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Exploring Differences in Epialleles

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Vardhman Rakyan
Title: Senior Lecturer, Barts and The London School of Medicine and Dentistry
Education: PhD, University of Sydney, 2002
Recommended by: Stephan Beck

While multiple international projects have been underway for some time to map the epigenome, Vardhman Rakyan knows what a daunting task it will be to put all this information in the context of disease susceptibility. His lab at Barts and The London uses all available systems biology tools — including microarrays and more recently, sequencing — to study "epialleles," loci where the epigenetic state can be affected by both genetic and environmental influences. His work integrates genetics, functional genomics, bioinformatics, model organisms, and human cohorts.

"The primary focus [of my lab] is the role of epigenetics in determining inter-individual variability of phenotypes," he says. "We're interested in exploring the epigenetic basis of why people look different and why people are susceptible to different diseases."

In a recent study using microarray profiling of identical twins, some of whom developed type 1 diabetes — which has a strong genetic component — and some of whom didn't, Rakyan found that "if one twin has type 1 diabetes, there's only about a 50 percent chance that the other twin will get type 1 diabetes even though they're genetically identical," he says. "We do find epigenetic differences in genes that are known to play a role in the pathogenesis of the disease."

He got his start in the field at the University of Sydney, where he studied epigenetic inheritance under Emma Whitelaw. "At the end of my PhD, I really wanted to look genome-wide, I didn't want to focus on just the single genes," he says. "That's why I joined the Sanger Institute [as a postdoc]." The decision to move to a large-scale study came after the publication of the human genome, which, Rakyan adds, really impressed upon him the power of approaching his work from a genome-wide perspective.

Most of the challenges for his lab lie in the area of bioinformatics, but Rakyan notes that funding bodies are realizing the need for better training and are taking action; Rakyan says he has a good team of computational scientists. "Right now, it's a very exciting time to get into bioinformatics or computational biology," he says. "There are so many jobs and so many different fields of biological research which you could enter."

Looking ahead

Rakyan sees improved data analysis as one area to look most forward to five years down the line for epigenomics. "It'd be really good — and people are doing this — [to start] to integrate all these different large data sets that have been generated, so people looking at gene expression, people looking at epigenetics, people looking at genetics," he says. "The integration of all this is going to be really powerful in the context of disease."

He also hopes to one day have the ability to visualize DNA methylation marks directly. While nanopore sequencing already exists and could provide this detail, the real challenge will be making it a "useful, high-throughput technology," Rakyan says. And, of course, being able to look at single cells is the holy grail. "We can't do that right now," he says. "What we look at is anywhere between 10,000 to 100,000 cells and we get an average of what's happening."

Publications of note

In a paper published in the Proceedings of the National Academy of Sciences in 2003 looking at inheritance of epigenetic marks, Rakyan found that these marks could be transmitted to future generations. "I'm now applying high-throughput methods to find if epigenetic inheritance is a general phenomenon," he says.

And the Nobel goes to...

Rakyan jokes that he would like to win the prize for "a discovery he hasn't made yet," adding that winning "is not what drives me."

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