3D Genomics to the Rescue?
(January 22nd, 2016) Mutations in one gene or many are behind numerous debilitating diseases. To be able to cure these diseases, we have to understand them. 3D genomics might do the trick, if it can overcome its teething troubles.
Deoxyribonucleic acid, or DNA, has always fascinated scientists. Proof is the enormous research into its structure and function. Its alpha-helix nature, for instance, was confirmed by Rosalind Franklin in the 1950s, followed by the Robert Holley publication, in 1964, of the nucleic acid sequence of alanine transfer RNA. A bit later, Marshall Nirenberg and Philip Leder discovered that the genetic code is read in triplets.
One of the most important developments, however, came from British biochemist, Frederick Sanger. In 1975, he published a paper (together with lab tech Alan Coulson), introducing a new method of sequencing DNA. His method, today simply called Sanger sequencing, has since revolutionised genetics. Although the technique was a breakthrough in genetics, it cannot be used to study, for instance, DNA function. This is where 3D genomics comes in, which provides powerful experimental approaches to predict and study DNA’s role when coupled to endogenous protein or environmental factors.
In contrast to Sanger sequencing and its variations, which analyses the primary sequence of DNA to search for individual nucleotide changes that might affect, for instance, disease development, 3D genomics looks at the more complex secondary and tertiary structures of DNA. Techniques, such as Chromosome Conformation Capture (3C) and its derivatives, DNA adenine methyltransferase identification (DamID) and Chromatin interaction analysis (ChIA) reveal intramolecular interactions between DNA and proteins. Employing these techniques has helped elucidate the molecular basis of, for instance, cancer or Duchenne muscular dystrophy.
As helpful as these methods are to understand complex diseases, they also create large amounts of data that need to be interpreted correctly. In December, the new project “Multi-Scale Complex Genomics” or MuG started, aiming to improve and standardise 3D genomics to make it available for a wider scientific audience. Funded by the European Commission, which promised to provide three million euros to five research centres in Spain, the United Kingdom and France, MuG wants to address some of the biggest problems that bug the field. These include the huge background noise in 3D genomics data, non-standardised analysis methods and miscommunication between bioinformatics databases.
“We are trying to correlate the genome with the phenome using only one dimension, while functionality of DNA depends on genome organisation in the space. What we are doing now will be like organising air traffic using only one dimension instead of three. A chaos, isn't it?” explains Modesto Orozco, coordinator of MuG project at the Institute for Research in Biomedicine (IRB) Barcelona. “This project will help nucleate and organise the community, fuelling the integration between high performance computing and genomics and moving towards a more realistic view of the genome organisation,” he adds.