Studying rare genome motifs

Gene regulation is an essential function in all life forms and it is a well-researched area of multicellular organisms as diverse as roundworms and humans. Now Miklos Cserzo believes he may have discovered a completely new aspect of this regulation and all he needs to do now is discover just quite what it all means. In this fascinating interview, he explains more.

Miklos Cserzo of Semmelweis University believes he may have discovered an as-yet unknown aspect of gene regulation by carrying out statistical analyses of the genomes of humans and mice.

His findings go against the currently accepted model of gene regulation, and suggest that there is a previously unidentified group of DNA motifs that play an extremely important role. Cserzo explains how he began his research into the subject: “In around 2003, I left a job at the University of Birmingham and moved back to Hungary to pursue a new project in genetics,” he says. “When I started looking at gene regulation, I had the idea of taking some of the statistical techniques that I had used previously and applying them to this new topic. To my surprise, I got some interesting results, and through this I formed the basis of my new project.”

Gene regulation is the group of processes that cells use to regulate the way that information in genes is turned into gene products. It is an essential function of most life-forms, as it allows cells to express particular proteins when needed, and also drives the processes of cellular differentiation by which multicellular organisms can create cells that possess the same genome sequence but have different functions.

“The methodology of the project involves a lot of long, laborious statistics – very boring in fact!” jokes Cserzo. “But this is often the way with many scientific projects, and they often lead to some very interesting discoveries.”

Cserzo’s approach involved taking a DNA motif – a specific sequence of nucleotides or amino acids – and scanning for it across the genomes of humans and mice. This process was then repeated for all of the possible motifs, of which there were approximately 6.5 million.

“As you can imagine, the data set I was left with was extremely comprehensive!” says Cserzo. “The challenge then was working out how to separate the interesting data from the vast quantities of information I had.

“In the human genome, it is well known that there are some over-represented motifs – ones that occur much more than you would expect by random chance,” explains Cserzo. “This is related to the repetitive DNA content of the genomes, and is actually a very well documented and studied area of genetics.

“What I decided to do was to go in the other direction by concentrating on motifs that occur less commonly than would be anticipated by random chance, which is a tricky thing to do. As far as I am aware, I am the only person doing this, which gives me hope that there are some extremely interesting findings to be made.”

After carrying out this exhaustive statistical analysis of the human and mouse genomes, Cserzo found that there was indeed a certain type of motif with a fairly defined length of between 20 and 30 base nucleotides that are very under-represented. However, when comparing them to transcription start sites and other genetic landmarks, he found that they were aligned in clusters, appearing in certain areas 60-80 times more than would be expected. The suggestion is that because they are under-represented generally but also massively over-represented in certain locations, that they are likely to play an important role.

“After examining the results, I realised that my data was not compatible with current views on gene regulation, which involves transcription factors and several other proteins making a giant initiation complex,” explains Cserzo.

“At the same time, I realised after submitting a first draft of my findings that my data fitted well with a theoretical paper published by Professor John Mattick of the University of Queensland that proposed that for eukaryotic organisms, the current view on protein-driven genetic control is almost impossible.”

Cserzo is now more and more convinced that his findings may represent a currently unknown aspect of gene regulation. “Imagine, for example, a large bustling city such as London,” analogises Cserzo. “The traffic is controlled by traffic lights and road signs. If you imagine then if someone were to move all of these lights and signs around into the wrong locations, chaos would ensue.

“This is how I envisage gene control; certain signs must be present in their meaningful place in the genome but nowhere else, because if they were present in unexpected locations, the result would be confusion and most likely a non-functioning organism. That is what I believe is the reason behind these under-represented genetic motifs – they appear in the positions in which they are vital, but there is also a selective pressure against the same motif appearing randomly in other locations.”

At present, Cserzo is unable to offer an explanation of the exact functions of these motifs. There is the possibility that the group he has singled out are a mixed population, meaning that there could well be a number of different types of motifs within the group with a number of different biological functions.

“I am currently looking at comparing certain parts of the human and mouse genomes,” says Cserzo. “You would not expect there to be a lot of conservation between the two in the non-coding regions; however in the case of my motifs, they are very well conserved on average compared to the neighbouring genetic material. This goes to support my hypothesis that these motifs have a new biological function that is completely unknown.”

“In the future, I would like to somehow link my findings to experimental data,” continues Cserzo. “I am able to access data from the public domain, for example that of Professor Mattick who has published many of his data sets. The rate at which I am able to predict certain parts of these data sets using my data would suggest that there are certainly some meaningful implications to the work.

“Seeking experimentalists to work on my research, to extend it into real experiments, remains my goal, because the obvious question remains: what does this identified group of motifs actually do?”

Click here to access the project website.

Published: Tuesday, 13th December 2011