these events – something that researchers are starting to do in a range of cancer types.

Jumping genes and oesophageal cancer

In the study published today, the Cambridge team – led by Rebecca Fitzgerald and Paul Edwards – analysed the genomes of 43 oesophageal tumour samples, gathered as part of an ongoing research project called the International Cancer Genome Consortium.

Surprisingly, they found new L1 insertions in around three quarters of the samples. On average there were around 100 jumps per tumour, although some had up to 700. And in some cases they had jumped into important ‘driver’ genes known to be involved in cancer.

The findings also have relevance for other researchers studying genetic mutations in cancer. Due to technical issues with analysing and interpreting genomic data, it looks like new L1 insertions are easily mistaken for other types of DNA damage, and may be much more widespread than previously thought.

So what are we to make of this discovery?

Finding evidence of widespread jumping genes doesn’t prove that they’re definitely involved in tumour growth, although it certainly looks very suspicious, and there are a lot of questions still to be answered.

For a start, we need to know more about how L1 jumps affect important genes, and whether they’re fuelling tumour growth.

It’s also unclear why these elements go on the move in cancer cells in such numbers: are they the cause of the genetic chaos, or does their mobilisation result from something else going awry as cancer develops for other reasons?

Looking more widely, and given that it seems to be particularly tricky to correctly identify new L1 jumps in DNA sequencing data, it’s still relatively unknown how widespread they are across many other types of cancer.

Finding the answers to these questions is vital. Rates of oesophageal cancer are rising, particularly among men, yet survival remains generally poor. As part of our research strategy we’ve highlighted the urgent need to change the outlook for people diagnosed with the disease, through research into understanding its origins, earlier diagnosis and more effective treatments.

By understanding what’s going on as L1 elements hopscotch their way across the genome, we’ll gain more insight into the genetic chaos that drives oesophageal cancer.

In turn, this could lead to new ideas for better ways to diagnose, treat and monitor the disease in future. Let’s jump to it.



Paterson et al. Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired end sequencing analysis. BioMed Central Genomics. DOI: 10.1186/s12864-015-1685-z.