Human genome structure mapped at base-pair resolution

The 3D structure of the human genome has been mapped at the level of individual bases, defining complex structures which control how DNA functions within the cell.

The technique, called Micro Capture-C ultra or MCCu, was developed by researchers at the Universities of Cambridge and Oxford, and published in the journal Cell. MCCu showed how different parts of the genome interact at extremely high resolution, demonstrating how gene expression is controlled 'in exquisite detail'.

'For the first time, we can see how the genome's control switches are physically arranged inside cells', said James Davies, professor of genomics at the University of Oxford, who led the study. 'This changes our understanding of how genes work and how things go wrong in disease.'

He added, 'We can now see how changes in the intricate structure of DNA leads to conditions like heart disease, autoimmune disorders, and cancer.'

Our DNA is made up of over three billion base pairs that are tightly packed into chromosomes. While our DNA sequence has been largely known for over twenty years (see BioNews 64 and 204), its exact shape is not known. This is important because this shape controls which genes can be expressed, and which are 'turned off'.

MCCu builds on a broader set of techniques called chromosome conformation capture, or 3C. Current 3C approaches which aim to determine how parts of the genome interact with each other are unable to resolve the smallest structures. This includes transcription factors, which are regions that control expression of downstream genes, and nucleosomes, which are tight DNA structures formed around proteins.

With MCCu, scientists were able to show at single-base resolution how these genomic features alter DNA's structure. For example, they highlighted how the positioning of nucleosomes, and the interactions within nucleotide-depleted regions, can alter expression.

'We now have a tool that lets us study how genes are controlled in exquisite detail', said Hangpeng Li, PhD student at the University of Oxford and a lead author of the study. 'That's a critical step toward understanding what goes wrong in disease, and what might be done to fix it.'

It is hoped that these findings will drive drug discovery and enable further research into how the structure of DNA may cause disease.