The human genomic melting map.

Fang Liu,Geir Ivar Jerstad,Tor-Kristian Jenssen,Eivind Tøstesen,Christoph Bock,William G Thilly,Eivind Hovig,Jostein K Sundet,Yves Van De Peer

doi:10.1371/journal.pcbi.0030093

Abstract

In a living cell, the antiparallel double-stranded helix of DNA is a dynamically changing structure. The structure relates to interactions between and within the DNA strands, and the array of other macromolecules that constitutes functional chromatin. It is only through its changing conformations that DNA can organize and structure a large number of cellular functions. In particular, DNA must locally uncoil, or melt, and become single-stranded for DNA replication, repair, recombination, and transcription to occur. It has previously been shown that this melting occurs cooperatively, whereby several base pairs act in concert to generate melting bubbles, and in this way constitute a domain that behaves as a unit with respect to local DNA single-strandedness. We have applied a melting map calculation to the complete human genome, which provides information about the propensities of forming local bubbles determined from the whole sequence, and present a first report on its basic features, the extent of cooperativity, and correlations to various physical and biological features of the human genome. Globally, the melting map covaries very strongly with GC content. Most importantly, however, cooperativity of DNA denaturation causes this correlation to be weaker at resolutions fewer than 500 bps. This is also the resolution level at which most structural and biological processes occur, signifying the importance of the informational content inherent in the genomic melting map. The human DNA melting map may be further explored at http://meltmap.uio.no.

Highlights

A community-wide effort is being pursued to understand how the genome itself, in concert with its epigenetic modifications and its organization in the cell nucleus, functions to provide each cell with the functionality and gene regulation that it requires at various levels of organization, such as cell state and tissue specificity
DNA is frequently depicted as an antiparallel double-stranded helix, but DNA may rather be viewed as having a dynamically changing structure
This happens by the aid of the enzymatic machinery, but it may be observed in experiments when a gradual increase in temperature produces bubbles

Summary

Introduction

A community-wide effort is being pursued to understand how the genome itself, in concert with its epigenetic modifications and its organization in the cell nucleus, functions to provide each cell with the functionality and gene regulation that it requires at various levels of organization, such as cell state and tissue specificity. Two important and distinct approaches towards this goal may be found: (1) data-driven statistical learning methods that can provide results in a relatively short time, with little knowledge of the biological mechanisms involved; (2) knowledge-driven physical modeling that can provide a mechanistic understanding of the system in terms of its molecular constituents. By nature the latter is a relatively slow and difficult process. Prediction algorithms for a number of DNA features based on sequence information have been developed, such as prediction of genes, alternative splicing, and transcription factor binding [4,5,6], leading to an increasing number of annotations being available for the most widely studied organisms [7]

Methods

Results

Discussion

Conclusion